Background: A proportion of patients with hypertrophic cardiomyopathy (HCM) have a diagnosis of cardiac amyloidosis. Hereditary transthyretin amyloid cardiomyopathy (ATTRv-CM) is caused by mutations in the TTR gene. Our aim was to study the prevalence of potentially amyloidogenic TTR variants in a whole-exome sequencing (WES) study of a large HCM cohort.

Methods and results: 770 consecutive HCM probands underwent WES and clinical characterisation. Patients with rare or known pathogenic variants in TTR underwent 99mTechnetium labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy and were retrospectively re-assessed for clinical features of amyloidosis. Two patients had rare TTR variants of unknown significance and four had the known pathogenic V122I (p.V142I) variant (one homozygous and also heterozygous for a likely pathogenic MYL3 variant and another double heterozygous for a likely pathogenic MYBPC3 variant). Four out of 6 patients with TTR variants underwent DPD scintigraphy; the only positive study was in the patient with the homozygous V122I (p.V142I) variant.

Conclusions: Pathogenic TTR variants are rare in carefully assessed HCM patients and may occur in double heterozygosity with pathogenic sarcomere variants. The lack of evidence for an amyloidosis phenotype in all but one TTR variant carrier illustrates the importance of complete clinical evaluation of HCM patients that harbour pathogenic TTR variants.

背景：一部分肥厚型心肌病 (HCM) 患者被诊断为心脏淀粉样变性。遗传性转甲状腺素蛋白淀粉样变心肌病 (ATTRv-CM) 是由TTR基因突变引起的。我们的目的是在大型 HCM 队列的全外显子组测序 (WES) 研究中研究潜在淀粉样变性TTR变异的患病率。

方法和结果： 770 名连续 HCM 先证者接受了 WES 和临床特征分析。TTR中罕见或已知致病性变异的患者接受 99mTechnetium 标记的 3,3-二膦酰基-1,2-丙二甲酸 (DPD) 闪烁扫描，并回顾性重新评估淀粉样变性的临床特征。两名患者具有未知意义的罕见TTR变异，四名患者具有已知的致病性 V122I ( p.V142I ) 变异（一名患者为可能致病性MYL3变异的纯合子和杂合子，另一名患者为可能致病性MYBPC3变异的双杂合子）。6 名TTR变异患者中有 4 名接受了 DPD 闪烁扫描；唯一的阳性研究是针对具有纯合 V122I ( p.V142I ) 变异的患者。

结论：在仔细评估的 HCM 患者中，致病性TTR变异很少见，并且可能以致病性肌节变异的双重杂合性发生。除一名TTR变异携带者外，其他所有携带者均缺乏淀粉样变性表型的证据，这说明对携带致病性TTR变异的 HCM 患者进行完整临床评估的重要性。