Background:Pathogenic variants in MYBPC3, encoding cardiac MyBP-C (myosin binding protein C), are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped hypertrophic cardiomyopathy cohorts have precluded detailed genotype-phenotype correlations.Methods:Patients with hypertrophic cardiomyopathy and MYBPC3 variants were identified from the Sarcomeric Human Cardiomyopathy Registry. Variant types and locations were analyzed, morphological severity was assessed, and time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, left ventricular assist device/transplant, atrial fibrillation). For selected missense variants falling in enriched domains, myofilament localization and degradation rates were measured in vitro.Results:Among 4756 genotyped patients with hypertrophic cardiomyopathy in Sarcomeric Human Cardiomyopathy Registry, 1316 patients were identified with adjudicated pathogenic truncating (N=234 unique variants, 1047 patients) or nontruncating (N=22 unique variants, 191 patients) variants in MYBPC3. Truncating variants were evenly dispersed throughout the gene, and hypertrophy severity and outcomes were not associated with variant location (grouped by 5′–3′ quartiles or by founder variant subgroup). Nontruncating pathogenic variants clustered in the C3, C6, and C10 domains (18 of 22, 82%, P<0.001 versus Genome Aggregation Database common variants) and were associated with similar hypertrophy severity and adverse event rates as observed with truncating variants. MyBP-C with variants in the C3, C6, and C10 domains was expressed in rat ventricular myocytes. C10 mutant MyBP-C failed to incorporate into myofilaments and degradation rates were accelerated by ≈90%, while C3 and C6 mutant MyBP-C incorporated normally with degradation rate similar to wild-type.Conclusions:Truncating variants account for 91% of MYBPC3 pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function. Nontruncating MYBPC3 pathogenic variants are regionally clustered, and a subset also cause loss of function through failure of myofilament incorporation and rapid degradation. Cardiac morphology and clinical outcomes are similar in patients with truncating versus nontruncating variants.

中文翻译：

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肥厚型心肌病患者 MYBPC3 致病变异的空间和功能分布及临床结果。

背景：编码心肌 MyBP-C（肌球蛋白结合蛋白 C）的MYBPC3致病变异是家族性肥厚型心肌病的最常见原因。大量独特的MYBPC3变异和相对较小的基因型肥厚型心肌病队列排除了详细的基因型-表型相关性。方法：肥厚型心肌病和MYBPC3患者从肌节人类心肌病登记处鉴定了变异体。分析了变异类型和位置，评估了形态学严重程度，并进行了时间-事件分析（猝死、III/IV 级心力衰竭、左心室辅助装置/移植、心房颤动的复合临床结果）。对于落入富集域的选定错义变异，在体外测量肌丝定位和降解率。 结果：在人类心肌病登记处的 4756 名肥厚型心肌病基因型患者中，1316 名患者被鉴定为经裁定的致病性截断（N = 234 独特变异，1047患者）或非截断（N = 22 个独特的变异，191 名患者）变异在MYBPC3. 截断变异均匀分布在整个基因中，肥大的严重程度和结果与变异位置无关（按 5'-3' 四分位数或创始人变异亚组分组）。非截短的致病变异聚集在 C3、C6 和 C10 域（22 个域中的 18 个，82%，与基因组聚合数据库常见变异相比P <0.001），并且与在截短变异中观察到的相似的肥大严重程度和不良事件发生率相关。在 C3、C6 和 C10 域中具有变体的 MyBP-C 在大鼠心室肌细胞中表达。C10 突变体 MyBP-C 未能整合到肌丝中，降解率加速了约 90%，而 C3 和 C6 突变体 MyBP-C 正常整合，降解率与野生型相似。结论：截短变体占 91%MYBPC3致病变异并导致相似的临床严重程度和结果，无论位置如何，与基因座无关的功能丧失一致。非截断的MYBPC3致病变异在区域上聚集，并且一个子集也会通过肌丝掺入失败和快速降解而导致功能丧失。截短变异与非截短变异患者的心脏形态和临床结果相似。