4762 lines
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Entry
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- #141749 - FETAL HEMOGLOBIN QUANTITATIVE TRAIT LOCUS 1; HBFQTL1
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- OMIM
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<p>
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<span class="h4">#141749</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/141749"><strong>Clinical Synopsis</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#history">History</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=(FETAL HEMOGLOBIN QUANTITATIVE TRAIT LOCUS) OR (HBG1 OR HBB OR HBG2)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=19175&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Delta-beta-thalassemia </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=19638&Typ=Pat" title="Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Hereditary persistence of … </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=10601&Typ=Pat" title="Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Hereditary persistence of … </a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/8427" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=141749[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=231237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Delta-beta-thalassemia</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251380" title="Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Hereditary persistence of …</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=46532" title="Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Hereditary persistence of …</a></div>
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div style="display: table-cell;">Cell Lines</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:141749" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="number" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 231237, 251380, 46532<br />
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">ICD+</a>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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141749
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</span>
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</span>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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FETAL HEMOGLOBIN QUANTITATIVE TRAIT LOCUS 1; HBFQTL1
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</h3>
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</div>
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<div>
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<br />
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<a id="alternativeTitles" class="mim-anchor"></a>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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HEMOGLOBIN F, HEREDITARY PERSISTENCE OF; HPFH<br />
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HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN, HB GENE CLUSTER-RELATED
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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DELTA-BETA THALASSEMIA, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<tbody>
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<span class="mim-font">
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<a href="/geneMap/11/110?start=-3&limit=10&highlight=110">
|
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11p15.4
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Delta-beta thalassemia
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</span>
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<a href="/entry/141749"> 141749 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/141900"> 141900 </a>
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11p15.4
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Hereditary persistence of fetal hemoglobin
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<a href="/entry/141749"> 141749 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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11p15.4
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Fetal hemoglobin quantitative trait locus 1
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<span class="mim-font">
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<a href="/entry/141749"> 141749 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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HBG1
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<span class="mim-font">
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<a href="/entry/142200"> 142200 </a>
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<span class="mim-font">
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<a href="/geneMap/11/114?start=-3&limit=10&highlight=114">
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11p15.4
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<span class="mim-font">
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Fetal hemoglobin quantitative trait locus 1
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<span class="mim-font">
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<a href="/entry/141749"> 141749 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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HBG2
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<span class="mim-font">
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<a href="/entry/142250"> 142250 </a>
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<a href="/clinicalSynopsis/141749" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/141749" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/141749" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
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<span class="h5 mim-font">
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<strong> HEMATOLOGY </strong>
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- Persistence of fetal hemoglobin (5-30% HbF) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675374&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675374</a>]</span><br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the hemoglobin beta gene (HBB, <a href="/entry/141900#0437">141900.0437</a>)<br /> -
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Caused by mutation in the hemoglobin gamma A gene (HBG1, <a href="/entry/142200#0026">142200.0026</a>)<br /> -
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Caused by mutation in the hemoglobin gamma B gene (HBG2, <a href="/entry/142250#0026">142250.0026</a>)<br />
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because hereditary persistence of fetal hemoglobin (HPFH) can result from deletions within or encompassing the beta-globin gene cluster (see HBB, <a href="/entry/141900">141900</a>) on chromosome 11p15, including deletions that also encompass the delta-globin gene (<a href="/entry/142000">142000</a>), or from point mutations in the promoter regions of either the HBG1 (<a href="/entry/142200">142200</a>) or the HBG2 (<a href="/entry/142250">142250</a>) gene.</p><p>Other fetal hemoglobin quantitative trait loci (QTL) include HBFQTL2 (<a href="/entry/142470">142470</a>) on chromosome 6q23, HBFQTL3 (<a href="/entry/305435">305435</a>) on chromosome Xp22.2, and HBFQTL5 (<a href="/entry/142335">142335</a>) on chromosome 2p15, and HBFQTL6 (<a href="/entry/613566">613566</a>), caused by mutation in the KLF1 gene (<a href="/entry/600599">600599</a>) on chromosome 19p13. A QTL on chromosome 8q (HBFQTL4; <a href="/entry/606789">606789</a>) is thought to interact with the common XmnI-G-gamma polymorphism in HBG2 (<a href="/entry/142250#0028">142250.0028</a>) to influence the production of HbF.</p>
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<a id="description" class="mim-anchor"></a>
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<strong>Description</strong>
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<p>Classic hereditary persistence of fetal hemoglobin (HPFH) is characterized by a substantial elevation of fetal hemoglobin (HbF) in adult red blood cells. There are no other phenotypic or hematologic manifestations. Expression of the HBG1 and HBG2 genes, which encode the gamma isoforms of HbF, is normally suppressed shortly before birth and replaced by expression of the beta- (HBB; <a href="/entry/141900">141900</a>) or delta- (HBD; <a href="/entry/142000">142000</a>) chains, which form adult hemoglobin. Adults normally have less than 1% HbF, whereas heterozygotes for HPFH have 5 to 30% HbF. HPFH heterozygotes have essentially normal red cell indices and a rather homogeneous distribution of HbF among red cells, termed 'pancellular.' Homozygotes for HPFH can express HbF in up to 100% of red blood cells (<a href="#56" class="mim-tip-reference" title="Thein, S. L., Craig, J. E. <strong>Genetics of Hb F/F cell variance in adults and heterocellular hereditary persistence of fetal hemoglobin.</strong> Hemoglobin 22: 401-414, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9859924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9859924</a>] [<a href="https://doi.org/10.3109/03630269809071538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9859924">Thein and Craig, 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9859924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Delta-beta thalassemia is a hemoglobin disorder characterized by decreased or absent synthesis of the delta- and beta-globin chains with a compensatory increase in expression of fetal gamma-chain synthesis from the affected chromosome. Individuals with delta-beta thalassemia have hypochromic, microcytic anemia and increased HbF, which may mitigate the anemia depending on the level of HbF. Delta-beta thalassemia and some forms of HPFH result from deletions within the beta-globin gene cluster on chromosome 11p15; this has been referred to as 'deletional' HPFH. HPFH can also result from point mutations in the promoter regions of the gamma globulin genes HBG1 and HBG2; this has been referred to as 'non-deletional' HPFH (<a href="#47" class="mim-tip-reference" title="Ottolenghi, S., Giglioni, B., Taramelli, R., Comi, P., Mazza, U., Saglio, G., Camaschella, C., Izzo, P., Cao, A., Galanello, R., Gimferrer, E., Baiget, M., Gianni, A. M. <strong>Molecular comparison of delta-beta-thalassemia and hereditary persistence of fetal hemoglobin DNAs: evidence of a regulatory area?</strong> Proc. Nat. Acad. Sci. 79: 2347-2351, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6179097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6179097</a>] [<a href="https://doi.org/10.1073/pnas.79.7.2347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6179097">Ottolenghi et al., 1982</a>; <a href="#23" class="mim-tip-reference" title="Forget, B. G. <strong>Molecular basis of hereditary persistence of fetal hemoglobin.</strong> Ann. N.Y. Acad. Sci. 850: 38-44, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668525</a>] [<a href="https://doi.org/10.1111/j.1749-6632.1998.tb10460.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668525">Forget, 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9668525+6179097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Forget, B. G. <strong>Molecular basis of hereditary persistence of fetal hemoglobin.</strong> Ann. N.Y. Acad. Sci. 850: 38-44, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668525</a>] [<a href="https://doi.org/10.1111/j.1749-6632.1998.tb10460.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668525">Forget (1998)</a> noted that HPFH and delta-beta thalassemia are not clearly distinct disorders, but rather show partially overlapping features that may defy classification. Higher expression of HbF is often termed 'pancellular,' whereas lower expression of HbF is often termed 'heterocellular,' although these represent a spectrum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Approximately 10% of the population has HPFH manifest as modest elevations of HbF (1 to 4%) present in a subset of red cells (about 4.5%) termed F cells. This is also sometimes referred to as 'heterocellular' HPFH, and is considered to be a multifactorial trait influenced by multiple genetic loci (<a href="#56" class="mim-tip-reference" title="Thein, S. L., Craig, J. E. <strong>Genetics of Hb F/F cell variance in adults and heterocellular hereditary persistence of fetal hemoglobin.</strong> Hemoglobin 22: 401-414, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9859924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9859924</a>] [<a href="https://doi.org/10.3109/03630269809071538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9859924">Thein and Craig, 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9859924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#15" class="mim-tip-reference" title="Conley, C. L., Weatherall, D. J., Richardson, S. N., Shepard, M. K., Charache, S. <strong>Hereditary persistence of fetal hemoglobin: a study of 79 affected persons in 15 Negro families in Baltimore.</strong> Blood 21: 261-281, 1963.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14022587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14022587</a>]" pmid="14022587">Conley et al. (1963)</a> reported hereditary persistence of fetal hemoglobin in 79 individuals from 15 African American families. Some individuals had only fetal hemoglobin with glycine-136 (HBG2), whereas others had both glycine-136 and alanine-136 (HBG1) forms of fetal hemoglobin. This trait was thereafter described in Greeks and sporadically in other ethnic groups, e.g., Thais (see bibliography of <a href="#59" class="mim-tip-reference" title="Wasi, P., Pootrakul, S. N., Na-Nakorn, S. <strong>Hereditary persistence of foetal haemoglobin in a Thai family: the first instance in the Mongol race and in association with haemoglobin E.</strong> Brit. J. Haemat. 14: 501-506, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5726236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5726236</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1968.tb07001.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5726236">Wasi et al., 1968</a>). Affected Greeks studied by <a href="#59" class="mim-tip-reference" title="Wasi, P., Pootrakul, S. N., Na-Nakorn, S. <strong>Hereditary persistence of foetal haemoglobin in a Thai family: the first instance in the Mongol race and in association with haemoglobin E.</strong> Brit. J. Haemat. 14: 501-506, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5726236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5726236</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1968.tb07001.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5726236">Wasi et al. (1968)</a> had only fetal hemoglobin of the alanine-136 type (HBG1). The differences were explained on the basis of various deletions involving a region containing several linked hemoglobin genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5726236+14022587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Schokker, R. C., Went, L. N., Bok, J. <strong>A new genetic variant of beta-thalassaemia.</strong> Nature 209: 44-46, 1966.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5925329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5925329</a>] [<a href="https://doi.org/10.1038/209044a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5925329">Schokker et al. (1966)</a> reported an association between beta-thalassemia (see <a href="/entry/141900">141900</a>) and a high fetal hemoglobin determinant in a pedigree of Dutch origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5925329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#60" class="mim-tip-reference" title="Weatherall, D. J., Cartner, R., Clegg, J. B., Wood, W. G., Macrae, I. A., Mackenzie, A. <strong>A form of hereditary persistence of fetal haemoglobin characterized by uneven cellular distribution of haemoglobin F and the production of haemoglobins A and A2 in homozygotes.</strong> Brit. J. Haemat. 29: 205-220, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/811241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">811241</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1975.tb01815.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="811241">Weatherall et al. (1975)</a> reported a British family in which 13 members had elevated levels of HbF that segregated into 2 groups with mean values of 19.8% and 8.9%, respectively. Genetic data indicated that the individuals in the former group were probably homozygous, and those in the latter group heterozygous, for the gene causing persistent HbF production. Biochemical studies showed that most of the HbF contained gamma-A (HBG1), with a small (10%) amount of the gamma-G (HBG2) in both homozygotes and heterozygotes. <a href="#60" class="mim-tip-reference" title="Weatherall, D. J., Cartner, R., Clegg, J. B., Wood, W. G., Macrae, I. A., Mackenzie, A. <strong>A form of hereditary persistence of fetal haemoglobin characterized by uneven cellular distribution of haemoglobin F and the production of haemoglobins A and A2 in homozygotes.</strong> Brit. J. Haemat. 29: 205-220, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/811241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">811241</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1975.tb01815.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="811241">Weatherall et al. (1975)</a>, who referred to this entity as the 'British' type of HPFH, noted that the condition differed from previously described forms of HPFH by virtue of the heterogeneous distribution of the HbF and the presence of beta and delta-chain synthesis in homozygotes. In the family reported by <a href="#60" class="mim-tip-reference" title="Weatherall, D. J., Cartner, R., Clegg, J. B., Wood, W. G., Macrae, I. A., Mackenzie, A. <strong>A form of hereditary persistence of fetal haemoglobin characterized by uneven cellular distribution of haemoglobin F and the production of haemoglobins A and A2 in homozygotes.</strong> Brit. J. Haemat. 29: 205-220, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/811241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">811241</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1975.tb01815.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="811241">Weatherall et al. (1975)</a>, <a href="#55" class="mim-tip-reference" title="Tate, V. E., Wood, W. G., Weatherall, D. J. <strong>The British form of hereditary persistence of fetal hemoglobin results from a single base mutation adjacent to an S1 hypersensitive site 5-prime to the A-gamma-globin gene.</strong> Blood 68: 1389-1393, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2430647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2430647</a>]" pmid="2430647">Tate et al. (1986)</a> identified a mutation in the promoter of the HBG1 gene (<a href="/entry/142200#0028">142200.0028</a>). This was referred to as a non-deletional form of HPFH due to variation at the beta-globin gene cluster on 11p15. Homozygotes were clinically and hematologically normal except for increased HbF, ranging from 18 to 21%. Heterozygotes had HbF of 3.5 to 10%. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=811241+2430647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Marinucci, M., Mavilio, F., Giuliani, A., Gabbianelli, M., Tentori, L., Jr., Tentori, L. <strong>Beta-thalassemia associated with increased Hb F production: evidence for the existence of a heterocellular hereditary persistence of fetal hemoglobin (HPFH) determinant linked to beta-thalassemia in a southern Italian population.</strong> Hemoglobin 5: 1-17, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6162827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6162827</a>] [<a href="https://doi.org/10.3109/03630268108996907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6162827">Marinucci et al. (1981)</a> observed a family in southern Italy in which beta-thalassemia was inherited over 3 generations together with a high HbF level (8-12%) and an increased number of F cells. Two individuals who were homozygous for beta-thalassemia had a mild phenotype with hemoglobin consisting mainly of HbF in almost all red cells (pancellular HPFH). <a href="#38" class="mim-tip-reference" title="Marinucci, M., Mavilio, F., Giuliani, A., Gabbianelli, M., Tentori, L., Jr., Tentori, L. <strong>Beta-thalassemia associated with increased Hb F production: evidence for the existence of a heterocellular hereditary persistence of fetal hemoglobin (HPFH) determinant linked to beta-thalassemia in a southern Italian population.</strong> Hemoglobin 5: 1-17, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6162827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6162827</a>] [<a href="https://doi.org/10.3109/03630268108996907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6162827">Marinucci et al. (1981)</a> noted the considerable clinical benefit of the coexistence of HPFH determinants capable of increasing the size of the F-cell population in patients with homozygous thalassemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6162827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a large Australian kindred with nondeletional heterocellular HPFH, <a href="#18" class="mim-tip-reference" title="Donald, J. A., Lammi, A., Trent, R. J. <strong>Hemoglobin F production in heterocellular hereditary persistence of fetal hemoglobin and its linkage to the beta globin gene complex.</strong> Hum. Genet. 80: 69-74, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2458313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2458313</a>] [<a href="https://doi.org/10.1007/BF00451459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2458313">Donald et al. (1988)</a> found that fetal hemoglobin was increased to values between 1.8 and 7.9% in 13 members. HbF was composed predominantly of gamma-A chains, and the phenotype was closely linked to the beta-globin gene cluster. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2458313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Bhardwaj, U., Zhang, Y.-H., Jackson, D. S., Buchanan, G. R., Therrell, B. L., Jr., McCabe, L. L., McCabe, E. R. B. <strong>DNA diagnosis confirms hemoglobin deletion in newborn screen follow-up.</strong> J. Pediat. 142: 346-348, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640388</a>] [<a href="https://doi.org/10.1067/mpd.2003.117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640388">Bhardwaj et al. (2003)</a> described a black female who was identified by newborn screening as having sickle cell disease (<a href="/entry/603903">603903</a>) with a carrier father and a mother without sickle trait. At 11 months, the child had microcytosis and borderline anemia with a high hemoglobin F (45%); the mother was found to have an elevated HbF (32.1%) consistent with being a carrier of HPFH. Subsequent molecular analysis with a specialized gap-PCR technique determined that both mother and daughter were heterozygous for a deletion in the HBB gene cluster. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12640388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Among several families with either sickle cell anemia or beta-thalassemia who also showed segregation of HPFH, <a href="#65" class="mim-tip-reference" title="Wood, W. G., Weatherall, D. J., Clegg, J. B. <strong>Interaction of heterocellular hereditary persistence of foetal haemoglobin with beta-thalassaemia and sickle cell anaemia.</strong> Nature 264: 247-249, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1004547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1004547</a>] [<a href="https://doi.org/10.1038/264247a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1004547">Wood et al. (1976)</a> found close linkage between the HPFH gene and the beta-globin gene on chromosome 11p15. The findings suggested that the HPFH locus in these families was identical to or closely related to the regulatory region for gamma-globin synthesis. The frequency of F cells was particularly high among those patients with beta-thalassemia and sickle cell anemia, consistent with preferential survival of F cells in bone marrow and peripheral blood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1004547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Marinucci, M., Mavilio, F., Giuliani, A., Gabbianelli, M., Tentori, L., Jr., Tentori, L. <strong>Beta-thalassemia associated with increased Hb F production: evidence for the existence of a heterocellular hereditary persistence of fetal hemoglobin (HPFH) determinant linked to beta-thalassemia in a southern Italian population.</strong> Hemoglobin 5: 1-17, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6162827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6162827</a>] [<a href="https://doi.org/10.3109/03630268108996907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6162827">Marinucci et al. (1981)</a> found linkage to the beta-globin locus on chromosome 11p15 in an Italian family with beta-thalassemia and HPFH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6162827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Dover, G. J., Boyer, S. H., Pembrey, M. E. <strong>F-cell production in sickle cell anemia: regulation by genes linked to the beta-hemoglobin locus.</strong> Science 211: 1441-1444, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6162200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6162200</a>] [<a href="https://doi.org/10.1126/science.6162200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6162200">Dover et al. (1981)</a> amassed 3 lines of evidence that a locus regulating generation of F cells was linked to the gamma-delta-beta complex. (1) The percentages of F reticulocytes, while widely divergent in the population of homozygous sickle cell patients, showed a correlation coefficient of 0.94 in homozygous sib pairs (correlation coefficient for within-person percentages for successive samples = 0.95). (2) Mid-parental F-cell levels in healthy heterozygous parents, while well within the normal adult range of 0.2 to 10%, correlated well (r = 0.92) with the percentage of F reticulocytes produced by their homozygous offspring. (3) In the isolated population of eastern Saudi Arabia the coefficient of variation for F-reticulocyte level in homozygous sickle persons is about 25% (not greatly different from the average coefficient of 23% for variation between sibs). On the other hand, in the outcrossed American Black population, the coefficient of variation is 66%. The Saudi population may be homozygous at the F-cell regulatory locus. Specifically, the Saudi homozygous patients have a high F-cell percentage. If American Blacks with sickle cell anemia and elevated percentages of F reticulocytes likewise are homozygotes, the frequency of the gene can be calculated as 0.35. There is other evidence that HbF and F-cell levels are genetically determined in baboon (<a href="#17" class="mim-tip-reference" title="DeSimone, J., Heller, P., Amsel, J., Usman, M. <strong>Magnitude of the fetal hemoglobin response to acute hemolytic anemia in baboons is controlled by genetic factors.</strong> J. Clin. Invest. 65: 224-226, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6765958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6765958</a>] [<a href="https://doi.org/10.1172/JCI109654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6765958">DeSimone et al., 1980</a>) and in man (<a href="#66" class="mim-tip-reference" title="Zago, M. A., Wood, W. G., Clegg, J. B., Weatherall, D. J., O'Sullivan, M., Gunson, H. <strong>Genetic control of F cells in human adults.</strong> Blood 53: 977-986, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/373818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">373818</a>]" pmid="373818">Zago et al., 1979</a>), both anemic and nonanemic. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6162200+373818+6765958" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Boyer, S. H., Dover, G. J. <strong>Linkage but nonidentity between the beta-globin locus and the regulator FCP locus governing F-cell production. (Abstract)</strong> Cytogenet. Cell Genet. 32: 255 only, 1982."None>Boyer and Dover (1982)</a> referred to 6 recombinants out of 39 opportunities for the linkage between F-cell production and the beta-globin locus. <a href="#9" class="mim-tip-reference" title="Boyer, S. H. <strong>Personal Communication.</strong> Baltimore, Md. 2/1983."None>Boyer (1983)</a> set the limits as 0.12 and 0.23 for the true recombination fraction for beta-globin and F-cell production.</p><p><a href="#46" class="mim-tip-reference" title="Old, J. M., Ayyub, H., Wood, W. G., Clegg, J. B., Weatherall, D. J. <strong>Linkage analysis of nondeletion hereditary persistence of fetal hemoglobin.</strong> Science 215: 981-982, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6186021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6186021</a>] [<a href="https://doi.org/10.1126/science.6186021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6186021">Old et al. (1982)</a> reported a family with HPFH in whom linkage analysis showed that the regulatory gene was close to or coincident with the beta-globin complex on chromosome 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6186021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Efremov, G. D., Gjorgovski, I., Stojanovski, N., Diaz-Chico, J. C., Harano, T., Kutlar, F., Huisman, T. H. J. <strong>One haplotype is associated with the Swiss type of hereditary persistence of fetal hemoglobin in the Yugoslavian population.</strong> Hum. Genet. 77: 132-136, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2443439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2443439</a>] [<a href="https://doi.org/10.1007/BF00272379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2443439">Efremov et al. (1987)</a> characterized the haplotype associated with heterocellular HPFH in Yugoslavia. The trait was associated with a chromosome 11p15 whose restriction enzyme haplotype was identical to that observed in African patients with sickle cell anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2443439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Heterogeneity</em></strong></p><p>
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<a href="#40" class="mim-tip-reference" title="Martinez, G., Colombo, B. <strong>A new type of hereditary persistence of fetal hemoglobin: is a diffusible factor regulating gamma-chain synthesis?</strong> Nature 252: 735-736, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4437631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4437631</a>] [<a href="https://doi.org/10.1038/252735a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4437631">Martinez and Colombo (1974)</a> reported a family of African origin in which HPFH occurred at a level of 5% HbF. Linkage analysis showed that the gene did not behave as an allele of the beta-globin complex, although the possibility of a crossover between the gamma and the beta loci could not be excluded. The authors suggested that a diffusible factor might regulate gamma-chain synthesis. In a follow-up of the family reported by <a href="#40" class="mim-tip-reference" title="Martinez, G., Colombo, B. <strong>A new type of hereditary persistence of fetal hemoglobin: is a diffusible factor regulating gamma-chain synthesis?</strong> Nature 252: 735-736, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4437631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4437631</a>] [<a href="https://doi.org/10.1038/252735a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4437631">Martinez and Colombo (1974)</a>, <a href="#41" class="mim-tip-reference" title="Martinez, G., Novelletto, A., DiRienzo, A., Felicetti, L., Colombo, B. <strong>A case of hereditary persistence of fetal hemoglobin caused by a gene not linked to the beta-globin cluster.</strong> Hum. Genet. 82: 335-337, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2472351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2472351</a>] [<a href="https://doi.org/10.1007/BF00273993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2472351">Martinez et al. (1989)</a> demonstrated that a determinant for HPFH segregated independently from the beta-globin gene cluster on 11p15. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2472351+4437631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#54" class="mim-tip-reference" title="Soummer, A. M., Testa, U., Dujardin, P., Guerrasio, A., Henri, A., Gazaix, M., Riou, J., Rochant, H., Beuzard, Y., Rosa, J. <strong>Genetic regulation of gamma-gene expression: study of the interaction of beta-thalassemia with heterocellular HPFH.</strong> Hum. Genet. 57: 371-375, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6169619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6169619</a>] [<a href="https://doi.org/10.1007/BF00281687" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6169619">Soummer et al. (1981)</a> reported a family of Algerian origin in which a father and daughter, the proposita, had both beta-thalassemia and HPFH. HbF levels were 3.6% and 6.15%, respectively, and 16% and 19% F cells, respectively. Two additional daughters had only HPFH, with HbF levels of 1.83% and 2.69%, respectively, and 12% and 17% F cells, respectively. A daughter of the proposita had only beta-thalassemia, with HbF level of 1.4% and F cell number of 8%. <a href="#54" class="mim-tip-reference" title="Soummer, A. M., Testa, U., Dujardin, P., Guerrasio, A., Henri, A., Gazaix, M., Riou, J., Rochant, H., Beuzard, Y., Rosa, J. <strong>Genetic regulation of gamma-gene expression: study of the interaction of beta-thalassemia with heterocellular HPFH.</strong> Hum. Genet. 57: 371-375, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6169619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6169619</a>] [<a href="https://doi.org/10.1007/BF00281687" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6169619">Soummer et al. (1981)</a> concluded that the father of the 3 daughters carried both genes for beta-thalassemia and HPFH, and transmitted both genes to the proposita, but only the HPFH gene to the other 2 daughters. The findings indicated that the 2 traits were unlinked, suggesting that a locus distinct from the beta-globin cluster is responsible for HPFH in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6169619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Gianni, A. M., Bregni, M., Cappellini, M. D., Giorelli, G., Taramelli, R., Giglioni, B., Comi, P., Ottolenghi, S. <strong>A gene controlling fetal hemoglobin expression in adults is not linked to the non-alpha globin cluster.</strong> EMBO J. 2: 921-925, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6196196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6196196</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1983.tb01522.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6196196">Gianni et al. (1983)</a> reported a Sardinian family in which a homozygous beta-thalassemic patient had an unusually mild form of the disease, which was ascribed to the coexistence of a gene causing heterocellular HPFH. Four family members had heterozygous beta-thalassemia with HPFH, and 5 had HPFH without beta-thalassemia. Linkage analysis using restriction polymorphisms indicated that HPFH in this family was not linked to the beta-globin gene cluster. <a href="#29" class="mim-tip-reference" title="Gianni, A. M., Bregni, M., Cappellini, M. D., Giorelli, G., Taramelli, R., Giglioni, B., Comi, P., Ottolenghi, S. <strong>A gene controlling fetal hemoglobin expression in adults is not linked to the non-alpha globin cluster.</strong> EMBO J. 2: 921-925, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6196196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6196196</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1983.tb01522.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6196196">Gianni et al. (1983)</a> postulated that the putative gene may code for a diffusible substance acting, directly or indirectly, on gamma-globin gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6196196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Giampaolo, A., Mavilio, F., Sposi, N. M., Care, A., Massa, A., Cianetti, L., Petrini, M., Russo, R., Cappellini, M. D., Marinucci, M. <strong>Heterocellular hereditary persistence of fetal hemoglobin (HPFH). Molecular mechanisms of abnormal gamma-gene expression in association with beta-thalassemia and linkage relationship with the beta-globin gene cluster.</strong> Hum. Genet. 66: 151-156, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6201431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6201431</a>] [<a href="https://doi.org/10.1007/BF00286590" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6201431">Giampaolo et al. (1984)</a> concluded that the HPFH mutation lies outside the gamma-delta-beta-globin DNA segment on 11p15. They observed independent segregation of HPFH and beta-thalassemia trait in 2 families, 1 of which showed no segregation of DNA polymorphisms within the segment when HPFH and beta-thalassemia segregated. By the coexistence of a polymorphic variant of the A-gamma chain (gamma-T), they were also able to demonstrate that the increased gamma-chain synthesis caused by the heterocellular HPFH determinant was directed by both chromosomes. This finding was in contrast to delta-beta thalassemia and pancellular HPFH, in which only the chromosomes carrying the mutation are affected via a cis effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6201431" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The frequency of F cells in sickle cell disease can range from 2 to 50%. By studying 59 sib pairs with sickle cell anemia from Jamaica and the US, <a href="#6" class="mim-tip-reference" title="Boyer, S. H., Dover, G. J., Serjeant, G. R., Smith, K. D., Antonarakis, S. E., Embury, S. H., Margolet, L., Noyes, A. N., Boyer, M. L., Bias, W. B. <strong>Production of F cells in sickle cell anemia: regulation by a genetic locus or loci separate from the beta-globin gene cluster.</strong> Blood 64: 1053-1058, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6207872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6207872</a>]" pmid="6207872">Boyer et al. (1984)</a> provided evidence for at least 1 locus distinct from the beta-globin locus that is important for the regulation of F-cell production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6207872" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a large family originating from northern India with heterocellular hereditary persistence of fetal hemoglobin, <a href="#50" class="mim-tip-reference" title="Sampietro, M., Thein, S. L. <strong>Heterocellular hereditary persistence of fetal haemoglobin: strategy for linkage analysis. (Abstract)</strong> Cytogenet. Cell Genet. 58: 1924-1925, 1991."None>Sampietro and Thein (1991)</a> demonstrated linkage to a polymorphic locus at 7q36, with a maximum lod score of 2.8 at a recombination fraction of 0.09 when their data were combined with those from a second pedigree of Italian origin. The propositus in the Indian family, despite being homozygous for beta-thalassemia and unable to produce any normal adult hemoglobin, had exceedingly mild clinical disease because of coinheritance of heterocellular HPFH.</p>
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<p><strong><em>Deletions in Chromosome 11p15</em></strong></p><p>
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<a href="#36" class="mim-tip-reference" title="Kan, Y. W., Holland, J. P., Dozy, A. M., Charache, S., Kazazian, H. H., Jr. <strong>Deletion of the beta-globin structural gene in hereditary persistence of foetal haemoglobin.</strong> Nature 258: 162-163, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1186896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1186896</a>] [<a href="https://doi.org/10.1038/258162a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1186896">Kan et al. (1975)</a> identified deletions in the delta and beta HB loci in individuals with increased HbF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1186896" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bernards, R., Flavell, R. A. <strong>Physical mapping of the globin gene deletion in hereditary persistence of foetal haemoglobin (HPFH).</strong> Nucleic Acids Res. 8: 1521-1534, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6159595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6159595</a>] [<a href="https://doi.org/10.1093/nar/8.7.1521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6159595">Bernards and Flavell (1980)</a> mapped the beta-like globin region in 2 HPFH patients: an African American who was homozygous for both G-gamma and A-gamma HbF expression, and a Greek who was heterozygous for A-gamma expression. In the first individual, there was a 24-kb deletion in the hemoglobin gene region that removed the gamma-, delta-, and beta-globin genes. The 5-prime break was situated about 9 kb upstream from the delta gene and the 3-prime break at least 7 kb past the beta gene. No deletion was detected in the heterozygous Greek. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6159595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Ottolenghi, S., Giglioni, B., Taramelli, R., Comi, P., Mazza, U., Saglio, G., Camaschella, C., Izzo, P., Cao, A., Galanello, R., Gimferrer, E., Baiget, M., Gianni, A. M. <strong>Molecular comparison of delta-beta-thalassemia and hereditary persistence of fetal hemoglobin DNAs: evidence of a regulatory area?</strong> Proc. Nat. Acad. Sci. 79: 2347-2351, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6179097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6179097</a>] [<a href="https://doi.org/10.1073/pnas.79.7.2347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6179097">Ottolenghi et al. (1982)</a> studied 3 Mediterranean families with delta-beta thalassemia and 1 Southern Italian family with HPFH using restriction enzyme mapping and expression of gamma-A and gamma-G. There was molecular heterogeneity of deletion sizes at the beta-globin locus: Sicilian and Calabrian delta-beta thalassemia patients showed a deletion starting from the delta-globin intron and ending several kilobases 3-prime to the beta-globin gene. In a Spanish family with thalassemia, the deletion started 2 to 3 kb 5-prime to the delta-globin gene and extended well beyond the beta-globin gene. In addition, the Spanish family was found to have a variant of gamma-A fetal hemoglobin (<a href="/entry/142200#0001">142200.0001</a>) which accounted for all of the gamma-A production in heterozygotes. These findings indicated that persistent production of gamma chains occurred in cis to the delta-beta gene deletion. Comparison with the deletions in HPFH suggested that deletion of a region about 3.5 kb 5-prime to the delta gene may be critical to the persistent expression of high levels of fetal hemoglobin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6179097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#57" class="mim-tip-reference" title="Tuan, D., Feingold, E., Newman, M., Weissman, S. M., Forget, B. G. <strong>Different 3-prime end points of deletions causing delta-beta-thalassemia and hereditary persistence of fetal hemoglobin: implications for the control of gamma-globin gene expression in man.</strong> Proc. Nat. Acad. Sci. 80: 6937-6941, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6196781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6196781</a>] [<a href="https://doi.org/10.1073/pnas.80.22.6937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6196781">Tuan et al. (1983)</a> found that the deletion in 2 types of HPFH was more extensive than that in 2 types of delta-beta thalassemia. In the former, the 3-prime end of the deletion was about 52 and 57 kb from the 3-prime end of the beta-globin gene; in the latter, the 3-prime end of the deletion was about 5 and 10 kb from the 3-prime end of the beta-globin gene. Thus, the extent of the deletion and the nature of the DNA that is consequently brought into proximity with the gamma-globin genes may be more important in determining the phenotype in these disorders than the nature of the deleted DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6196781" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Collins, F. S., Iannuzzi, M. C., Cole, J. L. <strong>Pulsed field gel electrophoresis blotting demonstrates a deletion of at least 110 kilobases in hereditary persistence of fetal hemoglobin. (Abstract)</strong> Am. J. Hum. Genet. 39: A192 only, 1986."None>Collins et al. (1986)</a> pointed out that the total length of the deleted DNA in 'type 1' and 'type 2' HPFH is nearly the same. Type 1 HPFH is the most common deletion form occurring in African Americans, and type 2 HPFH is the most common form occurring in Ghana. There is an Indian variety which has about half as long a deletion. <a href="#12" class="mim-tip-reference" title="Collins, F. S., Iannuzzi, M. C., Cole, J. L. <strong>Pulsed field gel electrophoresis blotting demonstrates a deletion of at least 110 kilobases in hereditary persistence of fetal hemoglobin. (Abstract)</strong> Am. J. Hum. Genet. 39: A192 only, 1986."None>Collins et al. (1986)</a> speculated that the deleted segment may represent one loop of DNA between 2 attachment sites in the nuclear matrix.</p><p>In the Vietnamese G-gamma/A-gamma HPFH, <a href="#45" class="mim-tip-reference" title="Motum, P. I., Hamilton, T. J., Lindeman, R., Le, H., Trent, R. J. <strong>Molecular characterisation of Vietnamese HPFH.</strong> Hum. Mutat. 2: 179-184, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7689901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7689901</a>] [<a href="https://doi.org/10.1002/humu.1380020305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7689901">Motum et al. (1993)</a> demonstrated a novel 30-kb deletion located downstream from the beta-globin gene cluster. They compared the sites of the 5-prime and 3-prime breakpoints of this deletion with those for other HPFH-producing deletions downstream from the HBB gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7689901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="de Andrade, T. G., Peterson, K. R., Cunha, A. F., Moreira, L. S., Fattori, A., Saad, S. T. O., Costa, F. F. <strong>Identification of novel candidate genes for globin regulation in erythroid cells containing large deletions of the human beta-globin gene cluster.</strong> Blood Cells Molec. Dis. 37: 82-90, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16952470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16952470</a>] [<a href="https://doi.org/10.1016/j.bcmd.2006.07.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16952470">De Andrade et al. (2006)</a> used suppressive subtractive hybridization to analyze differential gene expression in a patient with HPFH type 2, the Sicilian form of delta-beta-thalassemia, and normal reticulocytes. HPFH type 2, the Ghanaian form, is caused by a 100-kb deletion at 11p15 that completely removes the delta- and beta-globin genes, with the 3-prime breakpoint near an enhancer element downstream of the beta-globin cluster. Several genes were altered in HPFH and delta-beta-thalassemia compared to normal reticulocytes, including SLC25A37 (<a href="/entry/610387">610387</a>) and ZHX2 (<a href="/entry/609185">609185</a>). HBA1 (<a href="/entry/141800">141800</a>) was also decreased in both conditions compared to normal. The findings suggested an integrated model, including both cis and trans elements, to explain increased Hb-gamma expression in these conditions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16952470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#51" class="mim-tip-reference" title="Sankaran, V. G., Xu, J., Byron, R., Greisman, H. A., Fisher, C., Weatherall, D. J., Sabath, D. E., Groudine, M., Orkin, S. H., Premawardhena, A., Bender, M. A. <strong>A functional element necessary for fetal hemoglobin silencing.</strong> New Eng. J. Med. 365: 807-814, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21879898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21879898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21879898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1103070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21879898">Sankaran et al. (2011)</a> identified 3 families with unusual patterns of hemoglobin expression, suggestive of deletions in the locus of the beta-globin gene. The authors used array comparative genomic hybridization to map the deletions and confirmed breakpoints by PCR assays and DNA sequencing. They found a novel delta-beta-0-thalassemia deletion and a rare HPFH deletion with identical downstream breakpoints. Comparison of the 2 deletions resulted in the identification of a small intergenic region required for gamma-globin gene (HBG1; <a href="/entry/142200">142200</a>) silencing. <a href="#51" class="mim-tip-reference" title="Sankaran, V. G., Xu, J., Byron, R., Greisman, H. A., Fisher, C., Weatherall, D. J., Sabath, D. E., Groudine, M., Orkin, S. H., Premawardhena, A., Bender, M. A. <strong>A functional element necessary for fetal hemoglobin silencing.</strong> New Eng. J. Med. 365: 807-814, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21879898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21879898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21879898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1103070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21879898">Sankaran et al. (2011)</a> mapped a Kurdish beta-0-thalassemia deletion, which retained the required intergenic region, deleted other surrounding sequences, and maintained fetal hemoglobin silencing. By comparing these deletions and other previously mapped deletions, <a href="#51" class="mim-tip-reference" title="Sankaran, V. G., Xu, J., Byron, R., Greisman, H. A., Fisher, C., Weatherall, D. J., Sabath, D. E., Groudine, M., Orkin, S. H., Premawardhena, A., Bender, M. A. <strong>A functional element necessary for fetal hemoglobin silencing.</strong> New Eng. J. Med. 365: 807-814, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21879898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21879898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21879898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1103070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21879898">Sankaran et al. (2011)</a> elucidated a 3.5-kb intergenic region near the 5-prime end of the delta-globin gene that is necessary for gamma-globin silencing. They also found that BCL11A (<a href="/entry/606557">606557</a>) and its partners bind within this region in the chromatin of adult erythroid cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21879898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Point Mutations In or Near the HBG1 and HBG2 Genes</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Balsley, J. F., Rappaport, E., Schwartz, E., Surrey, S. <strong>The gamma-delta-beta-globin gene region in G-gamma-beta(+)-hereditary persistence of fetal hemoglobin.</strong> Blood 59: 828-831, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6174163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6174163</a>]" pmid="6174163">Balsley et al. (1982)</a> reported an African American mother and child with gamma-G (HBG2), beta-globin-positive HPFH. The affected chromosome in these persons directed the production of G gamma-chains and beta-chains, but not gamma-A (HBG1) chains. DNA analysis with several restriction enzymes did not detect any deletions in the beta-globin gene cluster region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6174163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#48" class="mim-tip-reference" title="Papayannopoulou, T., Lawn, R. M., Stamatoyannopoulos, G., Maniatis, T. <strong>Greek (A-gamma) variant of hereditary persistence of fetal haemoglobin: globin gene organization and studies of expression of fetal haemoglobins in clonal erythroid cultures.</strong> Brit. J. Haemat. 50: 387-399, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6175332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6175332</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1982.tb01934.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6175332">Papayannopoulou et al. (1982)</a> noted that the 'Greek' form of HPFH shows HbF predominantly of the gamma-A type. However, cell culture studies of Greek HPFH erythrocytes showed that both gamma genes could be expressed. Restriction endonuclease mapping indicated that the gamma-G, delta, and beta genes in cis to the Greek HPFH determinant were intact and there was no large deletion. This was in contrast to other forms of HPFH which had been associated with large deletions. <a href="#48" class="mim-tip-reference" title="Papayannopoulou, T., Lawn, R. M., Stamatoyannopoulos, G., Maniatis, T. <strong>Greek (A-gamma) variant of hereditary persistence of fetal haemoglobin: globin gene organization and studies of expression of fetal haemoglobins in clonal erythroid cultures.</strong> Brit. J. Haemat. 50: 387-399, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6175332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6175332</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1982.tb01934.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6175332">Papayannopoulou et al. (1982)</a> speculated that the genetic lesion may reside in regulatory sequences that control the level of gamma-A and gamma-G expression. <a href="#13" class="mim-tip-reference" title="Collins, F. S., Metherall, J. E., Yamakawa, M., Pan, J., Weissman, S. M., Forget, B. G. <strong>A point mutation in the A-gamma-globin gene promoter in Greek hereditary persistence of fetal haemoglobin.</strong> Nature 313: 325-326, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2578620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2578620</a>] [<a href="https://doi.org/10.1038/313325a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2578620">Collins et al. (1985)</a> determined that the Greek form of HPFH was due to a -117G-A SNP in the promoter region of the HBG1 gene (<a href="/entry/142200#0026">142200.0026</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2578620+6175332" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Farquhar, M., Gelinas, R., Tatsis, B., Murray, J., Yagi, M., Mueller, R., Stamatoyannopoulos, G. <strong>Restriction endonuclease mapping of gamma-delta-beta-globin region in G-gamma-beta(+) HPFH and a Chinese A-gamma HPFH variant.</strong> Am. J. Hum. Genet. 35: 611-620, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6192712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6192712</a>]" pmid="6192712">Farquhar et al. (1983)</a> performed restriction enzyme mapping of the beta-globin cluster in 2 forms of HPFH and could demonstrate no deletion or other abnormality. They suggested that if the DNA structure of the gamma-delta-beta region was indeed normal, these variants could be due to mutations of regulatory loci at sites outside this genomic region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6192712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Fetal Hb levels are influenced by single-nucleotide polymorphisms in the promoter regions of the HBG1 and HBG2 genes, which affect gene expression. Single-base changes influencing hereditary persistence of HbF in the HBG2 gene include -202C-G (<a href="/entry/142250#0026">142250.0026</a>) (<a href="#14" class="mim-tip-reference" title="Collins, F. S., Stoeckert, C. J., Jr., Serjeant, G. R., Forget, B. G., Weissman, S. M. <strong>G-gamma-beta(+) hereditary persistence of fetal hemoglobin: cosmid cloning and identification of a specific mutation 5-prime to the G-gamma gene.</strong> Proc. Nat. Acad. Sci. 81: 4894-4898, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6205403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6205403</a>] [<a href="https://doi.org/10.1073/pnas.81.15.4894" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6205403">Collins et al., 1984</a>), -175T-C (<a href="/entry/142250#0027">142250.0027</a>) (<a href="#30" class="mim-tip-reference" title="Huang, H. J., Stoming, T. A., Harris, H. F., Kutlar, F., Huisman, T. H. J. <strong>The Greek A-gamma-beta+/HPFH observed in a large black family.</strong> Am. J. Hemat. 25: 401-408, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2441598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2441598</a>] [<a href="https://doi.org/10.1002/ajh.2830250406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2441598">Huang et al., 1987</a>), and -158C-T (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a>; <a href="/entry/142250#0028">142250.0028</a>) (<a href="#43" class="mim-tip-reference" title="Miller, B. A., Olivieri, N., Salameh, M., Ahmed, M., Antognetti, G., Huisman, T. H. J., Nathan, D. G., Orkin, S. H. <strong>Molecular analysis of the high-hemoglobin-F phenotype in Saudi Arabian sickle cell anemia.</strong> New Eng. J. Med. 316: 244-250, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2432426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2432426</a>] [<a href="https://doi.org/10.1056/NEJM198701293160504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2432426">Miller et al., 1987</a>). Single base changes responsible for HPFH in the HBG1 gene include -117G-A (<a href="/entry/142200#0026">142200.0026</a>) (<a href="#13" class="mim-tip-reference" title="Collins, F. S., Metherall, J. E., Yamakawa, M., Pan, J., Weissman, S. M., Forget, B. G. <strong>A point mutation in the A-gamma-globin gene promoter in Greek hereditary persistence of fetal haemoglobin.</strong> Nature 313: 325-326, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2578620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2578620</a>] [<a href="https://doi.org/10.1038/313325a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2578620">Collins et al., 1985</a>) and -196C-T (<a href="/entry/142200#0027">142200.0027</a>) (<a href="#25" class="mim-tip-reference" title="Gelinas, R., Bender, M., Lotshaw, C., Waber, P., Kazazian, H., Jr., Stamatoyannopoulos, G. <strong>Chinese A-gamma fetal hemoglobin: C to T substitution at position -196 of the A-gamma gene promoter.</strong> Blood 67: 1777-1779, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2423160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2423160</a>]" pmid="2423160">Gelinas et al., 1986</a>). Several findings indicate that these substitutions cause the HPFH phenotype: (1) only the mutated gene is affected; (2) the substitutions are the only nonpolymorphic deviations from the normal sequence over a large region; and (3) there is a strong correlation between the base substitution and HPFH (<a href="#10" class="mim-tip-reference" title="Carlson, D. P., Ross, J. <strong>Point mutation associated with hereditary persistence of fetal hemoglobin decreases RNA polymerase III transcription upstream of the affected gamma-globin gene.</strong> Molec. Cell. Biol. 6: 3278-3282, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2431298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2431298</a>] [<a href="https://doi.org/10.1128/mcb.6.9.3278-3282.1986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2431298">Carlson and Ross, 1986</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2432426+2431298+6205403+2578620+2423160+2441598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a cohort of 1,275 African Americans with sickle cell disease, <a href="#37" class="mim-tip-reference" title="Lettre, G., Sankaran, V. G., Bezerra, M. A. C., Araujo, A. S., Uda, M., Sanna, S., Cao, A., Schlessinger, D., Costa, F. F., Hirschhorn, J. N. <strong>Orkin, S. H.: DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease.</strong> Proc. Nat. Acad. Sci. 105: 11869-11874, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18667698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18667698</a>] [<a href="https://doi.org/10.1073/pnas.0804799105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18667698">Lettre et al. (2008)</a> found a significant association between HbF levels and SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a> in the HBG2 gene (<a href="/entry/142250#0028">142250.0028</a>) (p = 4 x 10(-7)), which explained 2.2% of the variation in HbF levels. The association with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a> could not be tested in a Brazilian cohort because the variant was monomorphic in this population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18667698" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To fine map HbF association signals, <a href="#24" class="mim-tip-reference" title="Galarneau, G., Palmer, C. D., Sankaran, V. G., Orkin, S. H., Hirschhorn, J. N., Lettre, G. <strong>Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation.</strong> Nature Genet. 42: 1049-1051, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21057501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21057501</a>] [<a href="https://doi.org/10.1038/ng.707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21057501">Galarneau et al. (2010)</a> resequenced 175.2 kb from the BCL11A (<a href="/entry/606557">606557</a>), HBS1L-MYB (<a href="/entry/612450">612450</a>-<a href="/entry/189990">189990</a>), and beta-globin loci (representing HBFQTL5 (<a href="/entry/142335">142335</a>), HBFQTL2 (<a href="/entry/142470">142470</a>), and HBFQTL1, respectively) in 190 individuals including the HapMap European CEU and Nigerian YRI founders and 70 African Americans with sickle cell anemia. The authors discovered 1,489 sequence variants, including 910 previously unreported variants. Using this information and data from HapMap, <a href="#24" class="mim-tip-reference" title="Galarneau, G., Palmer, C. D., Sankaran, V. G., Orkin, S. H., Hirschhorn, J. N., Lettre, G. <strong>Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation.</strong> Nature Genet. 42: 1049-1051, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21057501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21057501</a>] [<a href="https://doi.org/10.1038/ng.707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21057501">Galarneau et al. (2010)</a> selected and genotyped 95 SNPs, including 43 at the beta-globin locus, in 1,032 African Americans with sickle cell anemia. An XmnI polymorphism (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a>) in the proximal promoter of HBG2 marks the Senegal and Arab-Indian haplotypes and is associated with HbF levels in African Americans with sickle cell disease (<a href="#37" class="mim-tip-reference" title="Lettre, G., Sankaran, V. G., Bezerra, M. A. C., Araujo, A. S., Uda, M., Sanna, S., Cao, A., Schlessinger, D., Costa, F. F., Hirschhorn, J. N. <strong>Orkin, S. H.: DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease.</strong> Proc. Nat. Acad. Sci. 105: 11869-11874, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18667698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18667698</a>] [<a href="https://doi.org/10.1073/pnas.0804799105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18667698">Lettre et al., 2008</a>). <a href="#24" class="mim-tip-reference" title="Galarneau, G., Palmer, C. D., Sankaran, V. G., Orkin, S. H., Hirschhorn, J. N., Lettre, G. <strong>Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation.</strong> Nature Genet. 42: 1049-1051, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21057501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21057501</a>] [<a href="https://doi.org/10.1038/ng.707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21057501">Galarneau et al. (2010)</a> replicated the association between <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a> and HbF levels (p = 3.7 x 10(-7)). However, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs10128556;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs10128556</a>, a T/C SNP located downstream of HBG1, was more strongly associated with HbF levels than <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a> by 2 orders of magnitude (p = 1.3 x 10(-9)). When conditioned on <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs10128556;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs10128556</a>, the HbF association result for <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a> was not significant, indicating that <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a> is not a causal variant for HbF levels in African Americans with sickle cell anemia. The results of a haplotype analysis of the 43 SNPs in the beta-globin locus using <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs10128556;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs10128556</a> as a covariate were not significant (p = 0.40), indicating that <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs10128556;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs10128556</a> or a marker in linkage disequilibrium with it is the principal HbF-influencing variant at the beta-globin locus in African Americans with sickle cell anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18667698+21057501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To identify potential cis-variants responsible for switching from fetal to adult hemoglobin, <a href="#11" class="mim-tip-reference" title="Chen, D., Zuo, Y., Zhang, X., Ye, Y., Bao, X., Huang, H., Tepakhan, W., Wang, L., Ju, J., Chen, G., Zheng, M., Liu, D., and 11 others. <strong>A genetic variant ameliorates beta-thalassemia severity by epigenetic-mediated elevation of human fetal hemoglobin expression.</strong> Am. J. Hum. Genet. 101: 130-138, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28669403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28669403</a>] [<a href="https://doi.org/10.1016/j.ajhg.2017.05.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28669403">Chen et al. (2017)</a> systematically investigated an 80-kb region spanning the beta-globin cluster by deep sequencing in 1,142 Chinese beta-thalassemia patients and identified 31 fetal hemoglobin (HbF)-associated haplotypes of 28 regulatory SNPs selected as tag SNPs in 7 linkage disequilibrium blocks. They identified <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs368698783;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs368698783</a> (<a href="/entry/142200#0038">142200.0038</a>) in the proximal promoter of HBG1 to be a significant predictor for beta-thalassemia clinical severity by epigenetic-mediated variant-dependent HbF elevation. The variant <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs368698783;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs368698783</a>A was identified as an ameliorating allele (p = 3 x 10(-14), hazard ratio 0.552, 95% confidence interval 0.473-0.643) after known mutations in KLF1 (<a href="/entry/600599">600599</a>) and HBB (<a href="/entry/141900">141900</a>). The GA and AA genotypes exhibited a significantly elevated level of HbF compared with the GG genotype in each of 3 cohorts from China, and the AA genotype exhibited significantly elevated HbF levels compared with GA in thalassemia and HbEE individuals as well as in 2 unrelated Chinese families with beta-thalassemia intermedia. The minor allele (A) of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs368698783;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs368698783</a> triggered the attenuation of LYAR (<a href="/entry/617684">617684</a>) and 2 repressive epigenetic regulators, DNMT3A (<a href="/entry/602769">602769</a>) and PRMT5 (<a href="/entry/604045">604045</a>), from the HBG promoters, mediating allele-based gamma-globin elevation by facilitating demethylation of HBG core promoter CpG sites in erythroid progenitor cells from beta-thalassemia patients. This regulatory SNP accounted for 41.6% of beta-hemoglobinopathy individuals as an ameliorating factor in a total of 2,738 individuals from southern China and Thailand. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28669403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Boyer, S. H., Dover, G. J. <strong>Linkage but nonidentity between the beta-globin locus and the regulator FCP locus governing F-cell production. (Abstract)</strong> Cytogenet. Cell Genet. 32: 255 only, 1982."None>Boyer and Dover (1982)</a> calculated a frequency of about 0.35 for the gene responsible for increased F-cell levels in African Americans.</p>
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<p>HPFH has been characterized by quantifications of HbF fractions and analysis of globin chains. The types of gamma chains, gamma-A or gamma-G, synthesized in HPFH carriers allowed the distinction of mutants with expression of one or both gamma chains, as well as variable expression of the beta and delta genes in cis. For example, 'gamma-G, delta, beta-positive HPFH' or 'gamma-A, gamma-G, delta, beta-negative HPFH' (<a href="#22" class="mim-tip-reference" title="Farquhar, M., Gelinas, R., Tatsis, B., Murray, J., Yagi, M., Mueller, R., Stamatoyannopoulos, G. <strong>Restriction endonuclease mapping of gamma-delta-beta-globin region in G-gamma-beta(+) HPFH and a Chinese A-gamma HPFH variant.</strong> Am. J. Hum. Genet. 35: 611-620, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6192712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6192712</a>]" pmid="6192712">Farquhar et al., 1983</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6192712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a case of a nondeletion form of Sicilian beta-0 hereditary persistence of fetal hemoglobin, <a href="#49" class="mim-tip-reference" title="Ragusa, A., Lombardo, M., Bouhassira, E., Beldjord, C., Lombardo, T., Nagel, R. L., Labie, D., Krishnamoorthy, R. <strong>Nucleotide variations in the 3-prime A-gamma enhancer region are linked to beta-gene cluster haplotypes and are unrelated to fetal hemoglobin expression.</strong> Am. J. Hum. Genet. 45: 106-111, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2472742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2472742</a>]" pmid="2472742">Ragusa et al. (1989)</a> found 3 nucleotide variations in the putative enhancer 3-prime to the A-gamma gene, identical to those observed in a case of Seattle HPFH (<a href="#27" class="mim-tip-reference" title="Gelinas, R., Rixon, M., Magis, W., Stamatoyannopoulos, G. <strong>Gamma gene promoter and enhancer structure in Seattle variant of hereditary persistence of fetal hemoglobin.</strong> Blood 71: 1108-1112, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2451548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2451548</a>]" pmid="2451548">Gelinas et al., 1988</a>). They concluded, however, that these variations were not responsible for the increased fetal hemoglobin expression since they were found in another patient homozygous for the same haplotype who did not have excessive fetal hemoglobin production. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2451548+2472742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Altay1977" class="mim-tip-reference" title="Altay, C., Huisman, T. H. J., Schroeder, W. A. <strong>Another form of the hereditary persistence of fetal hemoglobin (the Atlanta type)?</strong> Hemoglobin 1: 125-133, 1977.">Altay et al. (1977)</a>; <a href="#Bethlenfalvay1975" class="mim-tip-reference" title="Bethlenfalvay, N. C., Motulsky, A. G., Ringelhann, B., Lehmann, H., Humbert, J. R., Konotey-Ahulu, F. I. D. <strong>Hereditary persistence of fetal hemoglobin, beta thalassemia, and the hemoglobin delta-beta locus: further family data and genetic interpretations.</strong> Am. J. Hum. Genet. 27: 140-154, 1975.">Bethlenfalvay et al. (1975)</a>; <a href="#Boyer1977" class="mim-tip-reference" title="Boyer, S. H., Margolet, L., Boyer, M. L., Huisman, T. H. J., Schroeder, W. A., Wood, W. G., Weatherall, D. J., Clegg, J. B., Cartner, R. <strong>Inheritance of F cell frequency in heterocellular hereditary persistence of fetal hemoglobin: an example of allelic exclusion.</strong> Am. J. Hum. Genet. 29: 256-271, 1977.">Boyer et al.
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(1977)</a>; <a href="#Dover1981" class="mim-tip-reference" title="Dover, G. J., Boyer, S. H. <strong>The cellular distribution of fetal hemoglobin: normal adults and hemoglobinopathies.</strong> Texas Rep. Biol. Med. 40: 43-54, 1981.">Dover and Boyer (1981)</a>; <a href="#Gelinas1985" class="mim-tip-reference" title="Gelinas, R., Endlich, B., Pfeiffer, C., Yagi, M., Stamatoyannopoulos, G. <strong>G to A substitution in the distal CCAAT box of the A-gamma-globin gene in Greek hereditary persistence of fetal hemoglobin.</strong> Nature 313: 323-324, 1985.">Gelinas et al. (1985)</a>; <a href="#Huisman1975" class="mim-tip-reference" title="Huisman, T. H. J., Miller, A., Schroeder, W. A. <strong>A G-gamma type of the hereditary persistence of fetal hemoglobin with beta chain production in cis.</strong> Am. J. Hum. Genet. 27: 765-777, 1975.">Huisman et al.
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(1975)</a>; <a href="#Huisman1970" class="mim-tip-reference" title="Huisman, T. H. J., Schroeder, W. A., Stamatoyannopoulos, G., Bouver, N., Shelton, J. R., Shelton, J. B., Apell, G. <strong>Nature of fetal hemoglobin in the Greek type of hereditary persistence of fetal hemoglobin with and without concurrent beta-thalassemia.</strong> J. Clin. Invest. 49: 1035-1040, 1970.">Huisman et al. (1970)</a>; <a href="#Huisman1971" class="mim-tip-reference" title="Huisman, T. H. J., Schroeder, W. A., Charache, S., Bethlenfalvay, N. C., Bouver, N., Shelton, J. R., Shelton, J. B., Apell, G. <strong>Hereditary persistence of fetal hemoglobin: heterogeneity of fetal hemoglobin in homozygotes and in conjunction with beta-thalassemia.</strong> New Eng. J. Med. 285: 711-716, 1971.">Huisman et al. (1971)</a>; <a href="#Huisman1970" class="mim-tip-reference" title="Huisman, T. H. J., Schroeder, W. A., Stamatoyannopoulos, G., Bouver, N., Shelton, J. R., Shelton, J. B., Apell, G. <strong>Nature of fetal hemoglobin in the Greek type of hereditary persistence of fetal hemoglobin with and without concurrent beta-thalassemia.</strong> J. Clin. Invest. 49: 1035-1040, 1970.">Huisman et al.
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(1970)</a>; <a href="#Jagadeeswaran1982" class="mim-tip-reference" title="Jagadeeswaran, P., Tuan, D., Forget, B. G., Weissman, S. M. <strong>A gene deletion ending at the midpoint of a repetitive DNA sequence in one form of hereditary persistence of fetal haemoglobin.</strong> Nature 296: 469-470, 1982.">Jagadeeswaran et al. (1982)</a>; <a href="#Marti1963" class="mim-tip-reference" title="Marti, H. R. <strong>Normale und abnormale menschliche Haemoglobine.</strong> Berlin: Springer (pub.) 1963. P. 81.">Marti (1963)</a>; <a href="#Mason1982" class="mim-tip-reference" title="Mason, K. P., Grandison, Y., Hayes, R. J., Serjeant, B. E., Serjeant, G. R., Vaidya, S., Wood, W. G. <strong>Post-natal decline of fetal haemoglobin in homozygous sickle cell disease: relationship to parental Hb F levels.</strong> Brit. J. Haemat. 52: 455-463, 1982.">Mason et al.
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(1982)</a>; <a href="#Milner1984" class="mim-tip-reference" title="Milner, P. F., Leibfarth, J. D., Ford, J., Barton, B. P., Grenett, H. E., Garver, F. A. <strong>Increased HbF in sickle cell anemia is determined by a factor linked to the beta(S) gene from one parent.</strong> Blood 63: 64-72, 1984.">Milner et al. (1984)</a>; <a href="#Siegel1970" class="mim-tip-reference" title="Siegel, W., Cox, R., Schroeder, W., Huisman, T. H. J., Penner, O., Rowley, P. T. <strong>An adult homozygous for persistent fetal hemoglobin.</strong> Ann. Intern. Med. 72: 533-536, 1970.">Siegel et al. (1970)</a>; <a href="#Tuan1980" class="mim-tip-reference" title="Tuan, D., Murnane, M. J., deRiel, J. K., Forget, B. G. <strong>Heterogeneity in the molecular basis of hereditary persistence of fetal haemoglobin.</strong> Nature 285: 335-337, 1980.">Tuan et al.
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(1980)</a>; <a href="#Wheeler1961" class="mim-tip-reference" title="Wheeler, J. T., Krevans, J. R. <strong>The homozygous state of persistent fetal hemoglobin and interaction of persistent fetal hemoglobin with thalassemia.</strong> Bull. Johns Hopkins Hosp. 109: 217-233, 1961.">Wheeler and Krevans (1961)</a>; <a href="#Wilson1980" class="mim-tip-reference" title="Wilson, L. B., Huisman, T. H. J., Wilson, J. T. <strong>Gene structure in hereditary persistence of fetal hemoglobin individuals.</strong> Hemoglobin 4: 509-518, 1980.">Wilson et al. (1980)</a>; <a href="#Wood1979" class="mim-tip-reference" title="Wood, W. G., Clegg, J. B., Weatherall, D. J. <strong>Hereditary persistence of fetal haemoglobin (HPFH) and delta-beta thalassemia.</strong> Brit. J. Haemat. 43: 509-520, 1979.">Wood et al.
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(1979)</a>; <a href="#Wood1977" class="mim-tip-reference" title="Wood, W. G., Weatherall, D. J., Clegg, J. B., Hamblin, T. J., Edwards, J. H., Barlow, A. M. <strong>Heterocellular hereditary persistence of fetal haemoglobin (heterocellular HPFH) and its interaction with beta-thalassemia.</strong> Brit. J. Haemat. 36: 461-473, 1977.">Wood et al. (1977)</a>
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Altay, C., Huisman, T. H. J., Schroeder, W. A.
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<strong>Another form of the hereditary persistence of fetal hemoglobin (the Atlanta type)?</strong>
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Hemoglobin 1: 125-133, 1977.
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Balsley, J. F., Rappaport, E., Schwartz, E., Surrey, S.
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<strong>The gamma-delta-beta-globin gene region in G-gamma-beta(+)-hereditary persistence of fetal hemoglobin.</strong>
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Blood 59: 828-831, 1982.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6174163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6174163</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6174163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bernards, R., Flavell, R. A.
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<strong>Physical mapping of the globin gene deletion in hereditary persistence of foetal haemoglobin (HPFH).</strong>
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Nucleic Acids Res. 8: 1521-1534, 1980.
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[<a href="https://doi.org/10.1093/nar/8.7.1521" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/mcb.6.9.3278-3282.1986" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.81.15.4894" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00286590" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4437631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4437631</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4437631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/252735a0" target="_blank">Full Text</a>]
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<strong>A case of hereditary persistence of fetal hemoglobin caused by a gene not linked to the beta-globin cluster.</strong>
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[<a href="https://doi.org/10.1007/BF00273993" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1365-2141.1982.tb03915.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198701293160504" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.1380020305" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.6186021" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.79.7.2347" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1365-2141.1982.tb01934.x" target="_blank">Full Text</a>]
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Tuan, D., Murnane, M. J., deRiel, J. K., Forget, B. G.
|
|
<strong>Heterogeneity in the molecular basis of hereditary persistence of fetal haemoglobin.</strong>
|
|
Nature 285: 335-337, 1980.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6154897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6154897</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6154897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
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|
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[<a href="https://doi.org/10.1038/285335a0" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
|
|
<a id="59" class="mim-anchor"></a>
|
|
<a id="Wasi1968" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wasi, P., Pootrakul, S. N., Na-Nakorn, S.
|
|
<strong>Hereditary persistence of foetal haemoglobin in a Thai family: the first instance in the Mongol race and in association with haemoglobin E.</strong>
|
|
Brit. J. Haemat. 14: 501-506, 1968.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5726236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5726236</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5726236" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2141.1968.tb07001.x" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="60" class="mim-anchor"></a>
|
|
<a id="Weatherall1975" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Weatherall, D. J., Cartner, R., Clegg, J. B., Wood, W. G., Macrae, I. A., Mackenzie, A.
|
|
<strong>A form of hereditary persistence of fetal haemoglobin characterized by uneven cellular distribution of haemoglobin F and the production of haemoglobins A and A2 in homozygotes.</strong>
|
|
Brit. J. Haemat. 29: 205-220, 1975.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/811241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">811241</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=811241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2141.1975.tb01815.x" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="61" class="mim-anchor"></a>
|
|
<a id="Wheeler1961" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wheeler, J. T., Krevans, J. R.
|
|
<strong>The homozygous state of persistent fetal hemoglobin and interaction of persistent fetal hemoglobin with thalassemia.</strong>
|
|
Bull. Johns Hopkins Hosp. 109: 217-233, 1961.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14006447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14006447</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14006447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="62" class="mim-anchor"></a>
|
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<a id="Wilson1980" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wilson, L. B., Huisman, T. H. J., Wilson, J. T.
|
|
<strong>Gene structure in hereditary persistence of fetal hemoglobin individuals.</strong>
|
|
Hemoglobin 4: 509-518, 1980.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6158504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6158504</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6158504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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[<a href="https://doi.org/10.3109/03630268008996231" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="63" class="mim-anchor"></a>
|
|
<a id="Wood1979" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wood, W. G., Clegg, J. B., Weatherall, D. J.
|
|
<strong>Hereditary persistence of fetal haemoglobin (HPFH) and delta-beta thalassemia.</strong>
|
|
Brit. J. Haemat. 43: 509-520, 1979.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/93487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">93487</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=93487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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[<a href="https://doi.org/10.1111/j.1365-2141.1979.tb03784.x" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
|
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<a id="64" class="mim-anchor"></a>
|
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<a id="Wood1977" class="mim-anchor"></a>
|
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<div class="">
|
|
<p class="mim-text-font">
|
|
Wood, W. G., Weatherall, D. J., Clegg, J. B., Hamblin, T. J., Edwards, J. H., Barlow, A. M.
|
|
<strong>Heterocellular hereditary persistence of fetal haemoglobin (heterocellular HPFH) and its interaction with beta-thalassemia.</strong>
|
|
Brit. J. Haemat. 36: 461-473, 1977.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/889715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">889715</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=889715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
|
[<a href="https://doi.org/10.1111/j.1365-2141.1977.tb00986.x" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
|
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<a id="65" class="mim-anchor"></a>
|
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<a id="Wood1976" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wood, W. G., Weatherall, D. J., Clegg, J. B.
|
|
<strong>Interaction of heterocellular hereditary persistence of foetal haemoglobin with beta-thalassaemia and sickle cell anaemia.</strong>
|
|
Nature 264: 247-249, 1976.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1004547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1004547</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1004547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
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|
|
[<a href="https://doi.org/10.1038/264247a0" target="_blank">Full Text</a>]
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</p>
|
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</div>
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</li>
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<li>
|
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<a id="66" class="mim-anchor"></a>
|
|
<a id="Zago1979" class="mim-anchor"></a>
|
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<div class="">
|
|
<p class="mim-text-font">
|
|
Zago, M. A., Wood, W. G., Clegg, J. B., Weatherall, D. J., O'Sullivan, M., Gunson, H.
|
|
<strong>Genetic control of F cells in human adults.</strong>
|
|
Blood 53: 977-986, 1979.
|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/373818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">373818</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=373818" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="mim-text-font">
|
|
<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
|
|
</span>
|
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Ada Hamosh - updated : 03/24/2021
|
|
</span>
|
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</div>
|
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</div>
|
|
<div class="row collapse" id="mimCollapseContributors">
|
|
<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Ada Hamosh - updated : 9/9/2014<br>Ada Hamosh - updated : 7/7/2011<br>Cassandra L. Kniffin - reorganized : 6/4/2009<br>Cassandra L. Kniffin - updated : 6/3/2009<br>Natalie E. Krasikov - updated : 3/26/2004
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</span>
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</div>
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</div>
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</div>
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<div>
|
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<a id="creationDate" class="mim-anchor"></a>
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Victor A. McKusick : 2/3/1990
|
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</span>
|
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</div>
|
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</div>
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</div>
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<div>
|
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
|
<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
|
</span>
|
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
alopez : 03/24/2021
|
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</span>
|
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</div>
|
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</div>
|
|
<div class="row collapse" id="mimCollapseEditHistory">
|
|
<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
ckniffin : 08/29/2016<br>ckniffin : 02/15/2016<br>alopez : 9/9/2014<br>alopez : 10/3/2012<br>alopez : 3/13/2012<br>alopez : 7/15/2011<br>terry : 7/7/2011<br>carol : 5/18/2011<br>wwang : 9/23/2010<br>ckniffin : 9/20/2010<br>terry : 4/30/2010<br>carol : 6/17/2009<br>carol : 6/4/2009<br>ckniffin : 6/3/2009<br>alopez : 10/23/2007<br>carol : 3/26/2004<br>carol : 3/26/2004<br>terry : 4/30/1999<br>mimadm : 9/24/1994<br>terry : 5/9/1994<br>warfield : 4/8/1994<br>carol : 8/12/1993<br>carol : 11/20/1992<br>supermim : 3/16/1992
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
<strong>#</strong> 141749
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
FETAL HEMOGLOBIN QUANTITATIVE TRAIT LOCUS 1; HBFQTL1
|
|
|
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</span>
|
|
</h3>
|
|
</div>
|
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<div>
|
|
<br />
|
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</div>
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<div>
|
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<div >
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
HEMOGLOBIN F, HEREDITARY PERSISTENCE OF; HPFH<br />
|
|
HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN, HB GENE CLUSTER-RELATED
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
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<div>
|
|
<br />
|
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</div>
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<div>
|
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<div>
|
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<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
DELTA-BETA THALASSEMIA, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
|
|
|
|
<strong>ORPHA:</strong> 231237, 251380, 46532;
|
|
|
|
|
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|
|
</span>
|
|
</p>
|
|
</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
11p15.4
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Delta-beta thalassemia
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
141749
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
HBB
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
141900
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
11p15.4
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hereditary persistence of fetal hemoglobin
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
141749
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
HBB
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
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141900
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<span class="mim-font">
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11p15.4
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</td>
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<td>
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<span class="mim-font">
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Fetal hemoglobin quantitative trait locus 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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141749
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<td>
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<span class="mim-font">
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HBG1
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</span>
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</td>
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<td>
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<span class="mim-font">
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142200
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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11p15.4
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</span>
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</td>
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<td>
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<span class="mim-font">
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Fetal hemoglobin quantitative trait locus 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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141749
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<td>
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<span class="mim-font">
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HBG2
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</span>
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</td>
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<td>
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<span class="mim-font">
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142250
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because hereditary persistence of fetal hemoglobin (HPFH) can result from deletions within or encompassing the beta-globin gene cluster (see HBB, 141900) on chromosome 11p15, including deletions that also encompass the delta-globin gene (142000), or from point mutations in the promoter regions of either the HBG1 (142200) or the HBG2 (142250) gene.</p><p>Other fetal hemoglobin quantitative trait loci (QTL) include HBFQTL2 (142470) on chromosome 6q23, HBFQTL3 (305435) on chromosome Xp22.2, and HBFQTL5 (142335) on chromosome 2p15, and HBFQTL6 (613566), caused by mutation in the KLF1 gene (600599) on chromosome 19p13. A QTL on chromosome 8q (HBFQTL4; 606789) is thought to interact with the common XmnI-G-gamma polymorphism in HBG2 (142250.0028) to influence the production of HbF.</p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Classic hereditary persistence of fetal hemoglobin (HPFH) is characterized by a substantial elevation of fetal hemoglobin (HbF) in adult red blood cells. There are no other phenotypic or hematologic manifestations. Expression of the HBG1 and HBG2 genes, which encode the gamma isoforms of HbF, is normally suppressed shortly before birth and replaced by expression of the beta- (HBB; 141900) or delta- (HBD; 142000) chains, which form adult hemoglobin. Adults normally have less than 1% HbF, whereas heterozygotes for HPFH have 5 to 30% HbF. HPFH heterozygotes have essentially normal red cell indices and a rather homogeneous distribution of HbF among red cells, termed 'pancellular.' Homozygotes for HPFH can express HbF in up to 100% of red blood cells (Thein and Craig, 1998). </p><p>Delta-beta thalassemia is a hemoglobin disorder characterized by decreased or absent synthesis of the delta- and beta-globin chains with a compensatory increase in expression of fetal gamma-chain synthesis from the affected chromosome. Individuals with delta-beta thalassemia have hypochromic, microcytic anemia and increased HbF, which may mitigate the anemia depending on the level of HbF. Delta-beta thalassemia and some forms of HPFH result from deletions within the beta-globin gene cluster on chromosome 11p15; this has been referred to as 'deletional' HPFH. HPFH can also result from point mutations in the promoter regions of the gamma globulin genes HBG1 and HBG2; this has been referred to as 'non-deletional' HPFH (Ottolenghi et al., 1982; Forget, 1998). </p><p>Forget (1998) noted that HPFH and delta-beta thalassemia are not clearly distinct disorders, but rather show partially overlapping features that may defy classification. Higher expression of HbF is often termed 'pancellular,' whereas lower expression of HbF is often termed 'heterocellular,' although these represent a spectrum. </p><p>Approximately 10% of the population has HPFH manifest as modest elevations of HbF (1 to 4%) present in a subset of red cells (about 4.5%) termed F cells. This is also sometimes referred to as 'heterocellular' HPFH, and is considered to be a multifactorial trait influenced by multiple genetic loci (Thein and Craig, 1998). </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Conley et al. (1963) reported hereditary persistence of fetal hemoglobin in 79 individuals from 15 African American families. Some individuals had only fetal hemoglobin with glycine-136 (HBG2), whereas others had both glycine-136 and alanine-136 (HBG1) forms of fetal hemoglobin. This trait was thereafter described in Greeks and sporadically in other ethnic groups, e.g., Thais (see bibliography of Wasi et al., 1968). Affected Greeks studied by Wasi et al. (1968) had only fetal hemoglobin of the alanine-136 type (HBG1). The differences were explained on the basis of various deletions involving a region containing several linked hemoglobin genes. </p><p>Schokker et al. (1966) reported an association between beta-thalassemia (see 141900) and a high fetal hemoglobin determinant in a pedigree of Dutch origin. </p><p>Weatherall et al. (1975) reported a British family in which 13 members had elevated levels of HbF that segregated into 2 groups with mean values of 19.8% and 8.9%, respectively. Genetic data indicated that the individuals in the former group were probably homozygous, and those in the latter group heterozygous, for the gene causing persistent HbF production. Biochemical studies showed that most of the HbF contained gamma-A (HBG1), with a small (10%) amount of the gamma-G (HBG2) in both homozygotes and heterozygotes. Weatherall et al. (1975), who referred to this entity as the 'British' type of HPFH, noted that the condition differed from previously described forms of HPFH by virtue of the heterogeneous distribution of the HbF and the presence of beta and delta-chain synthesis in homozygotes. In the family reported by Weatherall et al. (1975), Tate et al. (1986) identified a mutation in the promoter of the HBG1 gene (142200.0028). This was referred to as a non-deletional form of HPFH due to variation at the beta-globin gene cluster on 11p15. Homozygotes were clinically and hematologically normal except for increased HbF, ranging from 18 to 21%. Heterozygotes had HbF of 3.5 to 10%. </p><p>Marinucci et al. (1981) observed a family in southern Italy in which beta-thalassemia was inherited over 3 generations together with a high HbF level (8-12%) and an increased number of F cells. Two individuals who were homozygous for beta-thalassemia had a mild phenotype with hemoglobin consisting mainly of HbF in almost all red cells (pancellular HPFH). Marinucci et al. (1981) noted the considerable clinical benefit of the coexistence of HPFH determinants capable of increasing the size of the F-cell population in patients with homozygous thalassemia. </p><p>In a large Australian kindred with nondeletional heterocellular HPFH, Donald et al. (1988) found that fetal hemoglobin was increased to values between 1.8 and 7.9% in 13 members. HbF was composed predominantly of gamma-A chains, and the phenotype was closely linked to the beta-globin gene cluster. </p><p>Bhardwaj et al. (2003) described a black female who was identified by newborn screening as having sickle cell disease (603903) with a carrier father and a mother without sickle trait. At 11 months, the child had microcytosis and borderline anemia with a high hemoglobin F (45%); the mother was found to have an elevated HbF (32.1%) consistent with being a carrier of HPFH. Subsequent molecular analysis with a specialized gap-PCR technique determined that both mother and daughter were heterozygous for a deletion in the HBB gene cluster. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Among several families with either sickle cell anemia or beta-thalassemia who also showed segregation of HPFH, Wood et al. (1976) found close linkage between the HPFH gene and the beta-globin gene on chromosome 11p15. The findings suggested that the HPFH locus in these families was identical to or closely related to the regulatory region for gamma-globin synthesis. The frequency of F cells was particularly high among those patients with beta-thalassemia and sickle cell anemia, consistent with preferential survival of F cells in bone marrow and peripheral blood. </p><p>Marinucci et al. (1981) found linkage to the beta-globin locus on chromosome 11p15 in an Italian family with beta-thalassemia and HPFH. </p><p>Dover et al. (1981) amassed 3 lines of evidence that a locus regulating generation of F cells was linked to the gamma-delta-beta complex. (1) The percentages of F reticulocytes, while widely divergent in the population of homozygous sickle cell patients, showed a correlation coefficient of 0.94 in homozygous sib pairs (correlation coefficient for within-person percentages for successive samples = 0.95). (2) Mid-parental F-cell levels in healthy heterozygous parents, while well within the normal adult range of 0.2 to 10%, correlated well (r = 0.92) with the percentage of F reticulocytes produced by their homozygous offspring. (3) In the isolated population of eastern Saudi Arabia the coefficient of variation for F-reticulocyte level in homozygous sickle persons is about 25% (not greatly different from the average coefficient of 23% for variation between sibs). On the other hand, in the outcrossed American Black population, the coefficient of variation is 66%. The Saudi population may be homozygous at the F-cell regulatory locus. Specifically, the Saudi homozygous patients have a high F-cell percentage. If American Blacks with sickle cell anemia and elevated percentages of F reticulocytes likewise are homozygotes, the frequency of the gene can be calculated as 0.35. There is other evidence that HbF and F-cell levels are genetically determined in baboon (DeSimone et al., 1980) and in man (Zago et al., 1979), both anemic and nonanemic. </p><p>Boyer and Dover (1982) referred to 6 recombinants out of 39 opportunities for the linkage between F-cell production and the beta-globin locus. Boyer (1983) set the limits as 0.12 and 0.23 for the true recombination fraction for beta-globin and F-cell production.</p><p>Old et al. (1982) reported a family with HPFH in whom linkage analysis showed that the regulatory gene was close to or coincident with the beta-globin complex on chromosome 11. </p><p>Efremov et al. (1987) characterized the haplotype associated with heterocellular HPFH in Yugoslavia. The trait was associated with a chromosome 11p15 whose restriction enzyme haplotype was identical to that observed in African patients with sickle cell anemia. </p><p><strong><em>Heterogeneity</em></strong></p><p>
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Martinez and Colombo (1974) reported a family of African origin in which HPFH occurred at a level of 5% HbF. Linkage analysis showed that the gene did not behave as an allele of the beta-globin complex, although the possibility of a crossover between the gamma and the beta loci could not be excluded. The authors suggested that a diffusible factor might regulate gamma-chain synthesis. In a follow-up of the family reported by Martinez and Colombo (1974), Martinez et al. (1989) demonstrated that a determinant for HPFH segregated independently from the beta-globin gene cluster on 11p15. </p><p>Soummer et al. (1981) reported a family of Algerian origin in which a father and daughter, the proposita, had both beta-thalassemia and HPFH. HbF levels were 3.6% and 6.15%, respectively, and 16% and 19% F cells, respectively. Two additional daughters had only HPFH, with HbF levels of 1.83% and 2.69%, respectively, and 12% and 17% F cells, respectively. A daughter of the proposita had only beta-thalassemia, with HbF level of 1.4% and F cell number of 8%. Soummer et al. (1981) concluded that the father of the 3 daughters carried both genes for beta-thalassemia and HPFH, and transmitted both genes to the proposita, but only the HPFH gene to the other 2 daughters. The findings indicated that the 2 traits were unlinked, suggesting that a locus distinct from the beta-globin cluster is responsible for HPFH in this family. </p><p>Gianni et al. (1983) reported a Sardinian family in which a homozygous beta-thalassemic patient had an unusually mild form of the disease, which was ascribed to the coexistence of a gene causing heterocellular HPFH. Four family members had heterozygous beta-thalassemia with HPFH, and 5 had HPFH without beta-thalassemia. Linkage analysis using restriction polymorphisms indicated that HPFH in this family was not linked to the beta-globin gene cluster. Gianni et al. (1983) postulated that the putative gene may code for a diffusible substance acting, directly or indirectly, on gamma-globin gene expression. </p><p>Giampaolo et al. (1984) concluded that the HPFH mutation lies outside the gamma-delta-beta-globin DNA segment on 11p15. They observed independent segregation of HPFH and beta-thalassemia trait in 2 families, 1 of which showed no segregation of DNA polymorphisms within the segment when HPFH and beta-thalassemia segregated. By the coexistence of a polymorphic variant of the A-gamma chain (gamma-T), they were also able to demonstrate that the increased gamma-chain synthesis caused by the heterocellular HPFH determinant was directed by both chromosomes. This finding was in contrast to delta-beta thalassemia and pancellular HPFH, in which only the chromosomes carrying the mutation are affected via a cis effect. </p><p>The frequency of F cells in sickle cell disease can range from 2 to 50%. By studying 59 sib pairs with sickle cell anemia from Jamaica and the US, Boyer et al. (1984) provided evidence for at least 1 locus distinct from the beta-globin locus that is important for the regulation of F-cell production. </p><p>In a large family originating from northern India with heterocellular hereditary persistence of fetal hemoglobin, Sampietro and Thein (1991) demonstrated linkage to a polymorphic locus at 7q36, with a maximum lod score of 2.8 at a recombination fraction of 0.09 when their data were combined with those from a second pedigree of Italian origin. The propositus in the Indian family, despite being homozygous for beta-thalassemia and unable to produce any normal adult hemoglobin, had exceedingly mild clinical disease because of coinheritance of heterocellular HPFH.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Deletions in Chromosome 11p15</em></strong></p><p>
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Kan et al. (1975) identified deletions in the delta and beta HB loci in individuals with increased HbF. </p><p>Bernards and Flavell (1980) mapped the beta-like globin region in 2 HPFH patients: an African American who was homozygous for both G-gamma and A-gamma HbF expression, and a Greek who was heterozygous for A-gamma expression. In the first individual, there was a 24-kb deletion in the hemoglobin gene region that removed the gamma-, delta-, and beta-globin genes. The 5-prime break was situated about 9 kb upstream from the delta gene and the 3-prime break at least 7 kb past the beta gene. No deletion was detected in the heterozygous Greek. </p><p>Ottolenghi et al. (1982) studied 3 Mediterranean families with delta-beta thalassemia and 1 Southern Italian family with HPFH using restriction enzyme mapping and expression of gamma-A and gamma-G. There was molecular heterogeneity of deletion sizes at the beta-globin locus: Sicilian and Calabrian delta-beta thalassemia patients showed a deletion starting from the delta-globin intron and ending several kilobases 3-prime to the beta-globin gene. In a Spanish family with thalassemia, the deletion started 2 to 3 kb 5-prime to the delta-globin gene and extended well beyond the beta-globin gene. In addition, the Spanish family was found to have a variant of gamma-A fetal hemoglobin (142200.0001) which accounted for all of the gamma-A production in heterozygotes. These findings indicated that persistent production of gamma chains occurred in cis to the delta-beta gene deletion. Comparison with the deletions in HPFH suggested that deletion of a region about 3.5 kb 5-prime to the delta gene may be critical to the persistent expression of high levels of fetal hemoglobin. </p><p>Tuan et al. (1983) found that the deletion in 2 types of HPFH was more extensive than that in 2 types of delta-beta thalassemia. In the former, the 3-prime end of the deletion was about 52 and 57 kb from the 3-prime end of the beta-globin gene; in the latter, the 3-prime end of the deletion was about 5 and 10 kb from the 3-prime end of the beta-globin gene. Thus, the extent of the deletion and the nature of the DNA that is consequently brought into proximity with the gamma-globin genes may be more important in determining the phenotype in these disorders than the nature of the deleted DNA. </p><p>Collins et al. (1986) pointed out that the total length of the deleted DNA in 'type 1' and 'type 2' HPFH is nearly the same. Type 1 HPFH is the most common deletion form occurring in African Americans, and type 2 HPFH is the most common form occurring in Ghana. There is an Indian variety which has about half as long a deletion. Collins et al. (1986) speculated that the deleted segment may represent one loop of DNA between 2 attachment sites in the nuclear matrix.</p><p>In the Vietnamese G-gamma/A-gamma HPFH, Motum et al. (1993) demonstrated a novel 30-kb deletion located downstream from the beta-globin gene cluster. They compared the sites of the 5-prime and 3-prime breakpoints of this deletion with those for other HPFH-producing deletions downstream from the HBB gene. </p><p>De Andrade et al. (2006) used suppressive subtractive hybridization to analyze differential gene expression in a patient with HPFH type 2, the Sicilian form of delta-beta-thalassemia, and normal reticulocytes. HPFH type 2, the Ghanaian form, is caused by a 100-kb deletion at 11p15 that completely removes the delta- and beta-globin genes, with the 3-prime breakpoint near an enhancer element downstream of the beta-globin cluster. Several genes were altered in HPFH and delta-beta-thalassemia compared to normal reticulocytes, including SLC25A37 (610387) and ZHX2 (609185). HBA1 (141800) was also decreased in both conditions compared to normal. The findings suggested an integrated model, including both cis and trans elements, to explain increased Hb-gamma expression in these conditions. </p><p>Sankaran et al. (2011) identified 3 families with unusual patterns of hemoglobin expression, suggestive of deletions in the locus of the beta-globin gene. The authors used array comparative genomic hybridization to map the deletions and confirmed breakpoints by PCR assays and DNA sequencing. They found a novel delta-beta-0-thalassemia deletion and a rare HPFH deletion with identical downstream breakpoints. Comparison of the 2 deletions resulted in the identification of a small intergenic region required for gamma-globin gene (HBG1; 142200) silencing. Sankaran et al. (2011) mapped a Kurdish beta-0-thalassemia deletion, which retained the required intergenic region, deleted other surrounding sequences, and maintained fetal hemoglobin silencing. By comparing these deletions and other previously mapped deletions, Sankaran et al. (2011) elucidated a 3.5-kb intergenic region near the 5-prime end of the delta-globin gene that is necessary for gamma-globin silencing. They also found that BCL11A (606557) and its partners bind within this region in the chromatin of adult erythroid cells. </p><p><strong><em>Point Mutations In or Near the HBG1 and HBG2 Genes</em></strong></p><p>
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Balsley et al. (1982) reported an African American mother and child with gamma-G (HBG2), beta-globin-positive HPFH. The affected chromosome in these persons directed the production of G gamma-chains and beta-chains, but not gamma-A (HBG1) chains. DNA analysis with several restriction enzymes did not detect any deletions in the beta-globin gene cluster region. </p><p>Papayannopoulou et al. (1982) noted that the 'Greek' form of HPFH shows HbF predominantly of the gamma-A type. However, cell culture studies of Greek HPFH erythrocytes showed that both gamma genes could be expressed. Restriction endonuclease mapping indicated that the gamma-G, delta, and beta genes in cis to the Greek HPFH determinant were intact and there was no large deletion. This was in contrast to other forms of HPFH which had been associated with large deletions. Papayannopoulou et al. (1982) speculated that the genetic lesion may reside in regulatory sequences that control the level of gamma-A and gamma-G expression. Collins et al. (1985) determined that the Greek form of HPFH was due to a -117G-A SNP in the promoter region of the HBG1 gene (142200.0026). </p><p>Farquhar et al. (1983) performed restriction enzyme mapping of the beta-globin cluster in 2 forms of HPFH and could demonstrate no deletion or other abnormality. They suggested that if the DNA structure of the gamma-delta-beta region was indeed normal, these variants could be due to mutations of regulatory loci at sites outside this genomic region. </p><p>Fetal Hb levels are influenced by single-nucleotide polymorphisms in the promoter regions of the HBG1 and HBG2 genes, which affect gene expression. Single-base changes influencing hereditary persistence of HbF in the HBG2 gene include -202C-G (142250.0026) (Collins et al., 1984), -175T-C (142250.0027) (Huang et al., 1987), and -158C-T (rs7482144; 142250.0028) (Miller et al., 1987). Single base changes responsible for HPFH in the HBG1 gene include -117G-A (142200.0026) (Collins et al., 1985) and -196C-T (142200.0027) (Gelinas et al., 1986). Several findings indicate that these substitutions cause the HPFH phenotype: (1) only the mutated gene is affected; (2) the substitutions are the only nonpolymorphic deviations from the normal sequence over a large region; and (3) there is a strong correlation between the base substitution and HPFH (Carlson and Ross, 1986). </p><p>In a cohort of 1,275 African Americans with sickle cell disease, Lettre et al. (2008) found a significant association between HbF levels and SNP rs7482144 in the HBG2 gene (142250.0028) (p = 4 x 10(-7)), which explained 2.2% of the variation in HbF levels. The association with rs7482144 could not be tested in a Brazilian cohort because the variant was monomorphic in this population. </p><p>To fine map HbF association signals, Galarneau et al. (2010) resequenced 175.2 kb from the BCL11A (606557), HBS1L-MYB (612450-189990), and beta-globin loci (representing HBFQTL5 (142335), HBFQTL2 (142470), and HBFQTL1, respectively) in 190 individuals including the HapMap European CEU and Nigerian YRI founders and 70 African Americans with sickle cell anemia. The authors discovered 1,489 sequence variants, including 910 previously unreported variants. Using this information and data from HapMap, Galarneau et al. (2010) selected and genotyped 95 SNPs, including 43 at the beta-globin locus, in 1,032 African Americans with sickle cell anemia. An XmnI polymorphism (rs7482144) in the proximal promoter of HBG2 marks the Senegal and Arab-Indian haplotypes and is associated with HbF levels in African Americans with sickle cell disease (Lettre et al., 2008). Galarneau et al. (2010) replicated the association between rs7482144 and HbF levels (p = 3.7 x 10(-7)). However, rs10128556, a T/C SNP located downstream of HBG1, was more strongly associated with HbF levels than rs7482144 by 2 orders of magnitude (p = 1.3 x 10(-9)). When conditioned on rs10128556, the HbF association result for rs7482144 was not significant, indicating that rs7482144 is not a causal variant for HbF levels in African Americans with sickle cell anemia. The results of a haplotype analysis of the 43 SNPs in the beta-globin locus using rs10128556 as a covariate were not significant (p = 0.40), indicating that rs10128556 or a marker in linkage disequilibrium with it is the principal HbF-influencing variant at the beta-globin locus in African Americans with sickle cell anemia. </p><p>To identify potential cis-variants responsible for switching from fetal to adult hemoglobin, Chen et al. (2017) systematically investigated an 80-kb region spanning the beta-globin cluster by deep sequencing in 1,142 Chinese beta-thalassemia patients and identified 31 fetal hemoglobin (HbF)-associated haplotypes of 28 regulatory SNPs selected as tag SNPs in 7 linkage disequilibrium blocks. They identified rs368698783 (142200.0038) in the proximal promoter of HBG1 to be a significant predictor for beta-thalassemia clinical severity by epigenetic-mediated variant-dependent HbF elevation. The variant rs368698783A was identified as an ameliorating allele (p = 3 x 10(-14), hazard ratio 0.552, 95% confidence interval 0.473-0.643) after known mutations in KLF1 (600599) and HBB (141900). The GA and AA genotypes exhibited a significantly elevated level of HbF compared with the GG genotype in each of 3 cohorts from China, and the AA genotype exhibited significantly elevated HbF levels compared with GA in thalassemia and HbEE individuals as well as in 2 unrelated Chinese families with beta-thalassemia intermedia. The minor allele (A) of rs368698783 triggered the attenuation of LYAR (617684) and 2 repressive epigenetic regulators, DNMT3A (602769) and PRMT5 (604045), from the HBG promoters, mediating allele-based gamma-globin elevation by facilitating demethylation of HBG core promoter CpG sites in erythroid progenitor cells from beta-thalassemia patients. This regulatory SNP accounted for 41.6% of beta-hemoglobinopathy individuals as an ameliorating factor in a total of 2,738 individuals from southern China and Thailand. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Boyer and Dover (1982) calculated a frequency of about 0.35 for the gene responsible for increased F-cell levels in African Americans.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Nomenclature</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>HPFH has been characterized by quantifications of HbF fractions and analysis of globin chains. The types of gamma chains, gamma-A or gamma-G, synthesized in HPFH carriers allowed the distinction of mutants with expression of one or both gamma chains, as well as variable expression of the beta and delta genes in cis. For example, 'gamma-G, delta, beta-positive HPFH' or 'gamma-A, gamma-G, delta, beta-negative HPFH' (Farquhar et al., 1983). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p>In a case of a nondeletion form of Sicilian beta-0 hereditary persistence of fetal hemoglobin, Ragusa et al. (1989) found 3 nucleotide variations in the putative enhancer 3-prime to the A-gamma gene, identical to those observed in a case of Seattle HPFH (Gelinas et al., 1988). They concluded, however, that these variations were not responsible for the increased fetal hemoglobin expression since they were found in another patient homozygous for the same haplotype who did not have excessive fetal hemoglobin production. </p>
|
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Altay et al. (1977); Bethlenfalvay et al. (1975); Boyer et al.
|
|
(1977); Dover and Boyer (1981); Gelinas et al. (1985); Huisman et al.
|
|
(1975); Huisman et al. (1970); Huisman et al. (1971); Huisman et al.
|
|
(1970); Jagadeeswaran et al. (1982); Marti (1963); Mason et al.
|
|
(1982); Milner et al. (1984); Siegel et al. (1970); Tuan et al.
|
|
(1980); Wheeler and Krevans (1961); Wilson et al. (1980); Wood et al.
|
|
(1979); Wood et al. (1977)
|
|
</span>
|
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<div>
|
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<br />
|
|
</div>
|
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
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</span>
|
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</h4>
|
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Altay, C., Huisman, T. H. J., Schroeder, W. A.
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<strong>Another form of the hereditary persistence of fetal hemoglobin (the Atlanta type)?</strong>
|
|
Hemoglobin 1: 125-133, 1977.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Balsley, J. F., Rappaport, E., Schwartz, E., Surrey, S.
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<strong>The gamma-delta-beta-globin gene region in G-gamma-beta(+)-hereditary persistence of fetal hemoglobin.</strong>
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Blood 59: 828-831, 1982.
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Bernards, R., Flavell, R. A.
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<strong>Physical mapping of the globin gene deletion in hereditary persistence of foetal haemoglobin (HPFH).</strong>
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Nucleic Acids Res. 8: 1521-1534, 1980.
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[PubMed: 6159595]
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<p class="mim-text-font">
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Bethlenfalvay, N. C., Motulsky, A. G., Ringelhann, B., Lehmann, H., Humbert, J. R., Konotey-Ahulu, F. I. D.
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<strong>Hereditary persistence of fetal hemoglobin, beta thalassemia, and the hemoglobin delta-beta locus: further family data and genetic interpretations.</strong>
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Am. J. Hum. Genet. 27: 140-154, 1975.
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[PubMed: 1124762]
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Bhardwaj, U., Zhang, Y.-H., Jackson, D. S., Buchanan, G. R., Therrell, B. L., Jr., McCabe, L. L., McCabe, E. R. B.
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<strong>DNA diagnosis confirms hemoglobin deletion in newborn screen follow-up.</strong>
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J. Pediat. 142: 346-348, 2003.
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Boyer, S. H., Dover, G. J., Serjeant, G. R., Smith, K. D., Antonarakis, S. E., Embury, S. H., Margolet, L., Noyes, A. N., Boyer, M. L., Bias, W. B.
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<strong>Production of F cells in sickle cell anemia: regulation by a genetic locus or loci separate from the beta-globin gene cluster.</strong>
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Blood 64: 1053-1058, 1984.
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[PubMed: 6207872]
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<p class="mim-text-font">
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Boyer, S. H., Dover, G. J.
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<strong>Linkage but nonidentity between the beta-globin locus and the regulator FCP locus governing F-cell production. (Abstract)</strong>
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Cytogenet. Cell Genet. 32: 255 only, 1982.
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<p class="mim-text-font">
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Boyer, S. H., Margolet, L., Boyer, M. L., Huisman, T. H. J., Schroeder, W. A., Wood, W. G., Weatherall, D. J., Clegg, J. B., Cartner, R.
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<strong>Inheritance of F cell frequency in heterocellular hereditary persistence of fetal hemoglobin: an example of allelic exclusion.</strong>
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Am. J. Hum. Genet. 29: 256-271, 1977.
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[PubMed: 868872]
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</p>
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<p class="mim-text-font">
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Boyer, S. H.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 2/1983.
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</p>
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<p class="mim-text-font">
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Carlson, D. P., Ross, J.
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<strong>Point mutation associated with hereditary persistence of fetal hemoglobin decreases RNA polymerase III transcription upstream of the affected gamma-globin gene.</strong>
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Molec. Cell. Biol. 6: 3278-3282, 1986.
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[PubMed: 2431298]
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[Full Text: https://doi.org/10.1128/mcb.6.9.3278-3282.1986]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chen, D., Zuo, Y., Zhang, X., Ye, Y., Bao, X., Huang, H., Tepakhan, W., Wang, L., Ju, J., Chen, G., Zheng, M., Liu, D., and 11 others.
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<strong>A genetic variant ameliorates beta-thalassemia severity by epigenetic-mediated elevation of human fetal hemoglobin expression.</strong>
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Am. J. Hum. Genet. 101: 130-138, 2017.
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[PubMed: 28669403]
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[Full Text: https://doi.org/10.1016/j.ajhg.2017.05.012]
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</p>
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<li>
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<p class="mim-text-font">
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Collins, F. S., Iannuzzi, M. C., Cole, J. L.
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<strong>Pulsed field gel electrophoresis blotting demonstrates a deletion of at least 110 kilobases in hereditary persistence of fetal hemoglobin. (Abstract)</strong>
|
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Am. J. Hum. Genet. 39: A192 only, 1986.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Collins, F. S., Metherall, J. E., Yamakawa, M., Pan, J., Weissman, S. M., Forget, B. G.
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<strong>A point mutation in the A-gamma-globin gene promoter in Greek hereditary persistence of fetal haemoglobin.</strong>
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Nature 313: 325-326, 1985.
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[PubMed: 2578620]
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[Full Text: https://doi.org/10.1038/313325a0]
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<p class="mim-text-font">
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Collins, F. S., Stoeckert, C. J., Jr., Serjeant, G. R., Forget, B. G., Weissman, S. M.
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<strong>G-gamma-beta(+) hereditary persistence of fetal hemoglobin: cosmid cloning and identification of a specific mutation 5-prime to the G-gamma gene.</strong>
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Proc. Nat. Acad. Sci. 81: 4894-4898, 1984.
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[PubMed: 6205403]
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[Full Text: https://doi.org/10.1073/pnas.81.15.4894]
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Conley, C. L., Weatherall, D. J., Richardson, S. N., Shepard, M. K., Charache, S.
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<strong>Hereditary persistence of fetal hemoglobin: a study of 79 affected persons in 15 Negro families in Baltimore.</strong>
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Blood 21: 261-281, 1963.
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[PubMed: 14022587]
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<p class="mim-text-font">
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de Andrade, T. G., Peterson, K. R., Cunha, A. F., Moreira, L. S., Fattori, A., Saad, S. T. O., Costa, F. F.
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<strong>Identification of novel candidate genes for globin regulation in erythroid cells containing large deletions of the human beta-globin gene cluster.</strong>
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<p class="mim-text-font">
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DeSimone, J., Heller, P., Amsel, J., Usman, M.
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<strong>Magnitude of the fetal hemoglobin response to acute hemolytic anemia in baboons is controlled by genetic factors.</strong>
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J. Clin. Invest. 65: 224-226, 1980.
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[PubMed: 6765958]
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Donald, J. A., Lammi, A., Trent, R. J.
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<strong>Hemoglobin F production in heterocellular hereditary persistence of fetal hemoglobin and its linkage to the beta globin gene complex.</strong>
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Hum. Genet. 80: 69-74, 1988.
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[PubMed: 2458313]
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Dover, G. J., Boyer, S. H., Pembrey, M. E.
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<strong>F-cell production in sickle cell anemia: regulation by genes linked to the beta-hemoglobin locus.</strong>
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Science 211: 1441-1444, 1981.
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Dover, G. J., Boyer, S. H.
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<strong>The cellular distribution of fetal hemoglobin: normal adults and hemoglobinopathies.</strong>
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Texas Rep. Biol. Med. 40: 43-54, 1981.
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Efremov, G. D., Gjorgovski, I., Stojanovski, N., Diaz-Chico, J. C., Harano, T., Kutlar, F., Huisman, T. H. J.
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<strong>One haplotype is associated with the Swiss type of hereditary persistence of fetal hemoglobin in the Yugoslavian population.</strong>
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Hum. Genet. 77: 132-136, 1987.
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[PubMed: 2443439]
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[Full Text: https://doi.org/10.1007/BF00272379]
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<strong>Restriction endonuclease mapping of gamma-delta-beta-globin region in G-gamma-beta(+) HPFH and a Chinese A-gamma HPFH variant.</strong>
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[PubMed: 6192712]
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[PubMed: 9668525]
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</p>
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<li>
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<p class="mim-text-font">
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Galarneau, G., Palmer, C. D., Sankaran, V. G., Orkin, S. H., Hirschhorn, J. N., Lettre, G.
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<strong>Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation.</strong>
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Nature Genet. 42: 1049-1051, 2010.
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[PubMed: 21057501]
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</p>
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<li>
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<p class="mim-text-font">
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Gelinas, R., Bender, M., Lotshaw, C., Waber, P., Kazazian, H., Jr., Stamatoyannopoulos, G.
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<strong>Chinese A-gamma fetal hemoglobin: C to T substitution at position -196 of the A-gamma gene promoter.</strong>
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Blood 67: 1777-1779, 1986.
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[PubMed: 2423160]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gelinas, R., Endlich, B., Pfeiffer, C., Yagi, M., Stamatoyannopoulos, G.
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<strong>G to A substitution in the distal CCAAT box of the A-gamma-globin gene in Greek hereditary persistence of fetal hemoglobin.</strong>
|
|
Nature 313: 323-324, 1985.
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[PubMed: 2578619]
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[Full Text: https://doi.org/10.1038/313323a0]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Gelinas, R., Rixon, M., Magis, W., Stamatoyannopoulos, G.
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<strong>Gamma gene promoter and enhancer structure in Seattle variant of hereditary persistence of fetal hemoglobin.</strong>
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Blood 71: 1108-1112, 1988.
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[PubMed: 2451548]
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</p>
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<li>
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<p class="mim-text-font">
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Giampaolo, A., Mavilio, F., Sposi, N. M., Care, A., Massa, A., Cianetti, L., Petrini, M., Russo, R., Cappellini, M. D., Marinucci, M.
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<strong>Heterocellular hereditary persistence of fetal hemoglobin (HPFH). Molecular mechanisms of abnormal gamma-gene expression in association with beta-thalassemia and linkage relationship with the beta-globin gene cluster.</strong>
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Hum. Genet. 66: 151-156, 1984.
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[PubMed: 6201431]
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[Full Text: https://doi.org/10.1007/BF00286590]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gianni, A. M., Bregni, M., Cappellini, M. D., Giorelli, G., Taramelli, R., Giglioni, B., Comi, P., Ottolenghi, S.
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<strong>A gene controlling fetal hemoglobin expression in adults is not linked to the non-alpha globin cluster.</strong>
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|
EMBO J. 2: 921-925, 1983.
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[PubMed: 6196196]
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[Full Text: https://doi.org/10.1002/j.1460-2075.1983.tb01522.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Huang, H. J., Stoming, T. A., Harris, H. F., Kutlar, F., Huisman, T. H. J.
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<strong>The Greek A-gamma-beta+/HPFH observed in a large black family.</strong>
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Am. J. Hemat. 25: 401-408, 1987.
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[PubMed: 2441598]
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[Full Text: https://doi.org/10.1002/ajh.2830250406]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Huisman, T. H. J., Miller, A., Schroeder, W. A.
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|
<strong>A G-gamma type of the hereditary persistence of fetal hemoglobin with beta chain production in cis.</strong>
|
|
Am. J. Hum. Genet. 27: 765-777, 1975.
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[PubMed: 1200028]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Huisman, T. H. J., Schroeder, W. A., Adams, H. R., Shelton, J. R., Shelton, J. B., Apell, G.
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<strong>A possible subclass of the hereditary persistence of fetal hemoglobin.</strong>
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|
Blood 36: 1-9, 1970.
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[PubMed: 5421741]
|
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<span class="text-nowrap mim-text-font">
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Ada Hamosh - updated : 03/24/2021<br>Ada Hamosh - updated : 9/9/2014<br>Ada Hamosh - updated : 7/7/2011<br>Cassandra L. Kniffin - reorganized : 6/4/2009<br>Cassandra L. Kniffin - updated : 6/3/2009<br>Natalie E. Krasikov - updated : 3/26/2004
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Victor A. McKusick : 2/3/1990
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alopez : 03/24/2021<br>ckniffin : 08/29/2016<br>ckniffin : 02/15/2016<br>alopez : 9/9/2014<br>alopez : 10/3/2012<br>alopez : 3/13/2012<br>alopez : 7/15/2011<br>terry : 7/7/2011<br>carol : 5/18/2011<br>wwang : 9/23/2010<br>ckniffin : 9/20/2010<br>terry : 4/30/2010<br>carol : 6/17/2009<br>carol : 6/4/2009<br>ckniffin : 6/3/2009<br>alopez : 10/23/2007<br>carol : 3/26/2004<br>carol : 3/26/2004<br>terry : 4/30/1999<br>mimadm : 9/24/1994<br>terry : 5/9/1994<br>warfield : 4/8/1994<br>carol : 8/12/1993<br>carol : 11/20/1992<br>supermim : 3/16/1992
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