右位心的患病阈值和多因素遗传模式  

Rare loss-of-function variants reveal threshold and multifactorial inheritance of dextrocardia

作　　者：陈仲中 高云倩 卢磊 李楠 刘佩 彭瑞 刘玲玲 黄荷凤 傅启华 洪海筏 张建国 王红艳 Zhongzhong Chen;Yunqian Gao;Lei Lu;Nan Li;Pei Liu;Rui Peng;Lingling Liu;Hefeng Huang;Qihua Fu;Haifa Hong;Jianguo Zhang;Hongyan Wang(Obstetrics and Gynecology Hospital,State Key Laboratory of Genetic Engineering,Institute of Reproduction and Development,Fudan University,Shanghai 200011,China;Pediatric Translational Medicine Institute,Shanghai Children’s Medical Center,School of Medicine,Shanghai Jiao Tong University,Shanghai 200127,China;Shanghai Key Laboratory of Metabolic Remodelling and Health,Institute of Metabolism and Integrative Biology,Fudan University,Shanghai 200438,China;BGI Genomics,Shenzhen 518083,China;Obstetrics and Gynecology Hospital of Fudan University,Shanghai 200090,China;Department of Cardiothoracic Surgery,Shanghai Children’s Medical Center,School of Medicine,Shanghai Jiao Tong University,Shanghai 200127,China;Children’s Hospital of Fudan University,Shanghai 201102,China)

机构地区：[1]Obstetrics and Gynecology Hospital,State Key Laboratory of Genetic Engineering,Institute of Reproduction and Development,Fudan University,Shanghai 200011,China [2]Pediatric Translational Medicine Institute,Shanghai Children’s Medical Center,School of Medicine,Shanghai Jiao Tong University,Shanghai 200127,China [3]Shanghai Key Laboratory of Metabolic Remodelling and Health,Institute of Metabolism and Integrative Biology,Fudan University,Shanghai 200438,China [4]BGI Genomics,Shenzhen 518083,China [5]Obstetrics and Gynecology Hospital of Fudan University,Shanghai 200090,China [6]Department of Cardiothoracic Surgery,Shanghai Children’s Medical Center,School of Medicine,Shanghai Jiao Tong University,Shanghai 200127,China [7]Children’s Hospital of Fudan University,Shanghai 201102,China

出　　处：《Science Bulletin》2023年第18期1993-1998,M0003,共7页科学通报（英文版）

基　　金：supported by the National Key R&D Program of China(2021YFC2701101);the National Natural Science Foundation of China(82150008,81930036,and 81970572);the Commission for Science and Technology of Shanghai Municipality(20JC1418500 and 20ZR1404800);the Open Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202202)。

摘　　要：右位心指正常生长于左侧的心脏位置或方向发生异常,常伴发复杂的先天性心脏病(先心),发病率约为十万分之八大规模小鼠表型的正向遗传学筛查表明,纤毛基因在先心的发病机制中起着关键作用。然而,右位心这类复杂先天性畸形的遗传模式,其中的遗传病因是否受纤毛基因驱动,以及适用于复杂性状的“全基因”模型能否解释尚不清楚。基于194名右位心患者及对照样本全基因组外显子测序的遗传学分析发现,“单例功能丧失性变异”(Singletonlossof functionvariant,SLoFV)的总数目与右位心显著相关(P=6.4x10-49).当个体携带的SLoFV个数大于8时,携带者发生右位心的风险呈指数增加。进一步通过斑马鱼模型,发现敲降心脏特异性高表达的核心基因,导致心脏结构的致畸率显著高于其他类型的相关基因.结果表明右位心存在基于SLoFV的全基因组遗传风险阈值,并证实了不同权重基因对心脏致畸的不同效应,丰富了全基因组模型下对核心基因遗传效应的理解,为理解复杂疾病右位心的遗传发病机制提供新的理论基础。Congenital heart disease(CHD)is the most common type of congenital malformation.Recent studies using massively parallel sequencing(MPS)have shown that some familial forms of CHD,previously considered to be Mendelian due to single-gene mutations,may actually be oligogenic or polygenic inheritance[1].Transcription factors,signaling molecules,and structural proteins,are all involved in cardiac development[2].Although the genetic architecture of CHD is not fully understood,more than half of the CHD-causing genes identified through whole-exome sequencing(WES)have been linked to ciliopathies in mouse models[3],indicating that CHD may be a new type of ciliopathy[4].

关 键 词：右位心 CONGENITAL 遗传模式 

分 类 号：R54[医药卫生—心血管疾病]