4.5 Article

Whole-exome sequencing reveals a monogenic cause in 56% of individuals with laterality disorders and associated congenital heart defects

期刊

JOURNAL OF MEDICAL GENETICS
卷 -, 期 -, 页码 -

出版社

BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2021-107775

关键词

congenital; Hereditary; and neonatal diseases and abnormalities; heart defects; congenital

资金

  1. National Human Genome Research Institute [UM1HG006504]
  2. National Heart, Lung, and Blood Institute [UM1HG006504]
  3. GSP Coordinating Center [U24 HG008956]

向作者/读者索取更多资源

This study aimed to elucidate the molecular basis of laterality disorders and associated congenital heart defects in a cohort of 30 unrelated probands of Arab-Muslim descent using next-generation sequencing techniques. A molecular diagnosis was reached for 56.7% of the probands, with known genes associated with heterotaxy and/or primary ciliary dyskinesia identified, as well as a novel recessive monogenic cause for heterotaxy in humans. Additionally, variants of uncertain significance were found in three probands.
Background The molecular basis of heterotaxy and congenital heart malformations associated with disruption of left-right asymmetry is broad and heterogenous, with over 25 genes implicated in its pathogenesis thus far. Objective We sought to elucidate the molecular basis of laterality disorders and associated congenital heart defects in a cohort of 30 unrelated probands of Arab-Muslim descent, using next-generation sequencing techniques. Methods Detailed clinical phenotyping followed by whole-exome sequencing (WES) was pursued for each of the probands and their parents (when available). Sanger sequencing was used for segregation analysis of disease-causing mutations in the families. Results Using WES, we reached a molecular diagnosis for 17 of the 30 probands (56.7%). Genes known to be associated with heterotaxy and/or primary ciliary dyskinesia, in which homozygous pathogenic or likely pathogenic variants were detected, included CFAP53 (CCDC11), CFAP298 (C21orf59), CFAP300, LRRC6, GDF1, DNAAF1, DNAH5, CCDC39, CCDC40, PKD1L1 and TTC25. Additionally, we detected a homozygous disease causing mutation in DAND5, as a novel recessive monogenic cause for heterotaxy in humans. Three additional probands were found to harbour variants of uncertain significance. These included variants in DNAH6, HYDIN, CELSR1 and CFAP46. Conclusions Our findings contribute to the current knowledge regarding monogenic causes of heterotaxy and its associated congenital heart defects and underscore the role of next-generation sequencing techniques in the diagnostic workup of such patients, and especially among consanguineous families.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.5
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据