Identification of Functional Variants for Cleft Lip with or without Cleft Palate in or near PAX7, FGFR2, and NOG by Targeted Sequencing of GWAS Loci.
Document Type
Article
Publication Date
3-5-2015
JAX Source
Am J Hum Genet 2015 Mar 5; 96(3):397-411.
Volume
96
Issue
3
First Page
397
Last Page
411
ISSN
1537-6605
PMID
25704602
Abstract
Although genome-wide association studies (GWASs) for nonsyndromic orofacial clefts have identified multiple strongly associated regions, the causal variants are unknown. To address this, we selected 13 regions from GWASs and other studies, performed targeted sequencing in 1,409 Asian and European trios, and carried out a series of statistical and functional analyses. Within a cluster of strongly associated common variants near NOG, we found that one, rs227727, disrupts enhancer activity. We furthermore identified significant clusters of non-coding rare variants near NTN1 and NOG and found several rare coding variants likely to affect protein function, including four nonsense variants in ARHGAP29. We confirmed 48 de novo mutations and, based on best biological evidence available, chose two of these for functional assays. One mutation in PAX7 disrupted the DNA binding of the encoded transcription factor in an in vitro assay. The second, a non-coding mutation, disrupted the activity of a neural crest enhancer downstream of FGFR2 both in vitro and in vivo. This targeted sequencing study provides strong functional evidence implicating several specific variants as primary contributory risk alleles for nonsyndromic clefting in humans. Am J Hum Genet 2015 Mar 5; 96(3):397-411.
Recommended Citation
Leslie E,
Taub M,
Liu H,
Steinberg K,
Koboldt D,
Zhang Q,
Carlson J,
Hetmanski J,
Wang H,
Larson D,
Fulton R,
Kousa Y,
Fakhouri W,
Naji A,
Ruczinski I,
Begum F,
Parker M,
Busch T,
Standley J,
Rigdon J,
Hecht J,
Scott A,
Wehby G,
Christensen K,
Czeizel A,
Deleyiannis F,
Schutte B,
Wilson R,
Cornell R,
Lidral A,
Weinstock GM,
Beaty T,
Marazita M,
Murray J.
Identification of Functional Variants for Cleft Lip with or without Cleft Palate in or near PAX7, FGFR2, and NOG by Targeted Sequencing of GWAS Loci. Am J Hum Genet 2015 Mar 5; 96(3):397-411.