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J Dent Res. 2017 Oct;96(11):1314-1321. doi: 10.1177/0022034517722761. Epub 2017 Aug 2.

Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing.

Author information

1
1 Institute of Human Genetics, University of Bonn, Bonn, Germany.
2
2 Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
3
3 German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
4
4 Cologne Center for Genomics, Department of Statistical Genetics and Bioinformatics, University of Cologne, Cologne, Germany.
5
5 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
6
6 Department of Orthodontics, University of Bonn, Bonn, Germany.
7
7 Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK.
8
8 Department of Oral and Maxillo-Facial Surgery, University of Leipzig, Leipzig, Germany.
9
9 Department of Orthodontics, University of Cologne, Cologne, Germany.
10
10 Clinics Karlsruhe, Department of Oral and Maxillo-Facial Surgery, Karlsruhe, Germany.
11
11 Department of Cleft Lip and Cleft Palate Surgery, Humboldt University of Berlin, Berlin, Germany.
12
12 Department of Orthodontics, College of Dentistry, Dhamar University, Dhamar, Yemen.
13
13 Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
14
14 Cologne Center for Genomics, University of Cologne, Cologne, Germany.
15
15 Department of Neonatology &Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany.
16
16 Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
17
17 Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Abstract

Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene grainyhead-like-3 ( GRHL3). Thus, the underlying genetic causes of nsCPO remain largely unknown. The present study aimed at identifying rare variants that might contribute to nsCPO risk, via whole-exome sequencing (WES), in multiply affected Central European nsCPO pedigrees. WES was performed in 2 affected first-degree relatives from each family. Variants shared between both individuals were analyzed for their potential deleterious nature and a low frequency in the general population. Genes carrying promising variants were annotated for 1) reported associations with facial development, 2) multiple occurrence of variants, and 3) expression in mouse embryonic palatal shelves. This strategy resulted in the identification of a set of 26 candidate genes that were resequenced in 132 independent nsCPO cases and 623 independent controls of 2 different ethnicities, using molecular inversion probes. No rare loss-of-function mutation was identified in either WES or resequencing step. However, we identified 2 or more missense variants predicted to be deleterious in each of 3 genes ( ACACB, PTPRS, MIB1) in individuals from independent families. In addition, the analyses identified a novel variant in GRHL3 in 1 patient and a variant in CREBBP in 2 siblings. Both genes underlie different syndromic forms of CPO. A plausible hypothesis is that the apparently nonsyndromic clefts in these 3 patients might represent hypomorphic forms of the respective syndromes. In summary, the present study identified rare variants that might contribute to nsCPO risk and suggests candidate genes for further investigation.

KEYWORDS:

craniofacial anomalies; developmental biology; genomics; growth/development; molecular genetics; orofacial cleft(s)

PMID:
28767323
DOI:
10.1177/0022034517722761
[Indexed for MEDLINE]

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