Turkowski Kari L, Tester David J, Bos J Martijn, Haugaa Kristina H, Ackerman Michael J
Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota, USA.
Department of Molecular Pharmacology & Experimental Therapeutics; Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
Congenit Heart Dis. 2017 Mar;12(2):226-235. doi: 10.1111/chd.12462. Epub 2017 Mar 21.
Arrhythmogenic cardiomyopathy (ACM) is a heritable disease characterized by fibrofatty replacement of cardiomyocytes, has a prevalence of approximately 1 in 5000 individuals, and accounts for approximately 20% of sudden cardiac death in the young (≤35 years). ACM is most often inherited as an autosomal dominant trait with incomplete penetrance and variable expression. While mutations in several genes that encode key desmosomal proteins underlie about half of all ACM, the remainder is elusive genetically.
Here, whole exome sequencing (WES) was performed with genomic triangulation in an effort to identify a novel explanation for a phenotype-positive, genotype-negative multi-generational pedigree with a presumed autosomal dominant, maternal inheritance of ACM.
WES and genomic triangulation was performed on a symptomatic 14-year-old female proband, her affected mother and affected sister, and her unaffected father to elucidate a novel ACM-susceptibility gene for this pedigree. Following variant filtering using Ingenuity® Variant Analysis, gene priority ranking was performed on the candidate genes using ToppGene and Endeavour. The phylogenetic and physiochemical properties of candidate mutations were assessed further by 6 in silico prediction tools. Species alignment and amino acid conservation analysis was performed using the Uniprot Consortium. Tissue expression data was abstracted from Expression Atlas.
Following WES and genomic triangulation, CDH2 emerged as a novel, autosomal dominant, ACM-susceptibility gene. The CDH2-encoded N-cadherin is a cell-cell adhesion protein predominately expressed in the heart. Cardiac dysfunction has been demonstrated in prior CDH2 knockout and over-expression animal studies. Further in silico mutation prediction, species conservation, and protein expression analysis supported the ultra-rare (minor allele frequency <0.005%) p.Asp407Asn-CDH2 variant as a likely pathogenic variant.
Herein, it is demonstrated that genetic mutations in CDH2-encoded N-cadherin may represent a novel pathogenetic basis for ACM in humans. The prevalence of CDH2-mediated ACM in heretofore genetically elusive ACM remains to be determined.
致心律失常性心肌病（ACM）是一种遗传性疾病，其特征为心肌细胞被纤维脂肪组织替代，发病率约为5000分之一，约占年轻人群（≤35岁）心源性猝死的20%。ACM通常以常染色体显性遗传特征遗传，具有不完全外显率和可变表达。虽然编码关键桥粒蛋白的几个基因的突变是约一半ACM病例的病因，但其余病例的遗传原因仍不清楚。
本文通过全外显子组测序（WES）和基因组三角剖分法，旨在为一个具有假定常染色体显性母系遗传的ACM多代家系中表型阳性、基因型阴性的情况寻找新的解释。
对一名有症状的14岁女性先证者、其患病母亲和患病姐姐以及未患病父亲进行WES和基因组三角剖分法，以阐明该家系中一个新的ACM易感基因。使用Ingenuity® Variant Analysis进行变异过滤后，使用ToppGene和Endeavour对候选基因进行基因优先级排序。通过6种计算机预测工具进一步评估候选突变的系统发育和理化性质。使用Uniprot Consortium进行物种比对和氨基酸保守性分析。从Expression Atlas提取组织表达数据。
经过WES和基因组三角剖分法，CDH2成为一个新的常染色体显性ACM易感基因。CDH2编码的N-钙黏着蛋白是一种主要在心脏中表达的细胞间黏附蛋白。先前的CDH2基因敲除和过表达动物研究已证实存在心脏功能障碍。进一步的计算机突变预测、物种保守性和蛋白质表达分析支持超罕见（次要等位基因频率<0.005%）的p.Asp407Asn-CDH2变异可能是致病变异。
本文证明，CDH2编码的N-钙黏着蛋白中的基因突变可能是人类ACM的一种新的致病基础。CDH2介导的ACM在迄今遗传原因不明的ACM中的患病率仍有待确定。
