Further evidence suggesting a role for variation in ARHGAP29 variants in nonsyndromic cleft lip/palate

Ariadne Letra, Lorena Maili, John B. Mulliken, Edward Buchanan, Susan H Blanton, Jacqueline T. Hecht

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect of complex etiology. Several genes have been implicated in the etiology of NSCL/P, although only a few have been replicated across datasets. Methods: ARHGAP29 was suggested as a candidate gene for NSCL/P as it is located in close proximity to ABCA4 (1p22), a gene previously identified in a genome-wide association study of NSCL/P. Results: Rare, potentially damaging, coding variants in ARHGAP29 were found in NSCL/P cases, and its expression was detected during murine craniofacial development. In this study, we investigated whether variations in ARHGAP29 were associated with NSCL/P in our family based dataset. Five single-nucleotide polymorphisms (SNPs) flanking and within ARHGAP29 were genotyped in our NSCL/P datasets consisting of simplex and multiplex families of non-Hispanic white (NHW, primarily European) and Hispanic ethnicities. Results showed strong association of three ARHGAP29 SNPs with NSCL/P in the NHW families. Two intronic SNPs (rs1541098 and rs3789688) showed strong association with NSCL/P in all NHW families (p=0.0005 and p=0.0002, respectively), and simplex NHW families (p=0.003 for both SNPs). A SNP in the 3′ untranslated region (rs1576593) also showed strong association with NSCL/P in all NHW families (p=0.002), and the multiplex subset (p=0.002). ARHGAP29 SNP haplotypes were also associated with NSCL/P. Evidence of gene-gene interaction was found between ARHGAP29 and additional cleft susceptibility genes. Conclusion: This study further supports ARHGAP29 as a candidate gene for human NSCL/P in families of Caucasian descent.

Original languageEnglish (US)
Pages (from-to)679-685
Number of pages7
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Volume100
Issue number9
DOIs
StatePublished - 2014

Fingerprint

Single Nucleotide Polymorphism
Genes
Cleft Lip
Genome-Wide Association Study
Cleft Palate
3' Untranslated Regions
Orofacial Cleft 1
Hispanic Americans
Haplotypes
Datasets

Keywords

  • ARHGAP29
  • Association
  • Cleft lip/palate
  • Gene
  • Gene interaction
  • Haplotype

ASJC Scopus subject areas

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

Cite this

Further evidence suggesting a role for variation in ARHGAP29 variants in nonsyndromic cleft lip/palate. / Letra, Ariadne; Maili, Lorena; Mulliken, John B.; Buchanan, Edward; Blanton, Susan H; Hecht, Jacqueline T.

In: Birth Defects Research Part A - Clinical and Molecular Teratology, Vol. 100, No. 9, 2014, p. 679-685.

Research output: Contribution to journalArticle

Letra, Ariadne ; Maili, Lorena ; Mulliken, John B. ; Buchanan, Edward ; Blanton, Susan H ; Hecht, Jacqueline T. / Further evidence suggesting a role for variation in ARHGAP29 variants in nonsyndromic cleft lip/palate. In: Birth Defects Research Part A - Clinical and Molecular Teratology. 2014 ; Vol. 100, No. 9. pp. 679-685.
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AU - Letra, Ariadne

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AU - Blanton, Susan H

AU - Hecht, Jacqueline T.

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AB - Background: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect of complex etiology. Several genes have been implicated in the etiology of NSCL/P, although only a few have been replicated across datasets. Methods: ARHGAP29 was suggested as a candidate gene for NSCL/P as it is located in close proximity to ABCA4 (1p22), a gene previously identified in a genome-wide association study of NSCL/P. Results: Rare, potentially damaging, coding variants in ARHGAP29 were found in NSCL/P cases, and its expression was detected during murine craniofacial development. In this study, we investigated whether variations in ARHGAP29 were associated with NSCL/P in our family based dataset. Five single-nucleotide polymorphisms (SNPs) flanking and within ARHGAP29 were genotyped in our NSCL/P datasets consisting of simplex and multiplex families of non-Hispanic white (NHW, primarily European) and Hispanic ethnicities. Results showed strong association of three ARHGAP29 SNPs with NSCL/P in the NHW families. Two intronic SNPs (rs1541098 and rs3789688) showed strong association with NSCL/P in all NHW families (p=0.0005 and p=0.0002, respectively), and simplex NHW families (p=0.003 for both SNPs). A SNP in the 3′ untranslated region (rs1576593) also showed strong association with NSCL/P in all NHW families (p=0.002), and the multiplex subset (p=0.002). ARHGAP29 SNP haplotypes were also associated with NSCL/P. Evidence of gene-gene interaction was found between ARHGAP29 and additional cleft susceptibility genes. Conclusion: This study further supports ARHGAP29 as a candidate gene for human NSCL/P in families of Caucasian descent.

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