Li Lili, Bainbridge Matthew Neil, Tan Yanli, Willerson James T, Marian Ali J
From the Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Sciences Center at Houston, and Texas Heart Institute.
Circ Res. 2017 Mar 31;120(7):1084-1090. doi: 10.1161/CIRCRESAHA.116.310559. Epub 2017 Feb 21.
Hypertrophic cardiomyopathy (HCM) is a prototypic single-gene disease caused mainly by mutations in genes encoding sarcomere proteins. Despite the remarkable advances, the causal genes in ≈40% of the HCM cases remain unknown, typically in small families and sporadic cases, wherein cosegregation could not be established.
To test the hypothesis that the missing causal genes in HCM is, in part, because of an oligogenic cause, wherein the pathogenic variants do not cosegregate with the phenotype.
A clinically affected trio with HCM underwent clinical evaluation, electrocardiography, echocardiography, magnetic resonance imaging, and whole exome sequencing. Pathogenic variants in the whole exome sequencing data were identified using established algorithms. Family members were genotyped by Sanger sequencing and cosegregation was analyzed. The siblings had a severe course, whereas the mother had a mild course. Variant analysis showed that the trio shared 145 heterozygous pathogenic variants in 139 genes, including 2 in cardiomyopathy genes and . The siblings also had the pathogenic variant p.Ala13Thr variant in , a known gene for HCM. The sibling's father also carried the p.Ala13Thr variant, in whom an unambiguous diagnosis of HCM could not be made because of concomitant severe aortic stenosis. The variant segregated with HCM, except in a 7-year-old boy, who had a normal phenotype. The variant, shared by the affected trio, did not segregate with the phenotype.
We posit that a subset of HCM might be oligogenic caused by multiple pathogenic variants that do not perfectly cosegregate with the phenotype.
肥厚型心肌病（HCM）是一种典型的单基因疾病，主要由编码肌节蛋白的基因突变引起。尽管取得了显著进展，但约40%的HCM病例中的致病基因仍然未知，通常是在小型家族和散发病例中，无法确定共分离情况。
检验HCM中缺失致病基因部分原因是寡基因病因的假设，即致病变异与表型不共分离。
对一个临床诊断为HCM的三联体进行临床评估、心电图、超声心动图、磁共振成像和全外显子测序。使用既定算法在全外显子测序数据中识别致病变异。通过桑格测序对家庭成员进行基因分型并分析共分离情况。兄弟姐妹病情严重，而母亲病情较轻。变异分析显示，该三联体在139个基因中共有145个杂合致病变异，其中包括心肌病基因中的2个变异。兄弟姐妹还携带HCM已知基因中的p.Ala13Thr变异。兄弟姐妹的父亲也携带p.Ala13Thr变异，但由于同时患有严重的主动脉瓣狭窄，无法明确诊断为HCM。除了一名表型正常的7岁男孩外，该变异与HCM共分离。该三联体共有的变异与表型不共分离。
我们认为，一部分HCM可能是由多个与表型不完全共分离的致病变异导致的寡基因病。
