Genetic architecture of laterality defects revealed by whole exome sequencing

Alexander H. Li, Neil A. Hanchard, Mahshid Azamian, Lisa C.A. D’Alessandro, Zeynep Coban-Akdemir, Keila N. Lopez, Nancy J. Hall, Heather Dickerson, Annarita Nicosia, Susan Fernbach, Philip M. Boone, Tomaz Gambin, Ender Karaca, Shen Gu, Bo Yuan, Shalini N. Jhangiani, Harsha Vardhan Doddapaneni, Jianhong Hu, Huyen Dinh, Joy JayaseelanDonna Muzny, Seema Lalani, Jeffrey Towbin, Daniel Penny, Charles Fraser, James Martin, James R. Lupski, Richard A. Gibbs, Eric Boerwinkle, Stephanie M. Ware, John W. Belmont

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)563-573
Number of pages11
JournalEuropean Journal of Human Genetics
Volume27
Issue number4
DOIs
StatePublished - Apr 1 2019

Fingerprint

Exome
Genes
Phenotype
Kartagener Syndrome
Genetic Models
Gene Deletion
Exons
Embryonic Structures

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Li, A. H., Hanchard, N. A., Azamian, M., D’Alessandro, L. C. A., Coban-Akdemir, Z., Lopez, K. N., ... Belmont, J. W. (2019). Genetic architecture of laterality defects revealed by whole exome sequencing. European Journal of Human Genetics, 27(4), 563-573. https://doi.org/10.1038/s41431-018-0307-z

Genetic architecture of laterality defects revealed by whole exome sequencing. / Li, Alexander H.; Hanchard, Neil A.; Azamian, Mahshid; D’Alessandro, Lisa C.A.; Coban-Akdemir, Zeynep; Lopez, Keila N.; Hall, Nancy J.; Dickerson, Heather; Nicosia, Annarita; Fernbach, Susan; Boone, Philip M.; Gambin, Tomaz; Karaca, Ender; Gu, Shen; Yuan, Bo; Jhangiani, Shalini N.; Doddapaneni, Harsha Vardhan; Hu, Jianhong; Dinh, Huyen; Jayaseelan, Joy; Muzny, Donna; Lalani, Seema; Towbin, Jeffrey; Penny, Daniel; Fraser, Charles; Martin, James; Lupski, James R.; Gibbs, Richard A.; Boerwinkle, Eric; Ware, Stephanie M.; Belmont, John W.

In: European Journal of Human Genetics, Vol. 27, No. 4, 01.04.2019, p. 563-573.

Research output: Contribution to journalArticle

Li, 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, HV, Hu, J, Dinh, H, Jayaseelan, J, Muzny, D, Lalani, S, Towbin, J, Penny, D, Fraser, C, Martin, J, Lupski, JR, Gibbs, RA, Boerwinkle, E, Ware, SM & Belmont, JW 2019, 'Genetic architecture of laterality defects revealed by whole exome sequencing', European Journal of Human Genetics, vol. 27, no. 4, pp. 563-573. https://doi.org/10.1038/s41431-018-0307-z
Li AH, Hanchard NA, Azamian M, D’Alessandro LCA, Coban-Akdemir Z, Lopez KN et al. Genetic architecture of laterality defects revealed by whole exome sequencing. European Journal of Human Genetics. 2019 Apr 1;27(4):563-573. https://doi.org/10.1038/s41431-018-0307-z
Li, Alexander H. ; Hanchard, Neil A. ; Azamian, Mahshid ; D’Alessandro, Lisa C.A. ; Coban-Akdemir, Zeynep ; Lopez, Keila N. ; Hall, Nancy J. ; Dickerson, Heather ; Nicosia, Annarita ; Fernbach, Susan ; Boone, Philip M. ; Gambin, Tomaz ; Karaca, Ender ; Gu, Shen ; Yuan, Bo ; Jhangiani, Shalini N. ; Doddapaneni, Harsha Vardhan ; Hu, Jianhong ; Dinh, Huyen ; Jayaseelan, Joy ; Muzny, Donna ; Lalani, Seema ; Towbin, Jeffrey ; Penny, Daniel ; Fraser, Charles ; Martin, James ; Lupski, James R. ; Gibbs, Richard A. ; Boerwinkle, Eric ; Ware, Stephanie M. ; Belmont, John W. / Genetic architecture of laterality defects revealed by whole exome sequencing. In: European Journal of Human Genetics. 2019 ; Vol. 27, No. 4. pp. 563-573.
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AU - Coban-Akdemir, Zeynep

AU - Lopez, Keila N.

AU - Hall, Nancy J.

AU - Dickerson, Heather

AU - Nicosia, Annarita

AU - Fernbach, Susan

AU - Boone, Philip M.

AU - Gambin, Tomaz

AU - Karaca, Ender

AU - Gu, Shen

AU - Yuan, Bo

AU - Jhangiani, Shalini N.

AU - Doddapaneni, Harsha Vardhan

AU - Hu, Jianhong

AU - Dinh, Huyen

AU - Jayaseelan, Joy

AU - Muzny, Donna

AU - Lalani, Seema

AU - Towbin, Jeffrey

AU - Penny, Daniel

AU - Fraser, Charles

AU - Martin, James

AU - Lupski, James R.

AU - Gibbs, Richard A.

AU - Boerwinkle, Eric

AU - Ware, Stephanie M.

AU - Belmont, John W.

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