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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2024/01/11" /><meta name="citation_author" content="Natalie Deuitch" /><meta name="citation_author" content="Elizabeth Broadbridge" /><meta name="citation_author" content="Lea Cunningham" /><meta name="citation_author" content="Paul Liu" /><meta name="citation_pmid" content="33661592" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK568319/" /><meta name="citation_keywords" content="Familial Platelet Disorder / Acute Myeloid Leukemia (FPD/AML)" /><meta name="citation_keywords" content="RUNX1 Familial Platelet Disorder (FPD)" /><meta name="citation_keywords" content="Familial Platelet Disorder / Acute Myeloid Leukemia (FPD/AML)" /><meta name="citation_keywords" content="RUNX1 Familial Platelet Disorder (FPD)" /><meta name="citation_keywords" content="Runt-related transcription factor 1" /><meta name="citation_keywords" content="RUNX1" /><meta name="citation_keywords" content="RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Natalie Deuitch" /><meta name="DC.Contributor" content="Elizabeth Broadbridge" /><meta name="DC.Contributor" content="Lea Cunningham" /><meta name="DC.Contributor" content="Paul Liu" /><meta name="DC.Date" content="2024/01/11" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK568319/" /><meta name="description" content="RUNX1 familial platelet disorder with associated myeloid malignancies (RUNX1-FPDMM) is characterized by prolonged bleeding and/or easy bruising and an increased risk of developing a hematologic malignancy. RUNX1-FPDMM is characterized by thrombocytopenia with normal platelet size; bleeding is often greater than expected due to qualitative platelet dysfunction. Myeloid malignancies are the most common, including acute myelogenous leukemia and myelodysplastic syndrome. T- and B-cell acute lymphoblastic leukemias and lymphomas have also been reported, as well as skin manifestations (e.g., eczema, psoriasis)." /><meta name="og:title" content="RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies" /><meta name="og:type" content="book" /><meta name="og:description" content="RUNX1 familial platelet disorder with associated myeloid malignancies (RUNX1-FPDMM) is characterized by prolonged bleeding and/or easy bruising and an increased risk of developing a hematologic malignancy. RUNX1-FPDMM is characterized by thrombocytopenia with normal platelet size; bleeding is often greater than expected due to qualitative platelet dysfunction. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK568319_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK568319_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/rrm2b-mtddepl/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/rvcl/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK568319_"><span class="title" itemprop="name"><i>RUNX1</i> Familial Platelet Disorder with Associated Myeloid Malignancies</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Familial Platelet Disorder / Acute Myeloid Leukemia (FPD/AML), <i>RUNX1</i> Familial Platelet Disorder (FPD)</div><p class="contrib-group"><span itemprop="author">Natalie Deuitch</span>, MS, CGC, <span itemprop="author">Elizabeth Broadbridge</span>, BS, <span itemprop="author">Lea Cunningham</span>, MD, and <span itemprop="author">Paul Liu</span>, MD, PhD.</p><a data-jig="ncbitoggler" href="#__NBK568319_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK568319_ai__"><div class="contrib half_rhythm"><span itemprop="author">Natalie Deuitch</span>, MS, CGC<div class="affiliation small">National Human Genome Research Institute<br />National Institutes of Health<br />Bethesda, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin@hctiued.eilatan" class="oemail">vog.hin@hctiued.eilatan</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Elizabeth Broadbridge</span>, BS<div class="affiliation small">National Human Genome Research Institute<br />National Institutes of Health<br />Bethesda, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin@egdirbdaorb.lseil" class="oemail">vog.hin@egdirbdaorb.lseil</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Lea Cunningham</span>, MD<div class="affiliation small">National Cancer Institute<br />National Institutes of Health<br />Bethesda, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin@mahgninnuc.ael" class="oemail">vog.hin@mahgninnuc.ael</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Paul Liu</span>, MD, PhD<div class="affiliation small">National Human Genome Research Institute<br />National Institutes of Health<br />Bethesda, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin.liam@uilp" class="oemail">vog.hin.liam@uilp</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">March 4, 2021</span>; Last Revision: <span itemprop="dateModified">January 11, 2024</span>.</p><p><em>Estimated reading time: 22 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="runx1.Summary" itemprop="description"><h2 id="_runx1_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> platelet disorder with associated myeloid malignancies (<i>RUNX1</i>-FPDMM) is characterized by prolonged bleeding and/or easy bruising and an increased risk of developing a hematologic malignancy. <i>RUNX1</i>-FPDMM is characterized by thrombocytopenia with normal platelet size; bleeding is often greater than expected due to qualitative platelet dysfunction. Myeloid malignancies are the most common, including acute myelogenous leukemia and myelodysplastic syndrome. T- and B-cell acute lymphoblastic leukemias and lymphomas have also been reported, as well as skin manifestations (e.g., eczema, psoriasis).</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>RUNX1</i>-FPDMM is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with suggestive findings and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>RUNX1</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations</i>: Use of clotting promotors (e.g., desmopressin, epsilon aminocaproic acid, tranexamic acid) in instances of surgeries, injuries, or dental treatments; platelet transfusions may be used for severe bleeding or procedures with a high bleeding risk. Allogenic stem cell transplantation may be considered in individuals with early signs of malignancy and hematopoietic stem cell transplant may be used to treat myelodysplasia; however, recommendations regarding the indications and timing of stem cell transplant can vary. Emollients and topical steroids as needed for eczema; consider providing a medical letter for the school explaining easy bruising; consider use of a medical alert bracelet.</p><p><i>Surveillance</i>: Clinical examination for signs/symptoms of neoplasm (e.g., constitutional symptoms such as fatigue, unexplained fever, unexplained weight loss, shortness of breath) every six to 12 months. Complete blood count with differential every three to four months; bone marrow examination if constitutional symptoms and/or abnormalities on complete blood count are identified; skin exam as needed.</p><p><i>Agents/circumstances to avoid</i>: Medications that affect platelet function (e.g., NSAIDs and antiplatelet agents), activities with a high risk of trauma (e.g., high-risk contact sports), unnecessary radiation, and smoking.</p><p><i>Evaluation of relatives at risk</i>: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance for malignancy and more targeted medical management.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>RUNX1</i>-FPDMM is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. Most individuals diagnosed with <i>RUNX1</i>-FPDMM inherited the causative <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from a parent who may or may not have recognized manifestations of the disorder. If a parent of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. If the <i>RUNX1</i> pathogenic variant identified in the proband is not detected in parental DNA, the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> to sibs is slightly greater than that of the general population because of the possibility either of a false negative result in a parent (due to preferential loss of the <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> with the <i>RUNX1</i> pathogenic variant), or of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>. Once the <i>RUNX1</i> pathogenic variant has been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="runx1.Diagnosis"><h2 id="_runx1_Diagnosis_">Diagnosis</h2><div id="runx1.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> platelet disorder with associated myeloid malignancies (<i>RUNX1</i>-FPDMM) <b>should be suspected</b> in individuals with the following findings.</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Abnormal bruising or bleeding (90%)</div><ul><li class="half_rhythm"><div>Bruising without known trauma</div></li><li class="half_rhythm"><div>Excessive bleeding following surgery or trauma</div></li><li class="half_rhythm"><div>Bleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractions</div></li><li class="half_rhythm"><div>Obstetric and gynecologic manifestations may include menorrhagia, miscarriage, and bleeding before or after childbirth.</div></li><li class="half_rhythm"><div>20%-25% of individuals require platelet transfusions or medications to assist primary hemostasis such as antifibrinolytics (e.g., tranexamic acid, aminocaproic acid).</div></li></ul></li><li class="half_rhythm"><div>Hematologic malignancy (up to 50%)</div></li><li class="half_rhythm"><div>Eczema (up to 50% of families)</div></li></ul><p>
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<b>Family history</b>
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</p><ul><li class="half_rhythm"><div>History of hematologic malignancy (50%) and/or abnormal bleeding or bruising consistent with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> inheritance (e.g., affected males and females in multiple consecutive generations)</div></li><li class="half_rhythm"><div>Note: Absence of a known family history does not preclude the diagnosis.</div></li></ul><p>
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<b>Laboratory findings</b>
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</p><ul><li class="half_rhythm"><div>Mild-to-moderate thrombocytopenia (50-150 x 10<sup>9</sup>/L). Platelet counts can be in the normal range in some individuals (>150 x 10<sup>9</sup>/L). Severe thrombocytopenia is usually not observed except in those with acute myelogenous leukemia or myelodysplastic syndrome (MDS).</div></li><li class="half_rhythm"><div>Platelets are typically normal in size; however, individuals with both smaller and larger than normal mean platelet volume have been reported.</div></li><li class="half_rhythm"><div>Qualitative platelet defect</div><ul><li class="half_rhythm"><div>Prolonged bleeding time (not clinically performed in the current era)</div></li><li class="half_rhythm"><div>Abnormal platelet aggregation studies are seen in most individuals with absent or decreased response to arachidonic acid and collagen. Platelets from these individuals also exhibit absent or decreased second wave response to adenosine diphosphate and epinephrine, indicating decreased platelet degranulation.</div></li><li class="half_rhythm"><div>Platelet storage pool disorder seen on electron microscopy in about half of individuals (decrease or absence of alpha-granules or dense granules)</div></li></ul></li></ul><p>
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<b>Bone marrow histopathology</b>
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</p><ul><li class="half_rhythm"><div>Baseline morphologic abnormalities may include:</div><ul><li class="half_rhythm"><div>Hypo- or normocellular marrow for age (Marrow may become hypercellular or more hypocellular in individuals with hematologic malignancy or bone marrow failure.)</div></li><li class="half_rhythm"><div>Atypical (but not frankly dysplastic) megakaryocytes (small in size with scant cytoplasm, and hypo-lobated nuclei with asynchronous nuclear cytoplasmic maturation)</div></li><li class="half_rhythm"><div>Eosinophilia</div></li></ul></li><li class="half_rhythm"><div>Pathologists who are not familiar with <i>RUNX1</i>-associated megakaryocytic atypia may misdiagnose megakaryocytic atypia as a dysplastic morphologic change (MDS should be considered if additional cytopenias, frank morphologic dysplasia, or expanded myeloblast populations are present).</div></li></ul></div><div id="runx1.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>RUNX1</i>-FPDMM <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with <a href="#runx1.Suggestive_Findings">suggestive findings</a> and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant in <i>RUNX1</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (<a href="/books/NBK568319/table/runx1.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobrunx1Tmoleculargenetictestingusedi">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "<a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bk_pop" href="#runx1.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>RUNX1</i> variant of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> does not establish or rule out the diagnosis. (3) Additional information on <i>RUNX1</i>-specific classification guidelines are available [<a class="bk_pop" href="#runx1.REF.luo.2019.2962">Luo et al 2019</a>].</p><p>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (single-gene testing, <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) and <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><p>Gene-targeted testing requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. Individuals with the distinctive findings described in <a href="#runx1.Suggestive_Findings">Suggestive Findings</a> may be diagnosed using gene-targeted testing (see <a href="#runx1.Option_1">Option 1</a>). However, individuals with a <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> can exhibit significant clinical heterogeneity. Individuals may present with platelet defects and/or hematologic malignancy that are indistinguishable from other inherited hematologic disorders [<a class="bk_pop" href="#runx1.REF.luo.2019.2962">Luo et al 2019</a>]. In such instances it may be more efficient to pursue genomic testing (see <a href="#runx1.Option_2">Option 2</a>).</p><div id="runx1.Option_1"><h4>Option 1</h4><p><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>RUNX1</i> is performed first to detect <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a>, multiexon, or whole-gene deletions/duplications may not be detected. Typically, if no variant is detected by the sequencing method used, the next step is to perform gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> to detect exon and whole-gene deletions or duplications.</p><p><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>RUNX1</i> and other genes of interest (see <a href="#runx1.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests.</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</p></div><div id="runx1.Option_2"><h4>Option 2</h4><p>Given that the <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> may be variable, and can be indistinguishable from many other inherited conditions, <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b>, which does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> is likely involved, may be a good option. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><p>Note: (1) Testing for a <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> should not be performed on blood or bone marrow during active hematologic malignancy. <i>RUNX1</i> pathogenic variants are found in the cells of approximately 10% of persons with hematologic malignancy [<a class="bk_pop" href="#runx1.REF.simon.2020.1882">Simon et al 2020</a>]. (2) When clinically possible, cultured skin fibroblasts are recommended for germline testing. If this source of DNA is not available, buccal samples can be considered. However, there is a risk of peripheral blood contamination. (3) Somatically acquired <a class="def" href="/books/n/gene/glossary/def-item/loss-of-heterozygosity/">loss of heterozygosity</a> due to <a class="def" href="/books/n/gene/glossary/def-item/uniparental-disomy/">uniparental disomy</a> 21 has been identified in hematopoietic tissue of individuals with a germline <i>RUNX1</i> pathogenic variant [<a class="bk_pop" href="#runx1.REF.glembotsky.2020.e535">Glembotsky et al 2020</a>]. This somatic change may cause a false negative molecular result when testing leukocyte or bone marrow DNA (see <a href="#runx1.Molecular_Pathogenesis">Molecular Pathogenesis</a>, <b><i>RUNX1</i>-specific laboratory technical considerations</b>).</p><div id="runx1.T.molecular_genetic_testing_used_i" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>RUNX</i>1 Familial Platelet Disorder with Associated Myeloid Malignancies</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK568319/table/runx1.T.molecular_genetic_testing_used_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__runx1.T.molecular_genetic_testing_used_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_runx1.T.molecular_genetic_testing_used_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_runx1.T.molecular_genetic_testing_used_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_runx1.T.molecular_genetic_testing_used_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic<br />Variants <sup>2, 3</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_runx1.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>RUNX1</i>
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</td><td headers="hd_h_runx1.T.molecular_genetic_testing_used_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>4</sup></td><td headers="hd_h_runx1.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~80% <sup>5</sup></td></tr><tr><td headers="hd_h_runx1.T.molecular_genetic_testing_used_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>6</sup></td><td headers="hd_h_runx1.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~20% <sup>5</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="runx1.TF.1.1"><p class="no_margin">See <a href="/books/NBK568319/#runx1.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="runx1.TF.1.2"><p class="no_margin">See <a href="#runx1.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="runx1.TF.1.3"><p class="no_margin">Individuals with contiguous <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions of various sizes that include <i>RUNX1</i> (not included in these calculations) have been reported (see <a href="#runx1.Genetically_Related_Allelic_Disord">Genetically Related Disorders</a>) [<a class="bk_pop" href="#runx1.REF.braddock.2016.2580">Braddock et al 2016</a>].</p></div></dd><dt>4. </dt><dd><div id="runx1.TF.1.4"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants and small intragenic deletions/insertions; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>5. </dt><dd><div id="runx1.TF.1.5"><p class="no_margin">Data derived from the <i>RUNX1</i> Research Program Database [<a class="bk_pop" href="#runx1.REF.brown.2020.1131">Brown et al 2020</a>]</p></div></dd><dt>6. </dt><dd><div id="runx1.TF.1.6"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd></dl></div></div></div></div></div></div><div id="runx1.Clinical_Characteristics"><h2 id="_runx1_Clinical_Characteristics_">Clinical Characteristics</h2><div id="runx1.Clinical_Description"><h3>Clinical Description</h3><p>To date, more than 130 individuals have been identified with a <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>RUNX1</i> [<a class="bk_pop" href="#runx1.REF.brown.2020.1131">Brown et al 2020</a>]. The following description of the phenotypic features associated with <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> platelet disorder with associated myeloid malignancies (<i>RUNX1</i>-FPDMM) is based on these reports.</p><div id="runx1.T.runx1_familial_platelet_disorder" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p><i>RUNX1</i> Familial Platelet Disorder with Associated Myeloid Malignancies: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK568319/table/runx1.T.runx1_familial_platelet_disorder/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__runx1.T.runx1_familial_platelet_disorder_lrgtbl__"><table><thead><tr><th id="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons w/Feature</th><th id="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Prolonged bleeding &/or easy bruising</td><td headers="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~90%</td><td headers="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Presentation can be variable.</td></tr><tr><td headers="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Myelodysplastic syndrome / acute myeloid leukemia</td><td headers="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~20%-50%</td><td headers="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a class="bk_pop" href="#runx1.REF.brown.2020.1131">Brown et al [2020]</a>, <a class="bk_pop" href="#runx1.REF.simon.2020.1882">Simon et al [2020]</a></td></tr><tr><td headers="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lymphoid malignancy</td><td headers="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown</td><td headers="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~25% of families have at least 1 member w/lymphoid malignancy [<a class="bk_pop" href="#runx1.REF.brown.2020.1131">Brown et al 2020</a>].</td></tr><tr><td headers="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eczema</td><td headers="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Up to 50%</td><td headers="hd_h_runx1.T.runx1_familial_platelet_disorder_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#runx1.REF.brown.2020.1131">Brown et al [2020]</a>
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</td></tr></tbody></table></div></div><p><b>Prolonged bleeding.</b> Almost all individuals with <i>RUNX1</i>-FPDMM will experience some degree of abnormal bleeding as a consequence of their quantitative and/or qualitative platelet defect at some point. The bleeding <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> may be highly variable, even within families. Bleeding may be subclinical in some individuals, who may not notice that their bleeding is abnormal compared to the general population or may not bring it to medical attention. Bleeding defects vary drastically in severity and may manifest as epistaxis, easy bruising, excessive bleeding during minor surgery or injuries, and/or menorrhagia. A minority of individuals require blood transfusions. Age of onset of bleeding can also be highly variable, with some individuals presenting in early infancy and others not recognizing their symptoms until much later in life.</p><p><b>Predisposition to hematologic malignancies.</b> Individuals with <i>RUNX1</i>-FPDMM have a 25%-50% lifetime risk of developing a hematologic malignancy [<a class="bk_pop" href="#runx1.REF.brown.2020.1131">Brown et al 2020</a>]. Myeloid malignancies including acute myelogenous leukemia and myelodysplastic syndrome are the most common. T- and B-cell acute lymphoblastic leukemias and lymphomas have also been reported. The median age of onset is 33 years [<a class="bk_pop" href="#runx1.REF.brown.2020.1131">Brown et al 2020</a>, <a class="bk_pop" href="#runx1.REF.difilippo.2020.2519">DiFilippo et al 2020</a>].</p><p><b>Eczema and other inflammatory features.</b> Eczema and other skin findings such as psoriasis have been reported in roughly 50% of families with <i>RUNX1</i>-FPDMM [<a class="bk_pop" href="#runx1.REF.brown.2016.1212">Brown et al 2016</a>]. Age of onset and severity of skin features is highly variable, but usually noted in childhood, mild, and managed topically.</p></div><div id="runx1.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No consistent clinically relevant <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> have been identified.</p></div><div id="runx1.Penetrance"><h3>Penetrance</h3><p>The <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> of <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <i>RUNX1</i> pathogenic variants is unknown. A minority of individuals have no clinical or laboratory features.</p></div><div id="runx1.Nomenclature"><h3>Nomenclature</h3><p><i>RUNX1</i> was previously referred to as <i>AML1</i> and <i>CBFA2</i> [<a class="bk_pop" href="#runx1.REF.van_wijnen.2004.4209">van Wijnen et al 2004</a>]<i>.</i></p></div><div id="runx1.Prevalence"><h3>Prevalence</h3><p>More than 130 individuals with <i>RUNX1</i>-FPDMM have been reported to date; however, it is likely that <i>RUNX1</i>-FPDMM is highly underdiagnosed [<a class="bk_pop" href="#runx1.REF.brown.2020.1131">Brown et al 2020</a>, <a class="bk_pop" href="#runx1.REF.simon.2020.1882">Simon et al 2020</a>].</p></div></div><div id="runx1.Genetically_Related_Allelic_Disord"><h2 id="_runx1_Genetically_Related_Allelic_Disord_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>RUNX1</i>.</p><p>A nonrecurrent 21q22 <a class="def" href="/books/n/gene/glossary/def-item/contiguous-gene-deletion-syndrome/">contiguous gene deletion syndrome</a> that includes <i>RUNX1</i> is known to be associated with Braddock-Carey syndrome [<a class="bk_pop" href="#runx1.REF.braddock.2016.2580">Braddock et al 2016</a>]. Because the breakpoints of the reported deletions of region 21q22 are variable, the resulting <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> depends on the size of the deletion and the gene content. In general, Braddock-Carey syndrome is characterized by Pierre Robin sequence, agenesis of the corpus callosum, <a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a> facies, developmental delay / intellectual disability, enamel hypoplasia, and <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> thrombocytopenia.</p><p>Sporadic hematopoietic neoplasms (e.g., acute myelogenous leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia), clonal cytopenias of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> [<a class="bk_pop" href="#runx1.REF.bellissimo.2017.111">Bellissimo & Speck 2017</a>], and <a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a> solid tumors (most notably breast cancer [<a class="bk_pop" href="#runx1.REF.chimge.2013.2121">Chimge & Frenkel 2013</a>]) frequently contain a <a class="def" href="/books/n/gene/glossary/def-item/somatic-pathogenic-variant/">somatic pathogenic variant</a> in <i>RUNX1</i> that is not present in the <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a>. In these circumstances predisposition to these hematopoietic neoplasms and tumors is not heritable. For more information, see <a href="#runx1.Cancer_and_Benign_Tumors">Cancer and Benign Tumors</a>.</p></div><div id="runx1.Differential_Diagnosis"><h2 id="_runx1_Differential_Diagnosis_">Differential Diagnosis</h2><div id="runx1.T.genes_of_interest_in_the_differe" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of <i>RUNX1</i> Familial Platelet Disorder with Associated Myeloid Malignancies</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK568319/table/runx1.T.genes_of_interest_in_the_differe/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__runx1.T.genes_of_interest_in_the_differe_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_2" style="text-align:left;vertical-align:middle;">DiffDx Disorder</th><th id="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Clinical Features of DiffDix Disorder</th></tr><tr><th headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4" id="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/<i>RUNX1</i>-FPDMM</th><th headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4" id="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from <i>RUNX1</i>-FPDMM</th></tr></thead><tbody><tr><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ANKRD26</i>
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</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/ankrd26/"><i>ANKRD26</i>-related thrombocytopenia</a>
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</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nonsyndromic thrombocytopenia w/normal platelet size & predisposition to myeloid neoplasms</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Some persons may have erythrocytosis (hemoglobin ≤18.5 g/dL) & leukocytosis.</td></tr><tr><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CEBPA</i>
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</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/cebpa-aml/"><i>CEBPA</i>-associated familial acute myeloid leukemia</a>
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</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Familial predisposition to AML & thrombocytopenia</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Leukopenia (w/↑ infections) & anemia</td></tr><tr><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>DDX41</i>
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</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/ddx41-mds/"><i>DDX41</i>-associated familial MDS/AML</a>
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</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Familial predisposition to MDS/AML</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Some persons may have erythroid or megakaryocytic dysplasia.<sup>1</sup></td></tr><tr><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ETV6</i>
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</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/etv6-tpl/"><i>ETV6</i>-related thrombocytopenia</a>
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</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nonsyndromic thrombocytopenia w/normal platelet size & predisposition to myeloid neoplasms</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Can have red cell macrocytosis & neutropenia; predisposes to lymphoid malignancy</td></tr><tr><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GATA2</i>
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</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">GATA2 deficiency</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Familial predisposition to MDS/AML</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Immunodeficiency (↓ or absent monocytes & B- & NK-cell lymphocytes)</td></tr><tr><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SRP72</i>
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||
</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bone marrow failure syndrome 1 (OMIM <a href="https://omim.org/entry/614675" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614675</a>)</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Familial predisposition to MDS</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Aplastic anemia, pancytopenia</td></tr><tr><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>TP53</i>
|
||
</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/li-fraumeni/">Li-Fraumeni syndrome</a>
|
||
</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Familial predisposition to MDS/AML</td><td headers="hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_1_4 hd_h_runx1.T.genes_of_interest_in_the_differe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">High <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> for non-hematologic cancers (breast cancer, osteosarcoma, soft tissue sarcomas)</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; AML = acute myeloid leukemia; DiffDx = differential diagnosis; MDS = myelodysplastic syndrome; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; <i>RUNX1</i>-FPDMM = <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> platelet disorder with associated myeloid malignancies</p></div></dd><dt>1. </dt><dd><div id="runx1.TF.3.1"><p class="no_margin">
|
||
<a class="bk_pop" href="#runx1.REF.lewinsohn.2016.1017">Lewinsohn et al [2016]</a>
|
||
</p></div></dd></dl></div></div></div><p>
|
||
<b>Acquired disorders in the differential diagnosis of <i>RUNX1</i>-FPDMM</b>
|
||
</p><ul><li class="half_rhythm"><div>Immune thrombocytopenia</div></li><li class="half_rhythm"><div>Secondary thrombocytopenia</div></li><li class="half_rhythm"><div>Medication-related (e.g., NSAIDs, antiplatelet agents, statins, furosemide, heparin, ranitidine, linezolid) increased risk of bruising and prolonged bleeding</div></li><li class="half_rhythm"><div>Leukemia</div></li></ul></div><div id="runx1.Management"><h2 id="_runx1_Management_">Management</h2><p>No clinical practice guidelines for <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> platelet disorder with associated myeloid malignancies (<i>RUNX1</i>-FPDMM) have been published.</p><div id="runx1.Evaluations_Following_Initial_Diag"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>RUNX1</i>-FPDMM, the evaluations summarized in <a href="/books/NBK568319/table/runx1.T.recommended_evaluations_followin/?report=objectonly" target="object" rid-ob="figobrunx1Trecommendedevaluationsfollowin">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="runx1.T.recommended_evaluations_followin" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with <i>RUNX1</i> Familial Platelet Disorder with Associated Myeloid Malignancies</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK568319/table/runx1.T.recommended_evaluations_followin/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__runx1.T.recommended_evaluations_followin_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_runx1.T.recommended_evaluations_followin_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_runx1.T.recommended_evaluations_followin_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_runx1.T.recommended_evaluations_followin_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_runx1.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hematologic</b>
|
||
</td><td headers="hd_h_runx1.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical eval by hematologist incl CBC, differential, reticulocyte count, & peripheral smear</td><td headers="hd_h_runx1.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Baseline bone marrow biopsy & aspirate may be considered.</td></tr><tr><td headers="hd_h_runx1.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Dermatologic</b>
|
||
</td><td headers="hd_h_runx1.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical eval for eczema or other skin concerns as needed</td><td headers="hd_h_runx1.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_runx1.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic</b>
|
||
<br />
|
||
<b>counseling</b>
|
||
</td><td headers="hd_h_runx1.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_runx1.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To obtain a <a class="def" href="/books/n/gene/glossary/def-item/pedigree/">pedigree</a> & inform affected persons & their families re nature, MOI, & implications of <i>RUNX1-</i>FPDMM to facilitate medical & personal decision making</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">CBC = complete blood count; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; <i>RUNX1</i>-FPDMM = <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> platelet disorder with associated myeloid malignancies</p></div></dd><dt>1. </dt><dd><div id="runx1.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse, or hematologist with expertise in these disorders</p></div></dd></dl></div></div></div></div><div id="runx1.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div id="runx1.T.treatment_of_manifestations_in_i" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with <i>RUNX1</i> Familial Platelet Disorder with Associated Myeloid Malignancies</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK568319/table/runx1.T.treatment_of_manifestations_in_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__runx1.T.treatment_of_manifestations_in_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Impaired clotting</b>
|
||
</td><td headers="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Use of clotting promotors (e.g., desmopressin, epsilon aminocaproic acid, tranexamic acid) for surgeries, injuries, or dental treatments</td><td headers="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Platelet transfusions may be used for severe bleeding or procedures w/high bleeding risk but are not first-line therapy due to risk of alloimmunization.</td></tr><tr><td headers="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Myelodysplastic syndromes & acute leukemias</b>
|
||
</td><td headers="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Allogenic stem cell transplantation may be considered in transplant-eligible persons w/early signs of malignancy.</td><td headers="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>FPDMM is not thought to be curable w/chemotherapy alone; HSCT is almost always required.</div></li><li class="half_rhythm"><div>Test for <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> prior to using a family member as a HSCT donor. <sup>1</sup></div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Eczema</b>
|
||
</td><td headers="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Emollients & topical steroids as needed</td><td headers="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support/</b>
|
||
<br />
|
||
<b>resources</b>
|
||
</td><td headers="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider:
|
||
<ul><li class="half_rhythm"><div>Providing a medical letter for school explaining easy bruising at baseline, as referrals for social services for concern of child abuse can occur;</div></li><li class="half_rhythm"><div>Use of a medical alert bracelet for thrombocytopenia, platelet dysfunction, or hematologic malignancy as indicated.</div></li></ul>
|
||
</td><td headers="hd_h_runx1.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">FPDMM = <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> platelet disorder with associated myeloid malignancies; HSCT = hematopoietic stem cell transplant</p></div></dd><dt>1. </dt><dd><div id="runx1.TF.5.1"><p class="no_margin">Recurrence of leukemia was reported after a donor sib was found to have the <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> [<a class="bk_pop" href="#runx1.REF.owen.2008.4639">Owen et al 2008</a>].</p></div></dd></dl></div></div></div></div><div id="runx1.Surveillance"><h3>Surveillance</h3><p>Guidelines on the type of testing or frequency of surveillance have not been published.</p><div id="runx1.T.recommended_surveillance_for_ind" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with <i>RUNX1</i> Familial Platelet Disorder with Associated Myeloid Malignancies</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK568319/table/runx1.T.recommended_surveillance_for_ind/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__runx1.T.recommended_surveillance_for_ind_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_runx1.T.recommended_surveillance_for_ind_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_runx1.T.recommended_surveillance_for_ind_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_runx1.T.recommended_surveillance_for_ind_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_runx1.T.recommended_surveillance_for_ind_1_1_1_1" rowspan="3" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hematologic</b>
|
||
<br />
|
||
<b>malignancy</b>
|
||
</td><td headers="hd_h_runx1.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical exam for constitutional signs & symptoms of neoplasm (e.g., fatigue, unexplained fever, unexplained weight loss, shortness of breath)</td><td headers="hd_h_runx1.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 6-12 mos or more frequently as clinically indicated</td></tr><tr><td headers="hd_h_runx1.T.recommended_surveillance_for_ind_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">CBC w/differential</td><td headers="hd_h_runx1.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 3-4 mos</td></tr><tr><td headers="hd_h_runx1.T.recommended_surveillance_for_ind_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Bone marrow exam</td><td headers="hd_h_runx1.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>If constitutional symptoms &/or abnormalities on CBC are identified</div></li><li class="half_rhythm"><div>Consider annually (although there is no consensus on this recommendation).</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_runx1.T.recommended_surveillance_for_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Eczema</b>
|
||
</td><td headers="hd_h_runx1.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Skin exam</td><td headers="hd_h_runx1.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As needed</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">CBC = complete blood count</p></div></dd></dl></div></div></div></div><div id="runx1.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Avoid the following:</p><ul><li class="half_rhythm"><div>Medications that affect platelet function, such as NSAIDs and antiplatelet agents</div></li><li class="half_rhythm"><div>Activities with a high risk of trauma, such as high-risk contact sports</div></li></ul><p>Factors such as smoking, chemical exposure, unnecessary radiation, and obesity may increase the risk of developing hematologic malignancy.</p></div><div id="runx1.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance for malignancy and more targeted medical management.</p><p>See <a href="#runx1.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="runx1.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Platelet counts and bleeding complications should be monitored during pregnancy. Qualitative and quantitative platelet disorders can lead to severe bleeding before, during, or after delivery. While thrombocytopenia itself (particularly if mild) in the absence of aggregation and storage pool disorders is unlikely to affect pregnancy, low platelet counts (<50 x 10<sup>9</sup>/L) can limit the ability to receive epidural analgesia or neuraxial anesthesia. Strategies to increase platelet count (transfusion) can be considered on an individual basis in consultation with the obstetrician, hematologist, and anesthesiologist.</p><p>See <a href="https://www.mothertobaby.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MotherToBaby</a> for further information on medication use during pregnancy.</p></div><div id="runx1.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>The NIH <i>RUNX1</i> Natural History Study (<a href="https://clinicaltrials.gov/study/NCT03854318" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT03854318</a>) is currently recruiting participants with known or suspected <i>RUNX1</i>-FPDMM. The goals of the study are to better understand the natural history of the condition and its underlying genetic mechanisms to develop better strategies for monitoring and treating affected individuals (see <a href="#runx1.Author_Notes">Author Notes</a>).</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="runx1.Genetic_Counseling"><h2 id="_runx1_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="runx1.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> platelet disorder with associated myeloid malignancies (<i>RUNX1</i>-FPDMM) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p></div><div id="runx1.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>Most individuals diagnosed with <i>RUNX1</i>-FPDMM inherited the causative <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from a parent, who may or may not have recognized manifestations of the disorder.</div></li><li class="half_rhythm"><div>Some individuals diagnosed with <i>RUNX1</i>-FPDMM have the disorder as the result of a <i>de novo RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. The proportion of probands who have a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> pathogenic variant is unknown.</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> appears to be the only affected family member (i.e., a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case), <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> is recommended for the parents of the proband to assess their genetic status and to allow reliable <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> counseling. Note: Because somatically acquired <a class="def" href="/books/n/gene/glossary/def-item/loss-of-heterozygosity/">loss of heterozygosity</a> may result in a false negative molecular result when testing leukocyte DNA, use of DNA derived from non-hematopoietic tissues (e.g., skin fibroblasts, hair roots) should be considered if feasible (see <a href="#runx1.Molecular_Pathogenesis">Molecular Pathogenesis</a>, <b><i>RUNX1</i>-specific laboratory technical considerations</b>).</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is not identified in either parent, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> may have a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. Note: A pathogenic variant is reported as "<i>de novo</i>" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed <i>de novo</i>" [<a class="bk_pop" href="#runx1.REF.richards.2015.405">Richards et al 2015</a>].</div></li><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> may have inherited a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from a parent with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> (or somatic and germline) <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a>. The frequency of <i>RUNX1</i> mosaicism is unknown. Note: Testing of parental leukocyte DNA may not detect all instances of <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a>.</div></li><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> may have inherited a <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from a parent with somatically acquired <a class="def" href="/books/n/gene/glossary/def-item/loss-of-heterozygosity/">loss of heterozygosity</a> (with preferential loss of chromosomes with a pathogenic <i>RUNX1</i> variant) [<a class="bk_pop" href="#runx1.REF.glembotsky.2020.e535">Glembotsky et al 2020</a>]. This somatic change (e.g., <a class="def" href="/books/n/gene/glossary/def-item/uniparental-disomy/">uniparental disomy</a> 21) may occur in hematopoietic tissue of individuals with a pathogenic <i>RUNX1</i> variant and may result in a decreased fraction of cells with the pathogenic variant and cause a false negative molecular result when testing leukocyte DNA (see <a href="#runx1.Molecular_Pathogenesis">Molecular Pathogenesis</a>, <b><i>RUNX1</i>-specific laboratory technical considerations</b>).</div></li></ul></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with <i>RUNX1</i>-FPDMM may appear to be negative because of failure to recognize the disorder in family members, due to <a class="def" href="/books/n/gene/glossary/def-item/variable-expressivity/">variable expressivity</a> (a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> family member may have subclinical or normalized symptoms), early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> has demonstrated that neither parent has the <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li></ul><p><b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The risk to sibs of a proband depends on the genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is affected and/or is known to have the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%.</div><ul><li class="half_rhythm"><div>Sibs who inherit a <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> may have symptoms of easy bruising or bleeding and will have an estimated overall lifetime risk of hematologic malignancy between 20% and 50% (see <a href="/books/NBK568319/table/runx1.T.runx1_familial_platelet_disorder/?report=objectonly" target="object" rid-ob="figobrunx1Trunx1familialplateletdisorder">Table 2</a>).</div></li><li class="half_rhythm"><div>Significant clinical variability is observed within families [<a class="bk_pop" href="#runx1.REF.liew.2011.1536">Liew & Owen 2011</a>].</div></li></ul></li><li class="half_rhythm"><div>If the <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is not detected in parental DNA, the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> to sibs is slightly greater than that of the general population because of the possibility of a false negative result in a parent due to preferential loss of the <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> with the <i>RUNX1</i> pathogenic variant and the possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> [<a class="bk_pop" href="#runx1.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the parents have not been tested for the <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> but are clinically unaffected, sibs are still presumed to be at increased risk for <i>RUNX1</i>-FPDMM because of the possibility that either: (1) a parent is <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> but does not have apparent manifestations of <i>RUNX1</i>-FPDMM because of <a class="def" href="/books/n/gene/glossary/def-item/variable-expressivity/">variable expressivity</a> or phenotypic modification resulting from somatically acquired <a class="def" href="/books/n/gene/glossary/def-item/loss-of-heterozygosity/">loss of heterozygosity</a>; or (2) a parent has <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>.</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Each child of an individual with <i>RUNX1</i>-FPDMM has a 50% chance of inheriting the <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents: if a parent has the <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the parent's family members may be at risk of having a <i>RUNX1</i> pathogenic variant and associated clinical manifestations including myeloid malignancy (see <a href="#runx1.Clinical_Description">Clinical Description</a>).</p></div><div id="runx1.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#runx1.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.</div></li></ul></div><div id="runx1.Prenatal_Testing_and_Preimplantati"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a>. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="runx1.Resources"><h2 id="_runx1_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>RUNX1 Research Program</b>
|
||
</div><div><b>Phone:</b> 805-880-4109</div><div><b>Email:</b> info@runx1-fpd.org</div><div>
|
||
<a href="https://www.runx1-fpd.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.runx1-fpd.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Alex’s Lemonade Stand Foundation</b>
|
||
</div><div>111 Presidential Boulevard</div><div>Suite 203</div><div>Bala Cynwyd PA 19004 </div><div><b>Phone:</b> 866-333-1213</div><div>
|
||
<a href="https://www.alexslemonade.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.alexslemonade.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Aplastic Anemia & MDS International Foundation, Inc.</b>
|
||
</div><div>4330 East West Highway</div><div>Suite 230</div><div>Bethesda MD 20814</div><div><b>Phone:</b> 800-747-2820</div><div><b>Email:</b> help@aamds.org</div><div>
|
||
<a href="http://www.aamds.org/about-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.aamds.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>National Cancer Institute (NCI)</b>
|
||
</div><div><b>Phone:</b> 800-422-6237</div><div><b>Email:</b> NCIinfo@nih.gov</div><div>
|
||
<a href="http://www.cancer.gov" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">cancer.gov</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Platelet Disorder Support Association</b>
|
||
</div><div><b>Phone:</b> 877-528-3538</div><div><b>Email:</b> pdsa@pdsa.org</div><div>
|
||
<a href="http://www.pdsa.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.pdsa.org</a>
|
||
</div></li></ul>
|
||
</div><div id="runx1.Molecular_Genetics"><h2 id="_runx1_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="runx1.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK568319/table/runx1.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__runx1.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_runx1.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_runx1.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_runx1.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_runx1.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_runx1.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_runx1.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_runx1.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/861" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>RUNX1</i>
|
||
</a>
|
||
</td><td headers="hd_b_runx1.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=861" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">21q22<wbr style="display:inline-block"></wbr>.12</a>
|
||
</td><td headers="hd_b_runx1.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q01196" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Runt-related transcription factor 1</a>
|
||
</td><td headers="hd_b_runx1.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/RUNX1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">RUNX1 database</a>
|
||
</td><td headers="hd_b_runx1.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=RUNX1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">RUNX1</a>
|
||
</td><td headers="hd_b_runx1.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=RUNX1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">RUNX1</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="runx1.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="runx1.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies (<a href="/omim/151385,601399" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK568319/table/runx1.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__runx1.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/151385" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">151385</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">RUNT-RELATED TRANSCRIPTION FACTOR 1; RUNX1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/601399" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">601399</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PLATELET DISORDER, FAMILIAL, WITH ASSOCIATED MYELOID MALIGNANCY; FPDMM</td></tr></tbody></table></div></div><div id="runx1.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>RUNX1</i> encodes Runt-related <a class="def" href="/books/n/gene/glossary/def-item/transcription-factor/">transcription factor</a> 1, which, along with its binding partner CBFβ, plays an important role in regulating genes associated with hematopoiesis. Known directed transcriptional targets of Runt-related transcription factor 1 include 12-lipoxygenase (ALOX12), platelet factor 4 (PF4), platelet myosin light chain (MYL9), protein kinase C-θ (PRKCQ), pallidin (PLDN), RAB1B, TREML1, ITGA2, thrombopoietin receptors (MPL), PAR4 and NFE2, NOTCH4, and A4GALT [<a class="bk_pop" href="#runx1.REF.songdej.2019">Songdej & Rao 2019</a>].</p><p>The majority of <i>RUNX1</i> pathogenic variants occur in the Runt homology <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a>; however, pathogenic variants that affect <a class="def" href="/books/n/gene/glossary/def-item/splicing/">splicing</a> as well as pathogenic variants in the transactivation domain have also been reported [<a class="bk_pop" href="#runx1.REF.luo.2019.2962">Luo et al 2019</a>, <a class="bk_pop" href="#runx1.REF.songdej.2019">Songdej & Rao 2019</a>]. There are several reviews describing the role of somatic and <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <i>RUNX1</i> pathogenic variants [<a class="bk_pop" href="#runx1.REF.sood.2017.2070">Sood et al 2017</a>, <a class="bk_pop" href="#runx1.REF.songdej.2019">Songdej & Rao 2019</a>].</p><p>Malignant transformation in individuals with <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> platelet disorder with associated myeloid malignancies (<i>RUNX1</i>-FPDMM) is often attributable to the accumulation of additional somatic pathogenic variants in other genes (e.g., <i>ASXL1</i>, <i>CBL</i>, <i>CDC25C</i>, <i>FLT3</i>, <i>PHF6</i>, <i>SRSF2</i>, and <i>WTI</i>) and/or a <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> variant in the other <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> [<a class="bk_pop" href="#runx1.REF.antonydebr_.2016.999">Antony-Debré et al 2016</a>].</p><p><b>Mechanism of disease causation.</b>
|
||
<i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> dosage is critical for thrombocyte differentiation. Functional studies have shown that <i>RUNX1</i> frameshift variants and large deletions are <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> variants, leading to <a class="def" href="/books/n/gene/glossary/def-item/haploinsufficiency/">haploinsufficiency</a>. Some <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> and <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> variants have been shown to act in a <a class="def" href="/books/n/gene/glossary/def-item/dominant-negative/">dominant-negative</a> mechanism by affecting DNA binding and/or transactivation [<a class="bk_pop" href="#runx1.REF.sood.2017.2070">Sood et al 2017</a>].</p><p><b><i>RUNX1</i>-specific laboratory technical considerations.</b> Somatically acquired <a class="def" href="/books/n/gene/glossary/def-item/loss-of-heterozygosity/">loss of heterozygosity</a> due to <a class="def" href="/books/n/gene/glossary/def-item/uniparental-disomy/">uniparental disomy</a> 21 has been identified in hematopoietic tissue of individuals with a pathogenic <i>RUNX1</i> variant [<a class="bk_pop" href="#runx1.REF.glembotsky.2020.e535">Glembotsky et al 2020</a>]. <i>RUNX1</i> is located on <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> 21 and loss of chromosomes with a pathogenic <i>RUNX1</i> variant may occur preferentially. This somatic change results in a decreased fraction of cells with the variant and may cause a false negative molecular result when testing leukocyte or bone marrow DNA. Therefore, evaluation of <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> abnormalities with <a class="def" href="/books/n/gene/glossary/def-item/snp-array/">SNP array</a> and/or evaluation of low-abundance variants with deep sequencing (>1000x read depth) should be considered in individuals clinically suspected for <i>RUNX1</i>-FPDMM who have a negative genetic test result. If feasible, using the DNA derived from non-hematopoietic tissues (e.g., skin fibroblasts, hair roots) may be considered.</p></div><div id="runx1.Cancer_and_Benign_Tumors"><h3>Cancer and Benign Tumors</h3><p>Sporadic hematopoietic neoplasms (e.g., acute myelogenous leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia) and <a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a> solid tumors (most notably, breast cancer) may occur as single tumors in the absence of any other findings of <i>RUNX1</i>-FPDMM and frequently contain a <a class="def" href="/books/n/gene/glossary/def-item/somatic-pathogenic-variant/">somatic pathogenic variant</a> in <i>RUNX1</i> that is not present in the <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> [<a class="bk_pop" href="#runx1.REF.chimge.2013.2121">Chimge & Frenkel 2013</a>, <a class="bk_pop" href="#runx1.REF.bellissimo.2017.111">Bellissimo & Speck 2017</a>, <a class="bk_pop" href="#runx1.REF.brown.2020.1131">Brown et al 2020</a>, <a class="bk_pop" href="#runx1.REF.simon.2020.1882">Simon et al 2020</a>]. In these circumstances, predisposition to these hematopoietic neoplasms and tumors is not heritable. A variant <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> fraction of less than 40% for the <i>RUNX1</i> pathogenic variant identified in tumor tissue is suggestive of a somatic variant.</p></div></div><div id="runx1.Chapter_Notes"><h2 id="_runx1_Chapter_Notes_">Chapter Notes</h2><div id="runx1.Author_Notes"><h3>Author Notes</h3><p>Natalie Deuitch and Paul Liu are actively involved in clinical research regarding individuals with <i>RUNX1</i> <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> platelet disorder with associated myeloid malignancies (<i>RUNX1</i>-FPDMM) through the NIH <i>RUNX1</i> Natural History Study. For questions regarding diagnosis or management of <i>RUNX1</i>-FPDMM or for potential enrollment in the natural history study email Natalie Deuitch (<a href="mailto:dev@null" data-email="vog.hin@hctiued.eilatan" class="oemail">vog.hin@hctiued.eilatan</a>). Natalie Deuitch and Paul Liu can also be contacted to inquire about review of <i>RUNX1</i> variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>.</p><p>Natalie Deuitch is a genetic counselor at the National Human Genome Research Institute (NHGRI). She works with patients enrolled in the <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <i>RUNX1</i> Natural History Study.</p><p>Liesl Broadridge is a <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> student at the Johns Hopkins University/NHGRI combined program. She previously studied <i>RUNX1</i> as a postbaccalaureate fellow in Dr Liu's lab at NHGRI.</p><p>Dr Lea Cunningham is a hematologist/oncologist and Director of the NIH Pediatric Bone Marrow Transplantation Fellowship Program.</p><p>Dr Paul Liu is Principle Investigator of the <i>RUNX1</i> Natural History Study and directs a lab that studies <i>RUNX1</i> and leukemogenesis at the NHGRI.</p></div><div id="runx1.Acknowledgments"><h3>Acknowledgments</h3><p>We would like to thank the <i>GeneReviews</i> Editors and Reviewers for their suggestions and contributions to the development of this <i>GeneReview</i> chapter.</p></div><div id="runx1.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>11 January 2023 (nd) Revision: added NIH <i>RUNX1</i> Natural History Study (<a href="https://clinicaltrials.gov/study/NCT03854318" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT03854318</a>) to <a href="#runx1.Therapies_Under_Investigation">Therapies Under Investigation</a></div></li><li class="half_rhythm"><div>6 May 2021 (ma) Revision: added Braddock-Carey syndrome to <a href="#runx1.Genetically_Related_Allelic_Disord">Genetically Related Disorders</a></div></li><li class="half_rhythm"><div>4 March 2021 (sw) Review posted live</div></li><li class="half_rhythm"><div>5 October 2020 (nd) Original submission</div></li></ul><p>Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the <i>GeneReview</i> "<i>RUNX1</i> Familial Platelet Disorder with Associated Myeloid Malignancies" is in the public domain in the United States of America.</p></div></div><div id="runx1.References"><h2 id="_runx1_References_">References</h2><div id="runx1.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="runx1.REF.antonydebr_.2016.999">Antony-Debré
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK568319/?report=reader">PubReader</a></li><li><a href="/books/NBK568319/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK568319" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK568319" style="display:none" title="Cite this Page"><div class="bk_tt">Deuitch N, Broadbridge E, Cunningham L, et al. 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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=8021[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">NUP214</a>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=26511[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">CHIC2</a>
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</li><li>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=2624[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">GATA2</a>
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</li><li>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=4869[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">NPM1</a>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=8301[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">PICALM</a>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=3845[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">KRAS</a>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=6455[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">SH3GL1</a>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=1050[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">CEBPA</a>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=1788[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">DNMT3A</a>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=2322[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">FLT3</a>
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</li><li>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=8028[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">MLLT10</a>
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</li><li>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=861[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">RUNX1</a>
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</li><li>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=2120[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">ETV6</a>
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</li><li>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=3717[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">JAK2</a>
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</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=5170152" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=5170152" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" 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