Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Department of Genetics Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Am J Med Genet A. 2019 Apr;179(4):608-614. doi: 10.1002/ajmg.a.61072. Epub 2019 Feb 14.
RASopathies are a group of developmental disorders caused by pathogenic variants in the RAS-MAPK pathway. Cardiomyopathy is a major feature of this group of disorders, specifically hypertrophic cardiomyopathy (HCM). HCM can be the first presenting feature in individuals with RASopathies. We conducted a retrospective study of all individuals who have had a cardiomyopathy gene panel ordered through our institution to determine the prevalence of pathogenic or likely pathogenic variants in RAS pathway genes in individuals with cardiomyopathy. We evaluated variants in the following genes: BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NF1, NRAS, PTPN11, RAF1, SHOC2, and SOS1. We reviewed 74 cases with cardiomyopathy, including 32 with HCM, 24 with dilated cardiomyopathy (DCM), nine with both left ventricular noncompaction (LVNC) and DCM, four with LVNC only, two with arrhythmogenic right ventricular cardiomyopathy (ARVC) and three with unspecified cardiomyopathy. We identified four patients (5.41%) with pathogenic or likely pathogenic variants in HRAS, PTPN11 and RAF1 (two individuals). Indication for testing for all four individuals was HCM. The prevalence of pathogenic or likely pathogenic variants in RASopathy genes in our HCM patient cohort is 12.5% (4/32). We conclude that the RASopathy genes should be included on multi-gene panels for cardiomyopathy to increase diagnostic yield for individuals with HCM.
RAS 病是一组由 RAS-MAPK 通路中的致病性变异引起的发育障碍。心肌病是该组疾病的一个主要特征,特别是肥厚型心肌病(HCM)。HCM 可能是 RAS 病患者的首发特征。我们对通过我们机构进行的心肌病基因小组进行了回顾性研究,以确定患有心肌病的个体中 RAS 通路基因中致病性或可能致病性变异的患病率。我们评估了以下基因中的变异:BRAF、CBL、HRAS、KRAS、MAP2K1、MAP2K2、NF1、NRAS、PTPN11、RAF1、SHOC2 和 SOS1。我们回顾了 74 例心肌病患者,其中 32 例为 HCM,24 例为扩张型心肌病(DCM),9 例为左心室致密化不全(LVNC)和 DCM,4 例为单纯 LVNC,2 例为致心律失常性右室心肌病(ARVC)和 3 例为未特指的心肌病。我们发现 4 名患者(5.41%)在 HRAS、PTPN11 和 RAF1 中存在致病性或可能致病性变异(两名患者)。所有 4 名患者的检测指征均为 HCM。我们 HCM 患者队列中 RAS 病基因的致病性或可能致病性变异的患病率为 12.5%(4/32)。我们得出结论,RAS 病基因应包含在心肌病的多基因小组中,以提高 HCM 患者的诊断率。