Murphy Jane, Kirk Claire W, Lambert Deborah M, McGorrian Catherine, Walsh Roddy, McVeigh Terri P, Prendiville Terence, Ward Deirdre, Galvin Joseph, Lynch Sally Ann
School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
Family Heart Screening Clinic, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland.
Ir J Med Sci. 2024 Aug;193(4):1775-1785. doi: 10.1007/s11845-024-03650-4. Epub 2024 Mar 15.
Inherited cardiomyopathies (HCM, DCM, ACM) and cardiac ion channelopathies (long QT/Brugada syndromes, CPVT) are associated with significant morbidity and mortality; however, diagnosis of a familial pathogenic variant in a proband allows for subsequent cascade screening of their at-risk relatives.
We investigated the diagnostic yield from cardiac gene panel testing and reviewed variants of uncertain significance from patients attending three specialist cardiogenetics services in Ireland in the years 2002 to 2020.
Reviewing molecular genetic diagnostic reports of 834 patients from 820 families, the initial diagnostic yield of pathogenic/likely pathogenic variants was 237/834 patients (28.4%), increasing to 276/834 patients (33.1%) following re-evaluation of cases with variant(s) of uncertain significance. Altogether, 42/85 patients with VUS reviewed (49.4%) had a re-classification that could change their clinical management. Females were more likely to carry pathogenic/likely pathogenic variants than males (139/374, 37.2% vs 137/460, 29.8%, respectively, p = 0.03), and the diagnostic yields were highest in the 0 to < 2 years age group (6/12, 50.0%) and amongst those tested for cardiomyopathy gene panels (13/35, 37.1%). Variants in the MYBPC3/MYH7 (87/109, 79.8%) and KCNQ1/KCNH2 (91/100, 91.0%) genes were the predominant genetic causes for hypertrophic cardiomyopathy and long QT syndrome, respectively.
Our study highlights the importance of collation and review of pre-ACMG genetic variants to increase diagnostic utility of genetic testing for inherited heart disease. Almost half of patients with pre-ACMG VUS reviewed had their variant re-classified to likely pathogenic/likely benign which resulted in a positive clinical impact for patients and their families.
遗传性心肌病（肥厚型心肌病、扩张型心肌病、致心律失常性右室心肌病）和心脏离子通道病（长QT综合征/ Brugada综合征、儿茶酚胺敏感性多形性室性心动过速）与显著的发病率和死亡率相关；然而，先证者中家族性致病变异的诊断有助于对其高危亲属进行后续的级联筛查。
我们调查了心脏基因检测板检测的诊断率，并回顾了2002年至2020年期间在爱尔兰三家专科心脏遗传学服务机构就诊患者的意义未明变异。
回顾820个家庭中834例患者的分子遗传学诊断报告，致病/可能致病变异的初始诊断率为237/834例患者（28.4%），对意义未明变异的病例进行重新评估后，诊断率增至276/834例患者（33.1%）。总共，42/85例接受评估的意义未明变异患者（49.4%）有重新分类，这可能改变他们的临床管理。女性比男性更有可能携带致病/可能致病变异（分别为139/374，37.2% 对137/460，29.8%，p = 0.03），诊断率在0至<2岁年龄组最高（6/12，50.0%），在接受心肌病基因检测板检测的患者中最高（13/35，37.1%）。MYBPC3/MYH7（87/109，79.8%）和KCNQ1/KCNH2（91/100，91.0%）基因变异分别是肥厚型心肌病和长QT综合征的主要遗传原因。
我们的研究强调了整理和回顾美国医学遗传学与基因组学学会（ACMG）之前的基因变异对于提高遗传性心脏病基因检测诊断效用的重要性。几乎一半接受评估的ACMG之前意义未明变异患者的变异被重新分类为可能致病/可能良性，这对患者及其家庭产生了积极的临床影响。
