PUBLICATION
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
- Authors
- Leslie, E.J., Taub, M.A., Liu, H., Steinberg, K.M., Koboldt, D.C., Zhang, Q., Carlson, J.C., Hetmanski, J.B., Wang, H., Larson, D.E., Fulton, R.S., Kousa, Y.A., Fakhouri, W.D., Naji, A., Ruczinski, I., Begum, F., Parker, M.M., Busch, T., Standley, J., Rigdon, J., Hecht, J.T., Scott, A.F., Wehby, G.L., Christensen, K., Czeizel, A.E., Deleyiannis, F.W., Schutte, B.C., Wilson, R.K., Cornell, R.A., Lidral, A.C., Weinstock, G.M., Beaty, T.H., Marazita, M.L., Murray, J.C.
- ID
- ZDB-PUB-150513-17
- Date
- 2015
- Source
- American journal of human genetics 96: 397-411 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Alleles
- Amino Acid Sequence
- Animals
- Asian People/genetics
- Brain/abnormalities*
- Carrier Proteins/genetics*
- Carrier Proteins/metabolism
- Cell Line
- Cleft Lip/genetics*
- Cleft Palate/genetics*
- Epithelial Cells/metabolism
- Gene Expression Regulation
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Mice
- Mice, Inbred C57BL
- Molecular Sequence Data
- Mutation, Missense
- PAX7 Transcription Factor/genetics*
- PAX7 Transcription Factor/metabolism
- Polymorphism, Single Nucleotide*
- Receptor, Fibroblast Growth Factor, Type 2/genetics*
- Receptor, Fibroblast Growth Factor, Type 2/metabolism
- Sequence Analysis, DNA
- Transcription Factors/genetics
- Transcription Factors/metabolism
- White People/genetics
- Zebrafish/genetics
- PubMed
- 25704602 Full text @ Am. J. Hum. Genet.
Citation
Leslie, E.J., Taub, M.A., Liu, H., Steinberg, K.M., Koboldt, D.C., Zhang, Q., Carlson, J.C., Hetmanski, J.B., Wang, H., Larson, D.E., Fulton, R.S., Kousa, Y.A., Fakhouri, W.D., Naji, A., Ruczinski, I., Begum, F., Parker, M.M., Busch, T., Standley, J., Rigdon, J., Hecht, J.T., Scott, A.F., Wehby, G.L., Christensen, K., Czeizel, A.E., Deleyiannis, F.W., Schutte, B.C., Wilson, R.K., Cornell, R.A., Lidral, A.C., Weinstock, G.M., Beaty, T.H., Marazita, M.L., Murray, J.C. (2015) 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. American journal of human genetics. 96:397-411.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping