心脏基因组诊所：在儿科心脏病中实施基因组测序。

The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease.

机构信息

Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.

CGEn, The Hospital for Sick Children, Toronto, ON, Canada.

出版信息

Genet Med. 2020 Jun;22(6):1015-1024. doi: 10.1038/s41436-020-0757-x. Epub 2020 Feb 10.

DOI:10.1038/s41436-020-0757-x

PMID:32037394

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7272322/

Abstract

PURPOSE

This study investigated the diagnostic utility of nontargeted genomic testing in patients with pediatric heart disease.

METHODS

We analyzed genome sequencing data of 111 families with cardiac lesions for rare, disease-associated variation.

RESULTS

In 14 families (12.6%), we identified causative variants: seven were de novo (ANKRD11, KMT2D, NR2F2, POGZ, PTPN11, PURA, SALL1) and six were inherited from parents with no or subclinical heart phenotypes (FLT4, DNAH9, MYH11, NEXMIF, NIPBL, PTPN11). Outcome of the testing was associated with the presence of extracardiac features (p = 0.02), but not a positive family history for cardiac lesions (p = 0.67). We also report novel plausible gene-disease associations for tetralogy of Fallot/pulmonary stenosis (CDC42BPA, FGD5), hypoplastic left or right heart (SMARCC1, TLN2, TRPM4, VASP), congenitally corrected transposition of the great arteries (UBXN10), and early-onset cardiomyopathy (TPCN1). The identified candidate genes have critical functions in heart development, such as angiogenesis, mechanotransduction, regulation of heart size, chromatin remodeling, or ciliogenesis.

CONCLUSION

This data set demonstrates the diagnostic and scientific value of genome sequencing in pediatric heart disease, anticipating its role as a first-tier diagnostic test. The genetic heterogeneity will necessitate large-scale genomic initiatives for delineating novel gene-disease associations.

摘要

目的

本研究旨在探讨非靶向基因组检测在儿科心脏病患者中的诊断效用。

方法

我们分析了 111 个有心脏病变家族的基因组测序数据，以寻找罕见的与疾病相关的变异。

结果

在 14 个家族（12.6%）中，我们鉴定出了致病变异：7 个为新生突变（ANKRD11、KMT2D、NR2F2、POGZ、PTPN11、PURA、SALL1），6 个来自无或亚临床心脏表型的父母（FLT4、DNAH9、MYH11、NEXMIF、NIPBL、PTPN11）。检测结果与是否存在心脏外特征相关（p=0.02），但与是否有心脏病变阳性家族史无关（p=0.67）。我们还报告了法洛四联症/肺动脉瓣狭窄（CDC42BPA、FGD5）、左或右心发育不全（SMARCC1、TLN2、TRPM4、VASP）、先天性矫正性大动脉转位（UBXN10）和早发性心肌病（TPCN1）的新的可能的基因-疾病关联。鉴定出的候选基因在心脏发育中具有关键功能，如血管生成、机械转导、心脏大小调节、染色质重塑或纤毛发生。