Marsili Luisa, van Lint Freyja H M, Russo Francesco, van Spaendonck-Zwarts Karin Y, Ader Flavie, Bichon Marie-Line, Faivre Laurence, Houweling Arjan C, Isidor Bertrand, Lekanne Deprez Ronald H, Cox Moniek G P J, Wilde Arthur A M, Mazel Benoit, Mercier Sandra, Dooijes Dennis, Millat Gilles, Nguyen Karine, Post Jan G, Richard Pascale, van de Beek Irma, Vermeer Alexa M C, Boven Ludolf, Jongbloed Jan D H, van Tintelen J Peter
Clinique de génétique Guy Fontaine, CHU Lille, 59000, Lille, France.
Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
Neth Heart J. 2023 Aug;31(7-8):300-307. doi: 10.1007/s12471-023-01798-9. Epub 2023 Jul 24.
The MYH7 c.5135G > A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect.
We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort.
In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8-74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients.
MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women < 30 years.
MYH7基因c.5135G>A p.(Arg1712Gln)变异已在全球数名患者中被鉴定出来，在ClinVar数据库中被分类为致病性变异。我们旨在描述其相关表型并评估潜在的奠基者效应。
我们回顾性收集了来自一个国际队列的22名先证者和74名家庭成员的临床和遗传数据。
共有53人携带MYH7 p.(Arg1712Gln)变异，其中38人（72%）被诊断为肥厚型心肌病（HCM）。HCM诊断时的平均年龄为48.8岁（标准差：18.1；范围：8 - 74岁）。临床表现从无症状HCM到心律失常（房颤和恶性室性心律失常）不等。一名68岁的先证者发生了导致HCM诊断的心脏性猝死（SCD）未遂事件，39%（5/13）的先证者报告有SCD家族史。未报告心力衰竭死亡或心脏移植情况。女性发病通常较晚，50岁时14%的女性携带者被诊断为HCM，而男性携带者为54%。在两性中，该疾病在75岁时完全显性。对35名患者进行了单倍型重建，结果显示在一部分患者中存在奠基者效应。
MYH7 p.(Arg1712Gln)是一种致病性奠基者变异，具有一致的HCM表型，可能存在延迟显性。这表明对于健康携带者，在70岁以后应进行临床随访，对于<30岁的健康女性，筛查间隔时间可以更长。
