Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease.
Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease.
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DOI：
10.1002/mgg3.1406
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发表时间：
2020-10
影响因子：
2
通讯作者：
Prakash SK
中科院分区：
文献类型：
--
作者：
Musfee FI;Guo D;Pinard AC;Hostetler EM;Blue EE;Nickerson DA;University of Washington Center for Mendelian Genomics (UW-CMG);Bamshad MJ;Milewicz DM;Prakash SK
二叶式主动脉瓣（BAV）是成人最常见的心血管畸形，患病率为0.5%-2%。由于胸主动脉瘤或急性主动脉夹层（AMI）而确定的队列中BAV的患病率高达20%。然而，致病BAV基因的贡献，以腹泻是未知的。因此，我们评估了在BAV患者中表现为BAV的GATA 4、NOTCH 1、SMAD 6或ROBO 4的罕见有害变体。我们的队列包括487例遗传性胸主动脉瘤或夹层先证者（HAV，12% BAV，29%女性）和63例二叶主动脉瓣疾病早发并发症先证者（EBAV，63% BAV，34%女性）。在全外显子组测序后，我们对GATA 4、NOTCH 1、SMAD 6和ROBO 4变异体进行了功能注释，并将这些基因中罕见变异体的患病率与无HSP 70的对照组进行了比较。我们在12例（18%）EBAV病例中鉴定了11种罕见的GATA 4、SMAD 6或ROBO 4有害变体。罕见SMAD 6和GATA 4变异体的负荷在EBAV中显著富集，但在HIV-HIV-HIV-HIV-BAV病例中没有显著富集（p <0.003）。NOTCH 1、ROBO 4、SMAD 6或GATA 4的罕见变异体对HAE队列中的BAV无显著影响。我们的结论是，BAV患者谁目前与HESIS是一个基因不同的亚组与基因检测和预后的影响。二叶式主动脉瓣（BAV）是成人中最常见的先天性心脏病，也是易诱发急性主动脉夹层（HSVs）的遗传性胸主动脉瘤的常见风险因素。为了阐明已知的致病BAV基因在HLAND中的作用，我们确定了同时存在BAV和HLAND的个体是否在NOTCH 1、GATA 4、SMAD 6或ROBO 4中具有增加的罕见有害变体负担。我们发现，这些基因的变异并不显着有助于HSP 70，即使在BAV的情况下。这些结果表明，由于心脏瓣膜病并发症而出现的BAV患者与由于心脏瓣膜病而出现的BAV患者相比具有明显不同的遗传和临床特征。因此，可能需要其他因素来驱动BAV患者中具有临床意义的动脉瘤扩大和夹层。
Bicuspid aortic valve (BAV) is the most common cardiovascular malformation in adults, with a prevalence of 0.5%–2%. The prevalence of BAV in cohorts who were ascertained due to thoracic aortic aneurysms or acute aortic dissections (TAD) is as high as 20%. However, the contribution of causal BAV genes to TAD is not known. Therefore, we evaluated rare deleterious variants of GATA4, NOTCH1, SMAD6, or ROBO4 in patients with BAV who presented with TAD. Our cohort consisted of 487 probands with Heritable Thoracic Aortic Aneurysms or Dissections (HTAD, 12% BAV, 29% female) and 63 probands with Early onset complications of Bicuspid Aortic Valve disease (EBAV, 63% TAD, 34% female). After whole exome sequencing, we functionally annotated GATA4, NOTCH1, SMAD6, and ROBO4 variants and compared the prevalence of rare variants in these genes to controls without HTAD. We identified 11 rare deleterious variants of GATA4, SMAD6, or ROBO4 in 12 (18%) EBAV cases. The burden of rare SMAD6 and GATA4 variants was significantly enriched in EBAV but not in HTAD cases, even among HTAD cases with BAV (p < .003). Rare variants of NOTCH1, ROBO4, SMAD6, or GATA4 do not significantly contribute to BAV in cohorts with HTAD. We conclude that BAV patients who present with HTAD are a genetically distinct subgroup with implications for genetic testing and prognosis. Bicuspid aortic valve (BAV) is the most common congenital heart defect in adults and is a frequent risk factor for heritable thoracic aortic aneurysms predisposing to acute aortic dissections (HTAD). To elucidate the roles of known causal BAV genes in HTAD, we determined if individuals who present with both BAV and HTAD harbor an increased burden of rare deleterious variants in NOTCH1, GATA4, SMAD6 or ROBO4. We found that variants of these genes do not significantly contribute to HTAD, even in cases with BAV. These results indicate that BAV patients who present due to complications of HTAD have markedly different genetic and clinical profiles than BAV patients who present due to valvular heart disease. Therefore, additional factors are probably required to drive clinically meaningful enlargement and dissection of aneurysms in BAV patients.
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影响因子：
30.8
作者：
Gould RA;Aziz H;Woods CE;Seman-Senderos MA;Sparks E;Preuss C;Wünnemann F;Bedja D;Moats CR;McClymont SA;Rose R;Sobreira N;Ling H;MacCarrick G;Kumar AA;Luyckx I;Cannaerts E;Verstraeten A;Björk HM;Lehsau AC;Jaskula-Ranga V;Lauridsen H;Shah AA;Bennett CL;Ellinor PT;Lin H;Isselbacher EM;Lino Cardenas CL;Butcher JT;Hughes GC;Lindsay ME;Baylor-Hopkins Center for Mendelian Genomics;MIBAVA Leducq Consortium;Mertens L;Franco-Cereceda A;Verhagen JMA;Wessels M;Mohamed SA;Eriksson P;Mital S;Van Laer L;Loeys BL;Andelfinger G;McCallion AS;Dietz HC
通讯作者：
Dietz HC
影响因子：
9.8
作者：
Kwartler, Callie S.;Gong, Limin;Milewicz, Dianna M.
通讯作者：
Milewicz, Dianna M.
影响因子：
24
作者：
Cripe, L;Andelfinger, G;Benson, DW
通讯作者：
Benson, DW
影响因子：
14.9
作者：
Wang K;Li M;Hakonarson H
通讯作者：
Hakonarson H
影响因子：
--
作者：
Zhang, Wenwen;Han, Qian;Zhou, Weimin
通讯作者：
Zhou, Weimin