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Eur J Hum Genet. 2019 Jan 8. doi: 10.1038/s41431-018-0307-z. [Epub ahead of print]

Genetic architecture of laterality defects revealed by whole exome sequencing.

Author information

1
Human Genetics Center, University of Texas Health Science Center, Houston, TX, USA.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
3
Texas Children's Hospital, Houston, TX, USA.
4
Division of Cardiology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
5
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
6
Pediatric Cardiology, University of Tennessee Health Science Center, Memphis, TN, USA.
7
Division of Cardiovascular Surgery, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
8
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
9
Departments of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
10
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. jbelmont@bcm.tmc.edu.
11
Texas Children's Hospital, Houston, TX, USA. jbelmont@bcm.tmc.edu.
12
Illumina Inc., San Diego, CA, USA. jbelmont@bcm.tmc.edu.

Abstract

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.

PMID:
30622330
DOI:
10.1038/s41431-018-0307-z

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