Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
Department of Pediatric Cardiology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
J Am Coll Cardiol. 2018 Nov 6;72(19):2324-2338. doi: 10.1016/j.jacc.2018.08.2171.
Childhood cardiomyopathies are progressive and often lethal disorders, forming the most common cause of heart failure in children. Despite severe outcomes, their genetic background is still poorly characterized.
The purpose of this study was to characterize the genetics of severe childhood cardiomyopathies in a countrywide cohort.
The authors collected a countrywide cohort, KidCMP, of 66 severe childhood cardiomyopathies from the sole center in Finland performing cardiac transplantation. For genetic diagnosis, next-generation sequencing and subsequent validation using genetic, cell biology, and computational approaches were used.
The KidCMP cohort presents remarkable early-onset and severe disorders: the median age of diagnosis was 0.33 years, and 17 patients underwent cardiac transplantation. The authors identified the pathogenic variants in 39% of patients: 46% de novo, 34% recessive, and 20% dominantly-inherited. The authors report NRAP underlying childhood dilated cardiomyopathy, as well as novel phenotypes for known heart disease genes. Some genetic diagnoses have immediate implications for treatment: CALM1 with life-threatening arrhythmias, and TAZ with good cardiac prognosis. The disease genes converge on metabolic causes (PRKAG2, MRPL44, AARS2, HADHB, DNAJC19, PPA2, TAZ, BAG3), MAPK pathways (HRAS, PTPN11, RAF1, TAB2), development (NEK8 and TBX20), calcium signaling (JPH2, CALM1, CACNA1C), and the sarcomeric contraction cycle (TNNC1, TNNI3, ACTC1, MYH7, NRAP).
Childhood cardiomyopathies are typically caused by rare, family-specific mutations, most commonly de novo, indicating that next-generation sequencing of trios is the approach of choice in their diagnosis. Genetic diagnoses may suggest intervention strategies and predict prognosis, offering valuable tools for prioritization of patients for transplantation versus conservative treatment.
儿童心肌病是一种进行性的，且常导致死亡的疾病，是儿童心力衰竭的最常见病因。尽管预后严重，但这些疾病的遗传背景仍知之甚少。
本研究旨在对芬兰唯一一家进行心脏移植的中心的全国性儿童心肌病队列进行遗传特征分析。
作者收集了一个全国性的儿童心肌病队列 KidCMP，该队列共纳入了 66 例来自芬兰的严重儿童心肌病患者。为了进行基因诊断，作者使用了下一代测序，并通过遗传、细胞生物学和计算方法进行了后续验证。
KidCMP 队列呈现出显著的早发和严重的疾病特征：中位诊断年龄为 0.33 岁，17 例患者接受了心脏移植。作者在 39%的患者中发现了致病性变异：46%为新生突变，34%为隐性遗传，20%为显性遗传。作者报告了 NRAP 是儿童扩张型心肌病的致病基因，以及已知心脏疾病基因的新表型。一些基因诊断对治疗具有直接的影响：CALM1 导致危及生命的心律失常，TAZ 则有较好的心脏预后。这些疾病基因与代谢相关（PRKAG2、MRPL44、AARS2、HADHB、DNAJC19、PPA2、TAZ、BAG3）、MAPK 通路（HRAS、PTPN11、RAF1、TAB2）、发育（NEK8 和 TBX20）、钙信号（JPH2、CALM1、CACNA1C）和肌节收缩循环（TNNC1、TNNI3、ACTC1、MYH7、NRAP）。
儿童心肌病通常由罕见的、家族特异性的突变引起，最常见的是新生突变，这表明对三代表型进行下一代测序是其诊断的首选方法。基因诊断可能提示干预策略并预测预后，为患者进行心脏移植或保守治疗提供了有价值的工具。
