Genetic architecture of laterality defects revealed by whole exome sequencing.

TitleGenetic architecture of laterality defects revealed by whole exome sequencing.
Publication TypeJournal Article
Year of Publication2019
AuthorsLi, AH, Hanchard, NA, Azamian, M, D'Alessandro, LCA, Coban-Akdemir, Z, Lopez, KN, Hall, NJ, Dickerson, H, Nicosia, A, Fernbach, S, Boone, PM, Gambin, T, Karaca, E, Gu, S, Yuan, B, Jhangiani, SN, Doddapaneni, H, Hu, J, Dinh, H, Jayaseelan, J, Muzny, DM, Lalani, S, Towbin, J, Penny, D, Fraser, C, Martin, J, Lupski, JR, Gibbs, RA, Boerwinkle, E, Ware, SM, Belmont, JW
JournalEur J Hum Genet
Volume27
Issue4
Pagination563-573
Date Published2019 Apr
ISSN1476-5438
KeywordsAnimals, Body Patterning, Embryonic Development, Exome Sequencing, Female, Genetic Association Studies, Genome, Human, Genomics, GTP Phosphohydrolases, Heart Defects, Congenital, Heterotaxy Syndrome, Humans, Male, Peroxidases, Zebrafish, Zebrafish Proteins
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.

DOI10.1038/s41431-018-0307-z
Alternate JournalEur J Hum Genet
PubMed ID30622330
PubMed Central IDPMC6460585
Grant ListU54 HD083092 / HD / NICHD NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
R01 HD039056 / HD / NICHD NIH HHS / United States
K23 HL127164 / HL / NHLBI NIH HHS / United States
R01 HL091771 / HL / NHLBI NIH HHS / United States
R01 HL090506 / HL / NHLBI NIH HHS / United States
P01 HL134599 / HL / NHLBI NIH HHS / United States

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