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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="#__NBK1485_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1485_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/tfap/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/taa/" 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="_NBK1485_"><span class="title" itemprop="name">Heritable Pulmonary Arterial Hypertension Overview</span></h1><p class="contrib-group"><span itemprop="author">Eric D Austin</span>, MD, MSCI, <span itemprop="author">John A Phillips, III</span>, MD, PhD, and <span itemprop="author">James E Loyd</span>, MD.</p><a data-jig="ncbitoggler" href="#__NBK1485_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1485_ai__"><div class="contrib half_rhythm"><span itemprop="author">Eric D Austin</span>, MD, MSCI<div class="affiliation small">Pediatric Pulmonary Medicine<br />Vanderbilt University Medical Center<br />Nashville, Tennessee<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.cmuv@nitsua.cire" class="oemail">gro.cmuv@nitsua.cire</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">John A Phillips, III</span>, MD, PhD<div class="affiliation small">Division of Medical Genetics<br />Vanderbilt University Medical Center<br />Nashville, Tennessee<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.tlibrednav@spillihp.a.nhoj" class="oemail">ude.tlibrednav@spillihp.a.nhoj</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">James E Loyd</span>, MD<div class="affiliation small">Allergy, Pulmonary, and Critical Care Medicine<br />Vanderbilt University Medical Center<br />Nashville, Tennessee<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.cmuv@dyol.mij" class="oemail">gro.cmuv@dyol.mij</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">July 18, 2002</span>; Last Update: <span itemprop="dateModified">December 23, 2020</span>.</p><p><em>Estimated reading time: 18 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="pph.Summary" itemprop="description"><h2 id="_pph_Summary_">Summary</h2><p>The purpose of this overview is to:</p><dl class="temp-labeled-list"><dt>1.</dt><dd><p class="no_top_margin">Describe the <a href="#pph.Clinical_Characteristics_of_Heritabl">clinical characteristics</a> of heritable pulmonary arterial hypertension (HPAH);</p></dd><dt>2.</dt><dd><p class="no_top_margin">Review the <a href="#pph.Genetic_Causes_of_Heritable_Pulmonar">genetic causes</a> of HPAH;</p></dd><dt>3.</dt><dd><p class="no_top_margin">Provide an <a href="#pph.Evaluation_Strategies_to_Identify_th">evaluation strategy</a> to identify the genetic cause of HPAH in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> (when possible);</p></dd><dt>4.</dt><dd><p class="no_top_margin">Review a high-level view of <a href="#pph.Management_of_Heritable_Pulmonary_Ar">management</a> of HPAH;</p></dd><dt>5.</dt><dd><p class="no_top_margin">Inform <a href="#pph.Genetic_Risk_Assessment_and_Surveill">genetic risk assessment</a> and surveillance of at-risk relatives for detection of early treatable manifestations of HPAH.</p></dd></dl>
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</div><div id="pph.Clinical_Characteristics_of_Heritabl"><h2 id="_pph_Clinical_Characteristics_of_Heritabl_">1. Clinical Characteristics of Heritable Pulmonary Arterial Hypertension</h2><p><b>Heritable pulmonary arterial hypertension (HPAH)</b> includes <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> PAH (i.e., PAH that occurs in ≥2 family members) and <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> PAH (i.e., a single occurrence in a family) when a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in one of the known genes has been identified.</p><p>Note: Pulmonary hypertension (PH) is a general designation for increased blood pressure in the lungs from any cause and is classified into five groups by the World Symposium of PH (WSPH) [<a class="bk_pop" href="#pph.REF.simonneau.2019.1801913">Simonneau et al 2019</a>]. PAH is classified as Group 1, and it is a clinical diagnosis that is established by excluding the others, including PH resulting from heart disease (Group 2), PH resulting from lung disease or hypoxia (Group 3), PH from chronic thromboembolic PH (Group 4), and a variety of miscellaneous causes, metabolic disorders, sarcoidosis, or splenectomy (Group 5).</p><p><b>The diagnosis of HPAH is established clinically</b> [<a class="bk_pop" href="#pph.REF.morrell.2019.1801899">Morrell et al 2019</a>] by the following in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>:</p><ul><li class="half_rhythm"><div class="half_rhythm">Confirmation of the presence of PAH (i.e., mean pulmonary artery pressure >20 mm Hg at rest during cardiac catheterization [<a class="bk_pop" href="#pph.REF.simonneau.2019.1801913">Simonneau et al 2019</a>])</div></li><li class="half_rhythm"><div class="half_rhythm">Exclusion of other known causes of PAH; see <a href="#pph.Differential_Diagnosis_of_HPAH">Differential Diagnosis of HPAH</a>.</div></li><li class="half_rhythm"><div class="half_rhythm">Identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant in one of the genes known to be associated with HPAH (<a href="/books/NBK1485/table/pph.T.heritable_pulmonary_arterial_hyper/?report=objectonly" target="object" rid-ob="figobpphTheritablepulmonaryarterialhyper">Table 1</a>) and/or confirmation of PAH in one or more of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s family members</div><div class="half_rhythm">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. 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> variant of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> in one of the genes known to be associated with HPAH does not establish or rule out the diagnosis.</div></li></ul><div id="pph.Clinical_Symptoms"><h3>Clinical Symptoms</h3><p>Clinical symptoms of HPAH include dyspnea, fatigue, chest pain, palpitation, syncope, or edema. HPAH affects all ages, including the very young and the elderly; the mean age at diagnosis is 34.9±14.9 years [<a class="bk_pop" href="#pph.REF.larkin.2012.892">Larkin et al 2012</a>].</p><p>Females are twice as likely to be affected as males; survival is worse in males than in females [<a class="bk_pop" href="#pph.REF.kozu.2018.939">Kozu et al 2018</a>].</p><p>The clinical course varies considerably, but untreated individuals gradually deteriorate, with a mean survival of 2.8 years after diagnosis. The variability in survival across individuals is broad, ranging from sudden death to decades (rare). The physiologic stress of pregnancy in an individual with HPAH is significant and maternal mortality is believed to be substantial, with risk variable according to pulmonary arterial pressure and right ventricular dysfunction [<a class="bk_pop" href="#pph.REF.ballard.2021.109">Ballard et al 2021</a>].</p></div><div id="pph.Clinical_Examination"><h3>Clinical Examination</h3><p>Because the symptoms of HPAH are nonspecific and develop slowly, affected individuals often mistakenly attribute their initial symptoms to aging, poor physical conditioning, or being overweight. Some individuals report no symptoms, and diagnosis is suspected on an incidental basis because of signs (abnormal findings on physical examination) including:</p><ul><li class="half_rhythm"><div>Accentuation of the pulmonic component of the second heart sound;</div></li><li class="half_rhythm"><div>Right ventricular heave or cardiac murmur such as tricuspid regurgitation resulting from right ventricular dilatation;</div></li><li class="half_rhythm"><div>Signs of right ventricular failure such as increased venous pressure, edema, or hepatomegaly (later in the course).</div></li></ul></div><div id="pph.Clinical_Testing_to_Confirm_PAH"><h3>Clinical Testing to Confirm PAH</h3><p>The approach to the individual with suspected PAH has been carefully described by several international guidelines [<a class="bk_pop" href="#pph.REF.gali_.2016.67">Galiè et al 2016</a>]. Note: It is generally advised, when possible, to involve a specialty pulmonary hypertension referral center during the diagnostic work up.</p><p>Once symptoms or signs concerning for PAH are identified on clinical exam, the following evaluations are recommended:</p><ul><li class="half_rhythm"><div>Electrocardiogram</div></li><li class="half_rhythm"><div>Transthoracic echocardiogram</div></li><li class="half_rhythm"><div>Laboratory work to include complete blood count, comprehensive metabolic panel, brain natriuretic peptide, antinuclear antibody, Rh factor, HIV testing, and coagulation studies</div></li><li class="half_rhythm"><div>Computed tomography of the chest and likely a ventilation/perfusion scan and pulmonary function studies</div></li></ul><p>Ultimately, the diagnosis of PAH is formally made at the time of cardiac catheterization at rest, which is recommended for all individuals with suspected PAH.</p><ul><li class="half_rhythm"><div>Specifically, cardiac catheterization is used to confirm the diagnosis of PAH by directly measuring pulmonary artery pressures and excluding other cardiac abnormalities.</div></li><li class="half_rhythm"><div>Challenge testing with vasodilators (i.e., inhaled nitric oxide) or fluid loading, or both, during catheterization is important to assess physiologic responses to guide appropriate therapy.</div></li></ul></div><div id="pph.Differential_Diagnosis_of_HPAH"><h3>Differential Diagnosis of HPAH</h3><p>Other cardiopulmonary causes of PH are far more common than PAH. Importantly, causes of PH associated with related conditions need to be excluded before the diagnosis of PAH can be established. Other causes of PH include connective tissue diseases, cirrhosis, HIV infection, treatment with appetite suppressants, and the following acquired and hereditary disorders [<a class="bk_pop" href="#pph.REF.badesch.2010.376">Badesch et al 2010</a>]:</p><ul><li class="half_rhythm"><div><b>Heart disease (WSPH Group 2).</b> Most advanced cardiac conditions, including left ventricular dysfunction, <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart disease, valvular disease, and cardiomyopathy, can cause PH. Heart diseases are detected by physical examination, electrocardiogram, echocardiography, and cardiac catheterization.</div></li><li class="half_rhythm"><div><b>Lung disease or hypoxia (WSPH Group 3).</b> The advanced stages of all lung diseases may cause PH. Most lung diseases that cause PH are identified by detection of abnormal lung sounds on physical examination, pulmonary function testing, and/or high-resolution computed tomographic lung imaging.</div></li><li class="half_rhythm"><div><b>Pulmonary embolism / disease of large pulmonary vessels (WSPH Group 4).</b> Pulmonary embolism or disease of large pulmonary vessels is detected by imaging procedures; traditionally, screening by lung perfusion scanning with confirmation by pulmonary arteriography. Although CT angiography has improved greatly, nuclear medicine perfusion scanning still has a role in screening for chronic thromboembolic pulmonary hypertension (CTEPH), a disorder in which pulmonary emboli are not resorbed normally by fibrinolysis. It is important to correctly diagnose CTEPH because surgical pulmonary thromboendarterectomy is highly effective under the appropriate medical circumstances [<a class="bk_pop" href="#pph.REF.kim.2013.d92">Kim et al 2013</a>].</div></li><li class="half_rhythm"><div><b>Acquired pulmonary venoocclusive disease and pulmonary capillary hemangiomatosis.</b> These conditions are typically acquired but may be hereditary on rare occasion (most often associated with <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>EIF2AK4</i>) [<a class="bk_pop" href="#pph.REF.best.2014.231">Best et al 2014</a>, <a class="bk_pop" href="#pph.REF.eyries.2014.65">Eyries et al 2014</a>].</div></li></ul></div></div><div id="pph.Genetic_Causes_of_Heritable_Pulmonar"><h2 id="_pph_Genetic_Causes_of_Heritable_Pulmonar_">2. Genetic Causes of Heritable Pulmonary Arterial Hypertension</h2><p>To date, ten genes are convincingly known to be associated with heritable pulmonary arterial hypertension (HPAH), although more discoveries will likely emerge over the next few years. <a href="/books/NBK1485/table/pph.T.heritable_pulmonary_arterial_hyper/?report=objectonly" target="object" rid-ob="figobpphTheritablepulmonaryarterialhyper">Table 1</a> lists the percentage of HPAH caused by pathogenic variants in each of these genes based on data from 2572 individuals with World Symposium of Pulmonary Hypertension (WSPH) Group1 PAH (including 1211 individuals with a clinical diagnosis of "<a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a>" or "<a class="def" href="/books/n/gene/glossary/def-item/idiopathic/">idiopathic</a>" PAH prior to genetic testing) enrolled in the <a href="https://www.pahbiobank.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PAH Biobank</a> as reported in <a class="bk_pop" href="#pph.REF.zhu.2019.69">Zhu et al [2019]</a>.</p><p>Of note:</p><ul><li class="half_rhythm"><div><i>BMPR2</i>-releated HPAH is associated with decreased <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a>: lifetime risk of developing PAH with a <i>BMPR2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in a male is 14% and 42% in a female.</div></li><li class="half_rhythm"><div><i>TBX4</i>-related HPAH is associated with a variable <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> with digit-limb-girdle abnormalities, developmental lung disease, developmental delay, and <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart disease, in addition to PAH (OMIM <a href="https://omim.org/entry/147891" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">147891</a>).</div></li></ul><div id="pph.T.heritable_pulmonary_arterial_hyper" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Heritable Pulmonary Arterial Hypertension (HPAH): Genes and Distinguishing Clinical Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1485/table/pph.T.heritable_pulmonary_arterial_hyper/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pph.T.heritable_pulmonary_arterial_hyper_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pph.T.heritable_pulmonary_arterial_hyper_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_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Individuals w/Pathogenic Variant in Gene <sup>2</sup></th><th id="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Allelic Disorders</th><th id="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference</th></tr></thead><tbody><tr><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ACVRL1</i>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare (16/2572)</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/hht/">Hereditary hemorrhagic telangiectasia</a>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bk_pop" href="#pph.REF.girerd.2010.851">Girerd et al [2010]</a>
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</td></tr><tr><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>BMPR1B</i>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare (4/2572)</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Acromesomelic chrondrodysplasia w/genital anomalies (OMIM <a href="https://omim.org/entry/609441" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">609441</a>)</div></li><li class="half_rhythm"><div>Brachydactyly (OMIM <a href="https://omim.org/entry/112600" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">112600</a> & <a href="https://omim.org/entry/616849" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">616849</a>)</div></li></ul>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bk_pop" href="#pph.REF.chida.2012.1501">Chida et al [2012]</a>
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</td></tr><tr><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>BMPR2</i>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">75% of HPAH cases <sup>3</sup><br />& 201/2572 PAH cases in the US <a href="https://www.pahbiobank.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PAH Biobank</a></td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Congenital heart disease <sup>4</sup></div></li><li class="half_rhythm"><div>Fenfluramine-assoc pulmonary arterial hypertension (fen-PAH) <sup>5</sup></div></li><li class="half_rhythm"><div><a href="/books/n/gene/hht/">Hereditary hemorrhagic telangiectasia</a></div></li><li class="half_rhythm"><div>Pulmonary venoocclusive disease (OMIM <a href="https://omim.org/entry/265450" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">265450</a>)</div></li></ul>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bk_pop" href="#pph.REF.cogan.2006.590">Cogan et al [2006]</a>
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</td></tr><tr><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CAV1</i>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare (10/2572)</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Congenital generalized lipodystrophy (OMIM <a href="https://omim.org/entry/612526" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">612526</a>)</div></li><li class="half_rhythm"><div>Type 3 partial lipodystrophy, <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> cataracts, & neurodegeneration syndrome (OMIM <a href="https://omim.org/entry/606721" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">606721</a>)</div></li></ul>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bk_pop" href="#pph.REF.austin.2012.336">Austin et al [2012]</a>
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</td></tr><tr><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ENG</i>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare (6/2572)</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/hht/">Hereditary hemorrhagic telangiectasia</a>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bk_pop" href="#pph.REF.girerd.2010.851">Girerd et al [2010]</a>
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</td></tr><tr><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>KCNK3</i>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare (3/2572)</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bk_pop" href="#pph.REF.ma.2013.351">Ma et al [2013]</a>
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</td></tr><tr><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>KDR</i>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare (4/2572)</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bk_pop" href="#pph.REF.swietlik.2020.e003155">Swietlik et al [2020]</a>
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</td></tr><tr><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SMAD9</i>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare (13/2572)</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bk_pop" href="#pph.REF.shintani.2009.331">Shintani et al [2009]</a>
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</td></tr><tr><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>TBX4</i>
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</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare (23/2572)</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Posterior amelia w/pelvic & pulmonary hypoplasia syndrome (OMIM <a href="https://omim.org/entry/601360" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">601360</a>)</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bk_pop" href="#pph.REF.kerstjensfrederikse.2013.500">Kerstjens-Frederikse et al [2013]</a>
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</td></tr><tr><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>TET2</i>
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|
</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare (10/2572)</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Myelodysplastic syndrome, somatic (OMIM <a href="https://omim.org/entry/614286" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614286</a>)</td><td headers="hd_h_pph.T.heritable_pulmonary_arterial_hyper_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bk_pop" href="#pph.REF.potus.2020.1986">Potus et al [2020]</a>
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</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Based on data from the <a href="https://www.pahbiobank.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">National Biological Sample and Data Repository for Pulmonary Arterial Hypertension</a> (PAH Biobank) [<a class="bk_pop" href="#pph.REF.zhu.2019.69">Zhu et al 2019</a>]</p></div></dd><dt></dt><dd><div><p class="no_margin">Note: HPAH caused by pathogenic variants in the genes listed in <a href="/books/NBK1485/table/pph.T.heritable_pulmonary_arterial_hyper/?report=objectonly" target="object" rid-ob="figobpphTheritablepulmonaryarterialhyper">Table 1</a> is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p></div></dd><dt>1. </dt><dd><div id="pph.TF.1.1"><p class="no_margin">Genes are listed alphabetically.</p></div></dd><dt>2. </dt><dd><div id="pph.TF.1.2"><p class="no_margin">Out of 2572 individuals with World Symposium of Pulmonary Hypertension (WSPH) Group 1 PAH</p></div></dd><dt>3. </dt><dd><div id="pph.TF.1.3"><p class="no_margin">Since the discovery of <i>BMPR2</i> [<a class="bk_pop" href="#pph.REF.astr_m.1999.299">Aström et al 1999</a>], numerous studies consistently show that among families with two or more individuals with confirmed PAH, approximately 75% have a detectable pathogenic <a class="def" href="/books/n/gene/glossary/def-item/germline-variant/">germline variant</a> in <i>BMPR2</i>.</p></div></dd><dt>4. </dt><dd><div id="pph.TF.1.4"><p class="no_margin"><a class="bk_pop" href="#pph.REF.roberts.2004.371">Roberts et al [2004]</a> described six individuals with complete type C atrioventricular canal, atrial septal defect, patent ductus arteriosus, partial anomalous pulmonary venous return, and aortopulmonary window with a ventricular septal defect.</p></div></dd><dt>5. </dt><dd><div id="pph.TF.1.5"><p class="no_margin">In a retrospective study, the records of all persons with a diagnosis of fen-PAH evaluated from 1986 to 2004 were studied. The median duration of fenfluramine exposure was six months, with a median of 4.5 years between exposure & onset of symptoms. Nine (22.5%) of the 40 persons evaluated had a <i>BMPR</i>2 <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> [<a class="bk_pop" href="#pph.REF.souza.2008.343">Souza et al 2008</a>].</p></div></dd></dl></div></div></div></div><div id="pph.Evaluation_Strategies_to_Identify_th"><h2 id="_pph_Evaluation_Strategies_to_Identify_th_">3. Evaluation Strategies to Identify the Genetic Cause of Heritable Pulmonary Arterial Hypertension in a Proband</h2><p>Establishing a specific genetic cause of heritable pulmonary arterial hypertension (HPAH):</p><ul><li class="half_rhythm"><div>Can aid in discussions of prognosis (which are beyond the scope of this <i>GeneReview</i>) and <a href="#pph.Management_of_Heritable_Pulmonary_Ar">genetic counseling</a>;</div></li><li class="half_rhythm"><div>Usually involves a medical history, physical examination, family history, and <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</div></li></ul><p><b>Medical history and physical examination.</b> No particular findings in the medical history or on physical examination distinguish among the various genetic causes of HPAH; however, skeletal anomalies (e.g., patellar irregularities), tracheal and/or bronchial diverticulosis (noted by CT scan or bronchoscopy), developmental delay, and <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart disease can be suggestive of <i>TBX4</i> syndrome [<a class="bk_pop" href="#pph.REF.austin.2020.2000585">Austin & Elliott 2020</a>].</p><p><b>Family history.</b> A three-generation family history should be taken, with attention to relatives with manifestations of HPAH and documentation of relevant findings through direct examination or review of medical records, including results of <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p><p><b>Molecular genetic testing</b> approaches can include a combination of <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing (<a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) and comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>). Gene-targeted testing requires the clinician to hypothesize which genes are likely involved, whereas genomic testing does not.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes the genes listed in <a href="/books/NBK1485/table/pph.T.heritable_pulmonary_arterial_hyper/?report=objectonly" target="object" rid-ob="figobpphTheritablepulmonaryarterialhyper">Table 1</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. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended.</div><div class="half_rhythm">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>.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> does not require the clinician to determine which genes are likely involved. <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.</div><div class="half_rhythm">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>.</div></li></ul></div><div id="pph.Management_of_Heritable_Pulmonary_Ar"><h2 id="_pph_Management_of_Heritable_Pulmonary_Ar_">4. Management of Heritable Pulmonary Arterial Hypertension</h2><p>See <a class="bk_pop" href="#pph.REF.abman.2015.2037">Abman et al [2015]</a> (<a href="https://www.ahajournals.org/doi/epub/10.1161/CIR.0000000000000329" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">full text</a>) and <a class="bk_pop" href="#pph.REF.gali_.2016.67">Galiè et al [2016]</a> (<a href="https://academic.oup.com/eurheartj/article/37/1/67/2887599" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">full text</a>) for evidence-based treatment algorithms for pediatric and adult populations respectively.</p><p>Referral centers specializing in diagnosis and therapy of pulmonary arterial hypertension (PAH) are available across the US (see Pulmonary Hypertension Association <a href="https://phassociation.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">website</a>). Consultation is encouraged for all persons suspected of having PAH because of the complexity and continuing evolution of diagnosis and treatment.</p><p>Unprecedented approval of medications for PAH by the FDA in the last two decades has led to availability of a dozen therapies which all demonstrate some efficacy. However, substantial limitations remain: none of them cures the disease, nor is effective in all patients, nor stops or reverses the underlying pathogenesis (obstruction of the pulmonary arteries).</p><p>The most effective among them, continuous IV prostacyclin or prostanoids, delivered by continuous IV or subcutaneous delivery, are the most complicated to administer as they require patient management of a pump for continuous infusion, with a myriad of possible problems, including sepsis related to chronic central venous catheters. Patient preference often dictates the route of medication administration (continuous IV or subcutaneous, aerosol, oral) or side effects determine which agents are personally acceptable.</p><p>There are no different therapeutic approaches for pregnant women with PAH; standard PAH-directed care remains a crucial component of care in addition to high-risk obstetric approaches.</p><p>Continuous patient monitoring for progression of disease and medication adjustment requires a dedicated multidisciplinary team that communicates seamlessly with multiple specialty pharmacies and insurers.</p></div><div id="pph.Genetic_Risk_Assessment_and_Surveill"><h2 id="_pph_Genetic_Risk_Assessment_and_Surveill_">5. Genetic Risk Assessment and Surveillance of At-Risk Relatives</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><p>Clarification of the genetic status of first-degree family members of an individual with heritable pulmonary arterial hypertension (HPAH) can allow early detection of HPAH and prompt initiation of treatment and improve long-term outcome. A basic view of HPAH genetic risk assessment and surveillance for at-risk relatives is presented in this section; issues that may be specific to a given family or genetic cause of HPAH are not comprehensively addressed.</p><p>Note: Given the complexity of the genetics and surveillance recommendations for HPAH, health care providers should consider referring at-risk asymptomatic relatives to a Pulmonary Hypertension Specialty Referral Center, or to a Cardiovascular Genetics Center or genetic counselor specializing in cardiac or cardiopulmonary genetics (see <a href="https://www.nsgc.org/page/find-a-genetic-counselor" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NSGC – Find a Genetic Counselor</a>).</p><div id="pph.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>HPAH is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p></div><div id="pph.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
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</p><ul><li class="half_rhythm"><div>Some individuals diagnosed with HPAH have an affected parent.</div></li><li class="half_rhythm"><div>Some individuals diagnosed with HPAH have the disorder as the result of 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>. The proportion of individuals with HPAH caused by a <i>de novo</i> 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) and has a known HPAH-causing <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, <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.</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a known HPAH-associated <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> that 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> has 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="#pph.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> 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>. 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></ul></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with HPAH may appear to be negative because of failure to recognize the disorder in affected family members, reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a>, 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 without appropriate clinical evaluation of the parents and/or <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (to establish that neither parent is <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for 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>).</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 the 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 HPAH-associated <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.</div></li><li class="half_rhythm"><div>Because of the significant possibility of reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> of PAH in an individual who is <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a PAH-associated <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> (and the possibility that an individual's sex may influence penetrance), a sib who inherits the pathogenic variant identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> may or may not develop clinically expressed PAH. For example, approximately 14% of males and 42% of females with a known <i>BMPR2</i> pathogenic variant will express PAH clinically in their lifetime [<a class="bk_pop" href="#pph.REF.larkin.2012.892">Larkin et al 2012</a>].</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a known HPAH-related <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> that cannot be detected in the leukocyte DNA of either parent, the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> to sibs is estimated to be approximately 1.3% or less because of the theoretic possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> [<a class="bk_pop" href="#pph.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the parents are clinically unaffected but their genetic status is unknown, the risk that a sib of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with a known PAH-associated <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has inherited the pathogenic variant is assumed to be 50% for clinical screening purposes (see <a href="#pph.Clinical_Surveillance_for_Relatives">Clinical Surveillance for Relatives at Risk</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 an HPAH-related <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is at a 50% risk of inheriting the pathogenic variant.</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 <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the parent's family members may be at risk.</p></div><div id="pph.Clinical_Surveillance_for_Relatives"><h3>Clinical Surveillance for Relatives at Risk</h3><p><b>Asymptomatic family members of an affected individual in whom the specific genetic cause of HPAH has not been identified.</b> The WSPH, American College of Cardiology, and American Heart Association recommend serial screening by echocardiography of at-risk family members every three to five years to enable early detection and treatment.</p><p><b>Asymptomatic family members of an affected individual who has a known <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in an HPAH-associated <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</b> If a definitive pathogenic variant is identified in the affected individual, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> can be performed in at-risk relatives to clarify their genetic risk:</p><ul><li class="half_rhythm"><div>Those identified as <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> present in the affected family member and thus at high risk for developing HPAH should be screened each year with a clinical evaluation and echocardiogram [<a class="bk_pop" href="#pph.REF.mclaughlin.2009a.1573">McLaughlin et al 2009a</a>, <a class="bk_pop" href="#pph.REF.mclaughlin.2009b.2250">McLaughlin et al 2009b</a>, <a class="bk_pop" href="#pph.REF.morrell.2019.1801899">Morrell et al 2019</a>].</div></li><li class="half_rhythm"><div>Those without the <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> HPAH-associated <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> are no longer considered to be at increased risk and thus may be discharged from cardiac surveillance.</div></li></ul></div></div><div id="pph.Resources"><h2 id="_pph_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>PHAWARE</b>
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</div><div>
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<a href="https://www.phaware.global/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.phaware.global</a>
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</div></li><li class="half_rhythm"><div>
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<b>Pulmonary Hypertension Association (PHA)</b>
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</div><div>8401 Colesville Road</div><div>Suite 00</div><div>Silver Spring MD 20910</div><div><b>Phone:</b> 301-565-3004</div><div><b>Fax:</b> 301-565-3994</div><div><b>Email:</b> PHA@PHAssociation.org</div><div>
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<a href="http://www.phassociation.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.phassociation.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>American Heart Association</b>
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</div><div>
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<a href="http://www.heart.org/HEARTORG/Conditions/HighBloodPressure/AboutHighBloodPressure/What-is-Pulmonary-Hypertension_UCM_301792_Article.jsp" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">What is Pulmonary Hypertension?</a>
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</div></li><li class="half_rhythm"><div>
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<b>American Lung Association</b>
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</div><div><b>Phone:</b> 800-586-4872</div><div>
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<a href="http://www.lung.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">lung.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>MedlinePlus</b>
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</div><div>
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<a href="https://medlineplus.gov/genetics/condition/pulmonary-arterial-hypertension/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Pulmonary arterial hypertension</a>
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</div></li></ul>
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</div><div id="pph.Chapter_Notes"><h2 id="_pph_Chapter_Notes_">Chapter Notes</h2><div id="pph.Author_Notes"><h3>Author Notes</h3><p>Genetic and <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> discovery efforts in PAH are rapidly progressing. Some sites of interest include the following:</p><ul><li class="half_rhythm"><div>
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<a href="https://www.pahbiobank.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PAH Biobank</a>
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</div></li><li class="half_rhythm"><div>
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<a href="https://www.ipahcohort.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">National Cohort Study of Idiopathic and Heritable PAH</a>
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</div></li><li class="half_rhythm"><div>
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<a href="https://www.ukbiobank.ac.uk/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UK Biobank</a>
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</div></li><li class="half_rhythm"><div>
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<a href="https://wchunglab.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Chung Lab at Columbia</a>
|
|
</div></li></ul><p><a href="https://www.vumc.org/pah/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri"><b>Pulmonary Hypertension Clinical & Research Team</b></a><br />Vanderbilt Research Registry of PAH Families, Idiopathic PAH Cases, and other PAH Forms<br />Kelly Fox Burke, Coordinator<br />Vanderbilt University Medical Center<br />Phone: 800-288-0378<br />Email: <a href="mailto:dev@null" data-email="gro.cmuv@ekrub.yllek" class="oemail">gro.cmuv@ekrub.yllek</a></p></div><div id="pph.Acknowledgments"><h3>Acknowledgments</h3><p>The authors – and the entire field – are indebted to the commitment and efforts of so many patients, families, and researchers who have propelled the genetics of PAH forward. While it is risky to list names for fear of omission, at a minimum we thank the following:</p><ul><li class="half_rhythm"><div>The countless patients, families, and related individuals who graciously participate in genetic studies of PAH across the world</div></li><li class="half_rhythm"><div>Lisa Wheeler, former Coordinator of Familial PAH efforts at Vanderbilt</div></li><li class="half_rhythm"><div>The countless collaborative research teams who work tirelessly to study PAH across the world</div></li><li class="half_rhythm"><div>Sources of funding, including the National Institutes of Health, which has funded work at Vanderbilt for many years on this topic</div></li></ul></div><div id="pph.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>23 December 2020 (ha) Comprehensive update posted live; scope changed to overview</div></li><li class="half_rhythm"><div>11 June 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>29 March 2011 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>18 July 2007 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>2 November 2004 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>18 July 2002 (me) Review posted live</div></li><li class="half_rhythm"><div>14 January 2002 (jl) Original submission</div></li></ul></div></div><div id="pph.References"><h2 id="_pph_References_">References</h2><div id="pph.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="pph.REF.abman.2015.2037">Abman
|
|
SH, Hansmann
|
|
G, Archer
|
|
SL, Ivy
|
|
DD, Adatia
|
|
I, Chung
|
|
WK, Hanna
|
|
BD, Rosenzweig
|
|
EB, Raj
|
|
JU, Cornfield
|
|
D, Stenmark
|
|
KR, Steinhorn
|
|
R, Thebaud
|
|
B, Fineman
|
|
JR, Kuehne
|
|
T, Feinstein
|
|
JA, Friedberg
|
|
MK, Earing
|
|
M, Barst
|
|
RJ, Keller
|
|
RL, Kinsella
|
|
JP, Mullen
|
|
M, Deterding
|
|
R, Kulik
|
|
T, Mallory
|
|
G, Humpl
|
|
T, Wessel
|
|
DL, et al.
|
|
Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society.
|
|
Circulation.
|
|
2015;132:2037-99.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/26534956" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26534956</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.astr_m.1999.299">Aström
|
|
AK, Jin
|
|
D, Imamura
|
|
T, Röijer
|
|
E, Rosenzweig
|
|
B, Miyazono
|
|
K, ten Dijke
|
|
P, Stenman
|
|
G. Chromosomal localization of three human genes encoding bone morphogenetic protein receptors.
|
|
Mamm Genome.
|
|
1999;10:299-302
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/10051328" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10051328</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.austin.2020.2000585">Austin
|
|
ED, Elliott
|
|
CG. TBX4 syndrome: a systemic disease highlighted by pulmonary arterial hypertension in its most severe form.
|
|
Eur Respir J.
|
|
2020;55:2000585.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/32409426" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32409426</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.austin.2012.336">Austin
|
|
ED, Ma
|
|
L, LeDuc
|
|
C, Berman Rosenzweig
|
|
E, Borczuk
|
|
A, Phillips
|
|
JA
|
|
3rd, Palomero
|
|
T, Sumazin
|
|
P, Kim
|
|
HR, Talati
|
|
MH, West
|
|
J, Loyd
|
|
JE, Chung
|
|
WK. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension.
|
|
Circ Cardiovasc Genet.
|
|
2012;5:336-43.
|
|
[<a href="/pmc/articles/PMC3380156/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3380156</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22474227" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22474227</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.badesch.2010.376">Badesch
|
|
DB, Raskob
|
|
GE, Elliott
|
|
CG, Krichman
|
|
AM, Farber
|
|
HW, Frost
|
|
AE, Barst
|
|
RJ, Benza
|
|
RL, Liou
|
|
TG, Turner
|
|
M, Giles
|
|
S, Feldkircher
|
|
K, Miller
|
|
DP, McGoon
|
|
MD. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry.
|
|
Chest.
|
|
2010;137:376-87.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/19837821" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19837821</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.ballard.2021.109">Ballard
|
|
W
|
|
3rd, Dixon
|
|
B, McEvoy
|
|
CA, Verma
|
|
AK. Pulmonary arterial hypertension in pregnancy.
|
|
Cardiol Clin.
|
|
2021;39:109-18.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/33222807" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33222807</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.best.2014.231">Best
|
|
DH, Sumner
|
|
KL, Austin
|
|
ED, Chung
|
|
WK, Brown
|
|
LM, Borczuk
|
|
AC, Rosenzweig
|
|
EB, Bayrak-Toydemir
|
|
P, Mao
|
|
R, Cahill
|
|
BC, Tazelaar
|
|
HD, Leslie
|
|
KO, Hemnes
|
|
AR, Robbins
|
|
IM, Elliott
|
|
CG. EIF2AK4 mutations in pulmonary capillary hemangiomatosis.
|
|
Chest.
|
|
2014;145:231-6.
|
|
[<a href="/pmc/articles/PMC3921094/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3921094</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24135949" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24135949</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.chida.2012.1501">Chida
|
|
A, Shintani
|
|
M, Nakayama
|
|
T, Furutani
|
|
Y, Hayama
|
|
E, Inai
|
|
K, Saji
|
|
T, Nonoyama
|
|
S, Nakanishi
|
|
T. Missense mutations of the BMPR1B (ALK6) gene in childhood idiopathic pulmonary arterial hypertension.
|
|
Circ J.
|
|
2012;76:1501-8.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/22374147" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22374147</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.cogan.2006.590">Cogan
|
|
JD, Pauciulo
|
|
MW, Batchman
|
|
AP, Prince
|
|
MA, Robbins
|
|
IM, Hedges
|
|
LK, Stanton
|
|
KC, Wheeler
|
|
LA, Phillips
|
|
JA
|
|
3rd, Loyd
|
|
JE, Nichols
|
|
WC. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension.
|
|
Am J Respir Crit Care Med.
|
|
2006;174:590-8.
|
|
[<a href="/pmc/articles/PMC2648061/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2648061</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16728714" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16728714</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.eyries.2014.65">Eyries
|
|
M, Montani
|
|
D, Girerd
|
|
B, Perret
|
|
C, Leroy
|
|
A, Lonjou
|
|
C, Chelghoum
|
|
N, Coulet
|
|
F, Bonnet
|
|
D, Dorfmüller
|
|
P, Fadel
|
|
E, Sitbon
|
|
O, Simonneau
|
|
G, Tregouët
|
|
DA, Humbert
|
|
M, Soubrier
|
|
F. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension.
|
|
Nat Genet.
|
|
2014;46:65-9.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/24292273" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24292273</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.gali_.2016.67">Galiè
|
|
N, Humbert
|
|
M, Vachiery
|
|
JL, Gibbs
|
|
S, Lang
|
|
I, Torbicki
|
|
A, Simonneau
|
|
G, Peacock
|
|
A, Vonk Noordegraaf
|
|
A, Beghetti
|
|
M, Ghofrani
|
|
A, Gomez Sanchez
|
|
MA, Hansmann
|
|
G, Klepetko
|
|
W, Lancellotti
|
|
P, Matucci
|
|
M, McDonagh
|
|
T, Pierard
|
|
LA, Trindade
|
|
PT, Zompatori
|
|
M, Hoeper
|
|
M, et al.
|
|
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
|
|
Eur Heart J.
|
|
2016;37:67-119.
|
|
</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.girerd.2010.851">Girerd
|
|
B, Montani
|
|
D, Coulet
|
|
F, Sztrymf
|
|
B, Yaici
|
|
A, Jaïs
|
|
X, Tregouet
|
|
D, Reis
|
|
A, Drouin-Garraud
|
|
V, Fraisse
|
|
A, Sitbon
|
|
O, O'Callaghan
|
|
DS, Simonneau
|
|
G, Soubrier
|
|
F, Humbert
|
|
M. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation.
|
|
Am J Respir Crit Care Med.
|
|
2010;181:851-61.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/20056902" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20056902</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.kerstjensfrederikse.2013.500">Kerstjens-Frederikse
|
|
WS, Bongers
|
|
EM, Roofthooft
|
|
MT, Leter
|
|
EM, Douwes
|
|
JM, Van Dijk
|
|
A, Vonk-Noordegraaf
|
|
A, Dijk-Bos
|
|
KK, Hoefsloot
|
|
LH, Hoendermis
|
|
ES, Gille
|
|
JJ, Sikkema-Raddatz
|
|
B, Hofstra
|
|
RM, Berger
|
|
RM. TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension.
|
|
J Med Genet.
|
|
2013;50:500-6.
|
|
[<a href="/pmc/articles/PMC3717587/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3717587</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23592887" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23592887</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.kim.2013.d92">Kim
|
|
NH, Delcroix
|
|
M, Jenkins
|
|
DP, Channick
|
|
R, Dartevelle
|
|
P, Jansa
|
|
P, Lang
|
|
I, Madani
|
|
MM, Ogino
|
|
H, Pengo
|
|
V, Mayer
|
|
E. Chronic thromboembolic pulmonary hypertension.J Am Coll Cardiol.
|
|
2013;62:D92-9.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/24355646" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24355646</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.kozu.2018.939">Kozu
|
|
K, Sugimura
|
|
K, Aoki
|
|
T, Tatebe
|
|
S, Yamamoto
|
|
S, Yaoita
|
|
N, Shimizu
|
|
T, Nochioka
|
|
K, Sato
|
|
H, Konno
|
|
R, Satoh
|
|
K, Miyata
|
|
S, Shimokawa
|
|
H. Sex differences in hemodynamic responses and long-term survival to optimal medical therapy in patients with pulmonary arterial hypertension.
|
|
Heart Vessels.
|
|
2018;33:939-47.
|
|
[<a href="/pmc/articles/PMC6060798/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6060798</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29441403" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29441403</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.larkin.2012.892">Larkin
|
|
EK, Newman
|
|
JH, Austin
|
|
ED, Hemnes
|
|
AR, Wheeler
|
|
L, Robbins
|
|
IM, West
|
|
JD, Phillips
|
|
JA
|
|
3rd, Hamid
|
|
R, Loyd
|
|
JE. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension.
|
|
Am J Respir Crit Care Med.
|
|
2012;186:892-6.
|
|
[<a href="/pmc/articles/PMC3530218/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3530218</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22923661" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22923661</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.ma.2013.351">Ma
|
|
L, Roman-Campos
|
|
D, Austin
|
|
ED, Eyries
|
|
M, Sampson
|
|
KS, Soubrier
|
|
F, Germain
|
|
M, Trégouët
|
|
DA, Borczuk
|
|
A, Rosenzweig
|
|
EB, Girerd
|
|
B, Montani
|
|
D, Humbert
|
|
M, Loyd
|
|
JE, Kass
|
|
RS, Chung
|
|
WK. A novel channelopathy in pulmonary arterial hypertension.N Engl J Med.
|
|
2013;369:351-61.
|
|
[<a href="/pmc/articles/PMC3792227/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3792227</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23883380" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23883380</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.mclaughlin.2009a.1573">McLaughlin
|
|
VV, Archer
|
|
SL, Badesch
|
|
DB, Barst
|
|
RJ, Farber
|
|
HW, Lindner
|
|
JR, Mathier
|
|
MA, McGoon
|
|
MD, Park
|
|
MH, Rosenson
|
|
RS, Rubin
|
|
LJ, Tapson
|
|
VF, Varga
|
|
J, et al.
|
|
ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association.
|
|
J Am Coll Cardiol.
|
|
2009a;53:1573-1619.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/19389575" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19389575</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.mclaughlin.2009b.2250">McLaughlin
|
|
VV, Archer
|
|
SL, Badesch
|
|
DB, Barst
|
|
RJ, Farber
|
|
HW, Lindner
|
|
JR, Mathier
|
|
MA, McGoon
|
|
MD, Park
|
|
MH, Rosenson
|
|
RS, Rubin
|
|
LJ, Tapson
|
|
VF, Varga
|
|
J, Harrington
|
|
RA, Anderson
|
|
JL, Bates
|
|
ER, Bridges
|
|
CR, Eisenberg
|
|
MJ, Ferrari
|
|
VA, Grines
|
|
CL, Hlatky
|
|
MA, Jacobs
|
|
AK, Kaul
|
|
S, Lichtenberg
|
|
RC, Lindner
|
|
JR, Moliterno
|
|
DJ, Mukherjee
|
|
D, Pohost
|
|
GM, Rosenson
|
|
RS, Schofield
|
|
RS, Shubrooks
|
|
SJ, Stein
|
|
JH, Tracy
|
|
CM, Weitz
|
|
HH, Wesley
|
|
DJ, et al.
|
|
ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association.
|
|
Circulation.
|
|
2009b;119:2250-94.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/19332472" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19332472</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.morrell.2019.1801899">Morrell
|
|
NW, Aldred
|
|
MA, Chung
|
|
WK, Elliott
|
|
CG, Nichols
|
|
WC, Soubrier
|
|
F, Trembath
|
|
RC, Loyd
|
|
JE. Genetics and genomics of pulmonary arterial hypertension.
|
|
Eur Respir J.
|
|
2019;53:1801899.
|
|
[<a href="/pmc/articles/PMC6351337/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6351337</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30545973" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30545973</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.potus.2020.1986">Potus
|
|
F, Pauciulo
|
|
MW, Cook
|
|
EK, Zhu
|
|
N, Hsieh
|
|
A, Welch
|
|
CL, Shen
|
|
Y, Tian
|
|
L, Lima
|
|
P, Mewburn
|
|
J, D'Arsigny
|
|
CL, Lutz
|
|
KA, Coleman
|
|
AW, Damico
|
|
R, Snetsinger
|
|
B, Martin
|
|
AY, Hassoun
|
|
PM, Nichols
|
|
WC, Chung
|
|
WK, Rauh
|
|
MJ, Archer
|
|
SL. Novel mutations and decreased expression of the epigenetic regulator TET2 in pulmonary arterial hypertension.
|
|
Circulation.
|
|
2020;141:1986-2000.
|
|
[<a href="/pmc/articles/PMC7299806/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7299806</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32192357" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32192357</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.rahbari.2016.126">Rahbari
|
|
R, Wuster
|
|
A, Lindsay
|
|
SJ, Hardwick
|
|
RJ, Alexandrov
|
|
LB, Turki
|
|
SA, Dominiczak
|
|
A, Morris
|
|
A, Porteous
|
|
D, Smith
|
|
B, Stratton
|
|
MR, Hurles
|
|
ME, et al.
|
|
Timing, rates and spectra of human germline mutation.
|
|
Nat Genet.
|
|
2016;48:126-33.
|
|
[<a href="/pmc/articles/PMC4731925/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4731925</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26656846" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26656846</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.richards.2015.405">Richards
|
|
S, Aziz
|
|
N, Bale
|
|
S, Bick
|
|
D, Das
|
|
S, Gastier-Foster
|
|
J, Grody
|
|
WW, Hegde
|
|
M, Lyon
|
|
E, Spector
|
|
E, Voelkerding
|
|
K, Rehm
|
|
HL, et al.
|
|
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
|
|
Genet Med.
|
|
2015;17:405-24.
|
|
[<a href="/pmc/articles/PMC4544753/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4544753</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25741868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25741868</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.roberts.2004.371">Roberts
|
|
KE, McElroy
|
|
JJ, Wong
|
|
WP, Yen
|
|
E, Widlitz
|
|
A, Barst
|
|
RJ, Knowles
|
|
JA, Morse
|
|
JH. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease.
|
|
Eur Respir J.
|
|
2004;24:371-4.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/15358693" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15358693</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.shintani.2009.331">Shintani
|
|
M, Yagi
|
|
H, Nakayama
|
|
T, Saji
|
|
T, Matsuoka
|
|
R.
|
|
A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension.
|
|
J Med Genet.
|
|
2009;46:331-7.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/19211612" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19211612</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.simonneau.2019.1801913">Simonneau
|
|
G, Montani
|
|
D, Celermajer
|
|
DS, Denton
|
|
CP, Gatzoulis
|
|
MA, Krowka
|
|
M, Williams
|
|
PG, Souza
|
|
R. Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
|
|
Eur Respir J.
|
|
2019;53:1801913.
|
|
[<a href="/pmc/articles/PMC6351336/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6351336</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30545968" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30545968</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.souza.2008.343">Souza
|
|
R, Humbert
|
|
M, Sztrymf
|
|
B, Jaïs
|
|
X, Yaïci
|
|
A, Le Pavec
|
|
J, Parent
|
|
F, Hervé
|
|
P, Soubrier
|
|
F, Sitbon
|
|
O, Simonneau
|
|
G. Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases.
|
|
Eur Respir J.
|
|
2008;31:343-8.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/17959632" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17959632</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.swietlik.2020.e003155">Swietlik
|
|
EM, Greene
|
|
D, Zhu
|
|
N, Megy
|
|
K, Cogliano
|
|
M, Rajaram
|
|
S, Pandya
|
|
D, Tilly
|
|
T, Lutz
|
|
KA, Welch
|
|
CCL, Pauciulo
|
|
MW, Southgate
|
|
L, Martin
|
|
JM, Treacy
|
|
CM, Penkett
|
|
CJ, Stephens
|
|
JC, Bogaard
|
|
HJ, Church
|
|
C, Coghlan
|
|
G, Coleman
|
|
AW, Condliffe
|
|
R, Eichstaedt
|
|
CA, Eyries
|
|
M, Gall
|
|
H, Ghio
|
|
S, Girerd
|
|
B, Grünig
|
|
E, Holden
|
|
S, Howard
|
|
L, Humbert
|
|
M, Kiely
|
|
DG, Kovacs
|
|
G, Lordan
|
|
J, Machado
|
|
RD, Mackenzie Ross
|
|
RV, McCabe
|
|
C, Moledina
|
|
S, Montani
|
|
D, Olschewski
|
|
H, Pepke-Zaba
|
|
J, Price
|
|
L, Rhodes
|
|
CJ, Seeger
|
|
W, Soubrier
|
|
F, Suntharalingam
|
|
J, Toshner
|
|
MR, Vonk Noordegraaf
|
|
A, Wharton
|
|
J, Wild
|
|
JM, Wort
|
|
SJ, Lawrie
|
|
A, Wilkins
|
|
MR, Trembath
|
|
RC, Shen
|
|
Y, Chung
|
|
WK, Swift
|
|
AJ, Nichols
|
|
WC, Morrell
|
|
NW, Gräf
|
|
S. Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension.
|
|
Circ Genom Precis Med.
|
|
2020;14:e003155.
|
|
[<a href="/pmc/articles/PMC7892262/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7892262</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33320693" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33320693</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="pph.REF.zhu.2019.69">Zhu
|
|
N, Pauciulo
|
|
MW, Welch
|
|
CL, Lutz
|
|
KA, Coleman
|
|
AW, Gonzaga-Jauregui
|
|
C, Wang
|
|
J, Grimes
|
|
JM, Martin
|
|
LJ, He
|
|
H, Shen
|
|
Y, Chung
|
|
WK, Nichols
|
|
WC, et al.
|
|
Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension.
|
|
Genome Med.
|
|
2019;11:69.
|
|
[<a href="/pmc/articles/PMC6857288/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6857288</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31727138" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31727138</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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Heritable Pulmonary Arterial Hypertension Overview. 2002 Jul 18 [Updated 2020 Dec 23]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. 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xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hereditary Hemorrhagic Telangiectasia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">McDonald J, Stevenson DA. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301312" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Loeys-Dietz Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Loeys-Dietz Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Loeys BL, Dietz HC. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301510" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Dietz H. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301625" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Retinoblastoma.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Retinoblastoma.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Lohmann DR, Gallie BL. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301722" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Shwachman-Diamond Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Shwachman-Diamond Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Nelson A, Myers K. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=20301658" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=20301658" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" 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offscreen_noflow">TTR transthyretin [Homo sapiens]<div class="brieflinkpopdesc">Gene ID:7276</div></div><div class="tertiary">Gene</div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=3" href="/portal/utils/pageresolver.fcgi?recordid=67d9ff482f30673f7be50cf0">Hereditary Spastic Paraplegia Overview - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Hereditary Spastic Paraplegia Overview - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=4" href="/portal/utils/pageresolver.fcgi?recordid=67d9ff4667c23b31e0998283">WNK1 WNK lysine deficient protein kinase 1 [Homo sapiens]</a><div class="ralinkpop offscreen_noflow">WNK1 WNK lysine deficient protein kinase 1 [Homo sapiens]<div class="brieflinkpopdesc">Gene ID:65125</div></div><div class="tertiary">Gene</div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=5" href="/portal/utils/pageresolver.fcgi?recordid=67d9ff442f30673f7be4f9d7">SCN9A sodium voltage-gated channel alpha subunit 9 [Homo sapiens]</a><div class="ralinkpop offscreen_noflow">SCN9A sodium voltage-gated channel alpha subunit 9 [Homo sapiens]<div class="brieflinkpopdesc">Gene ID:6335</div></div><div class="tertiary">Gene</div></li></ul><p class="HTOn">Your browsing activity is empty.</p><p class="HTOff">Activity recording is turned off.</p><p id="turnOn" class="HTOff"><a href="javascript:historyDisplayState('HTOn')">Turn recording back on</a></p><a class="seemore" href="/sites/myncbi/recentactivity">See more...</a></div></div></div>
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