Bioengineering approach to cardiac regeneration/repair

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and a frequent cause of heart failure and sudden cardiac death. Our understanding of the genetic bases and pathogenic mechanisms underlying HCM has improved significantly in the recent past, but the combined effect of various pathogenic gene variants and the influence of genetic modifiers in disease manifestation are very poorly understood. Here we set out to investigate genotype-phenotype relationships in two siblings with an extensive family history of hypertrophic cardiomyopathy (HCM), both carrying a pathogenic truncating variant in the MYBPC3 gene (p.Lys600Asnfs*2), but who exhibited highly divergent clinical manifestations. The pathogenic MYBPC3 variant was found to be necessary, but not sufficient, to induce iPSC-CM hyperexcitability, suggesting the presence of additional genetic modifiers. Whole-exome sequencing (WES) of the mutant carriers identified a variant of unknown significance (VUS) in the MYH7 gene (p.Ile1927Phe) uniquely present in the individual with severe HCM, the pathogenicity of which was assessed by functionally evaluating iPSC-CMs after editing the variant.

肥厚型心肌病（Hypertrophic cardiomyopathy, HCM）是最常见的遗传性心脏疾病，亦是心力衰竭与心源性猝死的常见诱因。近年来，学界对HCM的遗传基础与致病机制的认知已取得显著进展，但多种致病基因变异的联合效应，以及遗传修饰因子对疾病表型的影响，仍未得到充分阐释。本研究旨在探究一对携带有肥厚型心肌病广泛家族史的同胞的基因型-表型关联：二人均携带MYBPC3基因的致病性截短变异（p.Lys600Asnfs*2），但临床表现却截然不同。研究发现，该致病性MYBPC3变异是诱导诱导多能干细胞源性心肌细胞（induced pluripotent stem cell-derived cardiomyocytes, iPSC-CM）兴奋性过高的必要非充分条件，提示存在额外的遗传修饰因子。对两名变异携带者的全外显子组测序（Whole-exome sequencing, WES）显示，重症HCM患者的MYH7基因中存在一处意义未明变异（variant of unknown significance, VUS，p.Ile1927Phe）；研究通过编辑该变异位点后对iPSC-CM进行功能评估，验证了该变异的致病性。