Cann F, Corbett M, O'Sullivan D, Tennant S, Hailey H, Grieve J H K, Broadhurst P, Rankin R, Dean J C S
Department of Clinical Genetics, Ashgrove House, Aberdeen, Scotland.
Pathology Department, University Medical Buildings, Aberdeen, Scotland.
Clin Genet. 2017 Jan;91(1):22-29. doi: 10.1111/cge.12778. Epub 2016 May 11.
A phenotype-driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. A total of 46 cases aged 1-40 years had normal hearts and suspected arrhythmic death. Seven (15%) had likely pathogenic variants in ion channelopathy genes [KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)]. Fifty cases aged between 2 and 67 had a cardiomyopathy. Twenty-five had arrhythmogenic right ventricular cardiomyopathy (ARVC), 10 dilated cardiomyopathy (DCM) and 15 hypertrophic cardiomyopathy (HCM). Likely pathogenic variants were found in three ARVC cases (12%) in PKP2, DSC2 or DSP, two DCM cases (20%) in MYH7, and four HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In three families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths.
本文描述了一种基于多学科团队的分子尸检的表型驱动方法，该团队由临床和实验室遗传学、法医学和心脏病学专家组成。在13年的时间里，对96例心源性猝死病例进行了分子尸检。共有46例年龄在1至40岁之间的患者心脏正常，但怀疑死于心律失常。其中7例（15%）在离子通道病基因[KCNQ1（1例）、KCNH2（4例）、SCN5A（1例）、RyR2（1例）]中存在可能的致病变异。50例年龄在2至67岁之间的患者患有心肌病。其中25例为致心律失常性右室心肌病（ARVC），10例为扩张型心肌病（DCM），15例为肥厚型心肌病（HCM）。在3例ARVC患者（12%）的PKP2、DSC2或DSP基因中发现了可能的致病变异，在2例DCM患者（20%）的MYH7基因中发现了致病变异，在4例HCM患者（27%）的MYBPC3（3例）或MYH7（1例）基因中发现了致病变异。当在尸检时做出分子诊断时，亲属进行级联筛查的比例更高。在三个家族中，检测到了先前公布为致病的变异，但临床调查显示携带者亲属没有异常。采用结合家族表型信息和群体基因组数据的保守方法来定义序列变异的致病性，在15%的心源性猝死和18%的心肌病死亡病例中做出了分子诊断。
