Human Genetics Center, University of Texas Health Science Center, Houston, TX, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Eur J Hum Genet. 2019 Apr;27(4):563-573. doi: 10.1038/s41431-018-0307-z. Epub 2019 Jan 8.
Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects.
在人类胚胎发育过程中，左右模式的异常会导致广泛的先天性畸形。大多数左右侧缺陷的原因尚不清楚，已确定基因的变异仅占病例的<20%。我们通过对 323 例无关联的左右侧病例进行全外显子组测序，旨在描述这些疾病的遗传谱。我们研究了 1726 个来自模型生物、途径分析和人类表型的假定左右侧候选基因中罕见、预测有害变异的作用。我们还评估了纯合/半合子外显子缺失和基于基因的罕见变异负担的贡献。共鉴定出 28 个候选变异（26 个罕见的预测有害变异和 2 个半合子缺失），包括已知导致异构和原发性纤毛运动障碍的基因中的变异（ACVR2B、NODAL、ZIC3、DNAI1、DNAH5、HYDIN、MMP21），以及与人类表型无关、但具有胚胎左右侧或心脏发育作用的基因。对先证者及其父母的后者变异进行 Sanger 验证，发现没有新发变异，但存在明显的传递性杂合（ROCK2、ISL1、SMAD2）和半合子（RAI2、RIPPLY1）变异模式。总的来说，这些变异占我们研究对象的 7.1%。我们还观察到 PXDNL 和 BMS1 中罕见、预测的功能丧失变异的负担过多，这两个基因与更广泛的左右侧表型有关。这些发现突出了左右侧缺陷发育中的潜在新基因，并表明此类出生缺陷存在广泛的基因座异质性和复杂的遗传模型。
