Abstract：
BACKGROUND: Catalogues of pathogenic genetic mutations in hypertrophic cardiomyopathy (HCM) are disproportionately small when compared to that of the size of the population with South Asian ancestry and their collective increased risk of heart disease.
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.
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.
摘要：
背景：与具有南亚血统的人群相比，肥厚型心肌病（HCM）的致病性基因突变目录不成比例地小，并且他们的心脏病风险总体增加。
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。
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。
