METHODS: We conducted clinical exome sequencing of 200 HCM patients to identified cardiomyopathy-associated genetic mutations. The clinical and echocardiographic characteristics of genotype-positive and genotype-negative patients were compared, and the likelihood of detecting a positive genetic test result was evaluated. Allelic burden analysis was done to compare the minor allele frequencies (MAF) of the pathogenic or likely pathogenic (P/LP) variants and variants of uncertain significance (VUSs) identified in the cohort against various population genomics databases.
RESULTS: The genetic yield was 40% for P/LP variants, with MYBPC3 and MYH7 as the predominant sarcomere genes. Younger age-at-diagnosis, family history of HCM, asymmetric hypertrophic (ASH) pattern, the ratio of the interventricular septum to posterior wall thickness (IVS/PW ratio), left atrial (LA) dimensions, severe mitral regurgitation grade (MR grade), late gadolinium enhancement (LGE) detected fibrosis and absence of hypertension were associated with an increased likelihood of HCM-associated variants. Patients who experienced ventricular tachycardia and premature cardiovascular death were significantly likely to carry MYBPC3 or loss-of-function variants. LA and interventricular septal (IVS) dimensions were associated with MYH7 variants. The rare variant burden for P/LP variants and VUSs was significantly enriched in HCM cases compared to population controls.
CONCLUSIONS: Our study provides a comprehensive evaluation of HCM-associated genetic mutations from an Indian population. The identified genotype-phenotype associations could improve the yield of targeted genetic testing in HCM.
方法:我们对200例HCM患者进行了临床外显子组测序,以确定心肌病相关的基因突变。比较基因型阳性和基因型阴性患者的临床和超声心动图特征,并评估了检测到基因检测结果阳性的可能性。进行等位基因负荷分析以比较P/LP变体的次要等位基因频率(MAF)和在队列中针对各种群体基因组学数据库鉴定的VUS。
结果:致病性或可能的致病性变异的遗传产量为40%,以MYBPC3和MYH7为优势肌节基因。诊断年龄更年轻,HCM家族史,不对称肥大(ASH)模式,室间隔与后壁厚度之比(IVS/PW比),左心房(LA)尺寸,重度二尖瓣返流分级(MR分级),钆晚强化(LGE)检测到的纤维化和高血压缺失与HCM相关变异的可能性增加相关.经历室性心动过速和过早心血管死亡的患者很可能携带MYBPC3或功能丧失变异。LA和室间隔(IVS)尺寸与MYH7变异相关。与人群对照相比,HCM病例中P/LP变体和VUS的罕见变体负担显着丰富。
结论:我们的研究对来自印度人群的HCM相关基因突变进行了综合评估。确定的基因型-表型关联可以提高HCM中靶向基因检测的产量。