Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome-wide association on chromosome 1p22

Elizabeth J. Leslie, M. Adela Mansilla, Leah C. Biggs, Kristi Schuette, Steve Bullard, Margaret Cooper, Martine Dunnwald, Andrew C. Lidral, Mary L. Marazita, Terri H. Beaty, Jeffrey C. Murray

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with complex etiology reflecting the action of multiple genetic and environmental factors. Genome-wide association studies have successfully identified five novel loci associated with NSCL/P, including a locus on 1p22.1 near the ABCA4 gene. Because neither expression analysis nor mutation screening support a role for ABCA4 in NSCL/P, we investigated the adjacent gene ARHGAP29. METHODS: Mutation screening for ARHGAP29 protein coding exons was conducted in 180 individuals with NSCL/P and controls from the United States and the Philippines. Nine exons with variants in ARHGAP29 were then screened in an independent set of 872 cases and 802 controls. Arhgap29 expression was evaluated using in situ hybridization in murine embryos. RESULTS: Sequencing of ARHGAP29 revealed eight potentially deleterious variants in cases including a frameshift and a nonsense variant. Arhgap29 showed craniofacial expression and was reduced in a mouse deficient for Irf6, a gene previously shown to have a critical role in craniofacial development. CONCLUSION: The combination of genome-wide association, rare coding sequence variants, craniofacial specific expression, and interactions with IRF6 support a role for ARHGAP29 in NSCL/P and as the etiologic gene at the 1p22 genome-wide association study locus for NSCL/P. This work suggests a novel pathway in which the IRF6 gene regulatory network interacts with the Rho pathway via ARHGAP29.

Original languageEnglish (US)
Pages (from-to)934-942
Number of pages9
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Volume94
Issue number11
DOIs
StatePublished - Nov 2012

Keywords

  • ARHGAP29
  • Candidate gene
  • Cleft lip and palate
  • Complex traits
  • Rho signaling

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Embryology
  • Developmental Biology

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