Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome.
Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome.
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DOI：
10.1016/j.xhgg.2023.100232
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发表时间：
2023-10-12
期刊：
影响因子：
--
通讯作者：
Bamshad, Michael J.
中科院分区：
文献类型：
--
作者：
Blue, Elizabeth E.;White, Janson J.;Dush, Michael K.;Gordon, William W.;Wyatt, Brent H.;White, Peter;Marvin, Colby T.;Helle, Emmi;Ojala, Tiina;Priest, James R.;Jenkins, Mary M.;Almli, Lynn M.;Reefhuis, Jennita;Pangilinan, Faith;Brody, Lawrence C.;McBride, Kim L.;Garg, Vidu;Shaw, Gary M.;Romitti, Paul A.;Nembhard, Wendy N.;Browne, Marilyn L.;Werler, Martha M.;Kay, Denise M.;Mital, Seema;Chong, Jessica X.;Nascone-Yoder, Nanette M.;Bamshad, Michael J.
左心发育不全综合征(HLHS)是一种严重的先天性心脏缺陷(CHD)，其特征是左心室和主动脉发育不全，并伴有主动脉瓣和二尖瓣狭窄或闭锁。HLHS仅占∼所有CHD的4%-8%，但占∼死亡人数的25%。HLHS是70%的家庭中的一种孤立的缺陷(即iHLHS)，其中绝大多数是单纯性的。尽管进行了密集的研究，但iHLHS的遗传基础在很大程度上仍不清楚。我们对来自四个独立队列的331个iHLHS家系进行了外显子组测序。基于孟德尔模型的分析表明，iHLHS不是由于先前报道的iHLHS或CHD基因中的单个大效应等位基因所致，该队列中90%的家系是iHLHS或CHD的基础。基于基因的关联测试发现iHLHS的风险增加与CAPn2的变异相关(p=1.8x×10cm2−5)，编码一种参与功能黏附的蛋白质。在脊椎动物模型(非洲爪哇)中进行的功能验证研究证实，CAPN2对于心脏脑室的形态发生是必不可少的，在体内，钙蛋白酶功能的丧失会导致脑室表型发育不良，并表明人类CAPN2707C>；T和CAPN21112C>；T变异是亚型等位基因，分别在多个患有iHLHS的个体中发现。总而言之，我们的研究结果表明，iHLHS通常不是孟德尔式的疾病，证明CAPN2变异增加了iHLHS的风险，并确定了一条参与HLHS发病的新途径。Blue等人。描述孤立左心发育不良综合征(IHLHS)的遗传基础，通过非洲爪哇模型中的关联测试和功能验证发现CAPN2基因变异。他们的结果表明，iHLHS不是典型的孟德尔病，并发现了一种参与HLHS发病的新途径。
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%–8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10−5), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2707C>T and CAPN21112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis. Blue et al. characterize the genetic basis of isolated hypoplastic left heart syndrome (iHLHS), implicating hypomorphic CAPN2 variants through association testing and functional validation in a Xenopus laevis model. Their results suggest that iHLHS is not typically a Mendelian condition and identify a novel pathway involved in HLHS pathogenesis.
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影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
7.8
作者：
Bialkowska, K;Kulkarni, S;Fox, JEB
通讯作者：
Fox, JEB
影响因子：
2.7
作者：
Dedieu, S;Mazères, G;Cottin, P
通讯作者：
Cottin, P
DOI：
10.1083/jcb.200703185
发表时间：
2007-11-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Flevaris P;Stojanovic A;Gong H;Chishti A;Welch E;Du X
通讯作者：
Du X
影响因子：
4.8
作者：
Chan, Keefe T.;Bennin, David A.;Huttenlocher, Anna
通讯作者：
Huttenlocher, Anna