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Am J Hum Genet. 2016 Apr 7;98(4):755-62. doi: 10.1016/j.ajhg.2016.02.013. Epub 2016 Mar 24.

Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate.

Author information

1
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany. Electronic address: e.mangold@uni-bonn.de.
2
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
3
Department of Orthodontics, University of Bonn, 53127 Bonn, Germany.
4
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
5
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany; Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, 53113 Bonn, Germany.
6
Clinic for Maxillofacial Surgery, University Hospital Leipzig, 04103 Leipzig, Germany.
7
Department of Oral and Maxillofacial Surgery, Head and Neck Centre, Asklepios Klinik Nord, Heidberg, 22417 Hamburg, Germany.
8
Department of Oral and Maxillofacial Surgery, University of Göttingen, 37075 Göttingen, Germany.
9
Department of Orthodontics, University of Cologne, 50931 Cologne, Germany.
10
Department of Oral and Maxillo-Facial-Plastic Surgery, University of Bonn, 53111 Bonn, Germany.
11
Department of Cleft Lip and Cleft Palate Surgery, Humboldt University of Berlin, 13353 Berlin, Germany.
12
Section of Phoniatrics and Pedaudiology, Department of Otolaryngology - Head and Neck Surgery, University of Ulm, 89070 Ulm, Germany.
13
Medical Genetics and Mitochondrial Research Group, Latvian Biomedical Research and Study Centre, Riga 1067, Latvia.
14
Institute of Child Health, University College London, London WC1N 1EH, UK.
15
Institute of Human Genetics, Ulm University, 89073 Ulm, Germany.
16
Orthodontic Department, College of Dentistry, Thamar University, Thamar, Yemen.
17
Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, 53127 Bonn, Germany.

Abstract

Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, ∼5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced its coding region in 576 Europeans with nsCL/P and 96 with nsCPO. Most strikingly, nsCPO-affected individuals had a higher minor allele frequency for rs41268753 (0.099) than control subjects (0.049; p = 1.24 × 10(-2)). This association was replicated in nsCPO/control cohorts from Latvia, Yemen, and the UK (pcombined = 2.63 × 10(-5); ORallelic = 2.46 [95% CI 1.6-3.7]) and reached genome-wide significance in combination with imputed data from a GWAS in nsCPO triads (p = 2.73 × 10(-9)). Notably, rs41268753 is not associated with nsCL/P (p = 0.45). rs41268753 encodes the highly conserved p.Thr454Met (c.1361C>T) (GERP = 5.3), which prediction programs denote as deleterious, has a CADD score of 29.6, and increases protein binding capacity in silico. Sequencing also revealed four novel truncating GRHL3 mutations including two that were de novo in four families, where all nine individuals harboring mutations had nsCPO. This is important for genetic counseling: given that VWS is rare compared to nsCPO, our data suggest that dominant GRHL3 mutations are more likely to cause nonsyndromic than syndromic CPO. Thus, with rare dominant mutations and a common risk variant in the coding region, we have identified an important contribution for GRHL3 in nsCPO.

PMID:
27018475
PMCID:
PMC4833214
DOI:
10.1016/j.ajhg.2016.02.013
[Indexed for MEDLINE]
Free PMC Article

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