Universität zu Köln

Hoebel, A. K., Drichel, D., van de Vorst, M., Boehmer, A. C., Sivalingam, S., Ishorst, N., Klamt, J., Goelz, L., Alblas, M., Maaser, A., Keppler, K., Zink, A. M., Dixon, M. J., Dixon, J., Hemprich, A., Kruse, T., Graf, I., Dunsche, A., Schmidt, G., Daratsianos, N., Nowak, S., Aldhorae, K. A., Noethen, M. M., Knapp, M., Thiele, H., Gilissen, C., Reutter, H., Hoischen, A., Mangold, E. and Ludwig, K. U. (2017). Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing. J. Dent. Res., 96 (11). S. 1314 - 1322. THOUSAND OAKS: SAGE PUBLICATIONS INC. ISSN 1544-0591

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hoebel, A. K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Drichel, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED van de Vorst, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boehmer, A. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sivalingam, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ishorst, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klamt, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goelz, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Alblas, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Maaser, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Keppler, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zink, A. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dixon, M. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dixon, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hemprich, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kruse, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Graf, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dunsche, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Daratsianos, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nowak, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Aldhorae, K. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Noethen, M. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Knapp, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gilissen, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reutter, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoischen, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mangold, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ludwig, K. U. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-216748
DOI:	10.1177/0022034517722761
Journal or Publication Title:	J. Dent. Res.
Volume:	96
Number:	11
Page Range:	S. 1314 - 1322
Date:	2017
Publisher:	SAGE PUBLICATIONS INC
Place of Publication:	THOUSAND OAKS
ISSN:	1544-0591
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENOME-WIDE ASSOCIATION; MOLECULAR INVERSION PROBES; SUSCEPTIBILITY LOCUS; MULTIPLEX FAMILIES; ORAL CLEFTS; RISK LOCI; LIP; MUTATIONS; RELATIVES; VARIANTS Multiple languages Dentistry, Oral Surgery & Medicine Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21674