Abstract：
BACKGROUND: 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.
OBJECTIVE: 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.
RESULTS: 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.
CONCLUSIONS: 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.
OBJECTIVE: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：遗传性心肌病（HCM，DCM,ACM）和心脏离子通道病（长QT/Brugada综合征，CPVT)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允许随后对其高危亲属进行级联筛查.
目的：我们调查了2002年至2020年在爱尔兰参加三项心脏遗传学专科服务的患者的心脏基因小组检测的诊断率，并回顾了具有不确定意义的变异。
结果：回顾820个家庭的834例患者的分子遗传学诊断报告，致病性/可能致病性变异的初始诊断率为237/834名患者(28.4%)，增加到276/834患者（33.1％）后，重新评估具有不确定意义的变异病例。总之,42/85例接受VUS检查的患者（49.4％）进行了重新分类，这可能会改变他们的临床管理。女性比男性更容易携带致病性/可能的致病性变异（139/374，37.2%vs137/460，29.8%，分别,p=0.03),在0至<2岁年龄组(6/12,50.0%)和心肌病基因组测试组(13/35,37.1%)中,诊断率最高。MYBPC3/MYH7(87/109,79.8%)和KCNQ1/KCNH2(91/100,91.0%)基因变异是肥厚型心肌病和长QT综合征的主要遗传原因,分别。
结论：我们的研究强调了对ACMG前遗传变异进行整理和回顾的重要性，以增加遗传检测对遗传性心脏病的诊断实用性。几乎一半的ACMG前VUS患者将其变异重新分类为可能的致病性/可能的良性，这对患者及其家人产生了积极的临床影响。
目的：我们调查了2002年至2020年在爱尔兰参加三项心脏遗传学专科服务的患者的心脏基因小组检测的诊断率，并回顾了具有不确定意义的变异。
结果：回顾820个家庭的834例患者的分子遗传学诊断报告，致病性/可能致病性变异的初始诊断率为237/834名患者(28.4%)，增加到276/834患者（33.1％）后，重新评估具有不确定意义的变异病例。总之,42/85例接受VUS检查的患者（49.4％）进行了重新分类，这可能会改变他们的临床管理。女性比男性更容易携带致病性/可能的致病性变异（139/374，37.2%vs137/460，29.8%，分别,p=0.03),在0至<2岁年龄组(6/12,50.0%)和心肌病基因组测试组(13/35,37.1%)中,诊断率最高。MYBPC3/MYH7(87/109,79.8%)和KCNQ1/KCNH2(91/100,91.0%)基因变异是肥厚型心肌病和长QT综合征的主要遗传原因,分别。
结论：我们的研究强调了对ACMG前遗传变异进行整理和回顾的重要性，以增加遗传检测对遗传性心脏病的诊断实用性。几乎一半的ACMG前VUS患者将其变异重新分类为可能的致病性/可能的良性，这对患者及其家人产生了积极的临床影响。
