Thieme, Frederic, Henschel, Leonie, Hammond, Nigel L., Ishorst, Nina, Hausen, Jonas, Adamson, Antony D., Biedermann, Angelika, Bowes, John, Zieger, Hanna K., Maj, Carlo, Kruse, Teresa, Buness, Andreas, Hoischen, Alexander ORCID: 0000-0002-8072-4476, Gilissen, Christian ORCID: 0000-0003-1693-9699, Kreusch, Thomas, Jaeger, Andreas, Goelz, Lina, Braumann, Bert, Aldhorae, Khalid ORCID: 0000-0002-5920-8004, Rojas-Martinez, Augusto, Krawitz, Peter M., Mangold, Elisabeth, Dixon, Michael J. and Ludwig, Kerstin U. (2021). Extending the allelic spectrum at noncoding risk loci of orofacial clefting. Hum. Mutat., 42 (8). S. 1066 - 1079. HOBOKEN: WILEY. ISSN 1098-1004

Full text not available from this repository.

Abstract

Genome-wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and limited access to disease-relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single-molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree- and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Thieme, FredericUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henschel, LeonieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammond, Nigel L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ishorst, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hausen, JonasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adamson, Antony D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Biedermann, AngelikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bowes, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zieger, Hanna K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maj, CarloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kruse, TeresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buness, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoischen, AlexanderUNSPECIFIEDorcid.org/0000-0002-8072-4476UNSPECIFIED
Gilissen, ChristianUNSPECIFIEDorcid.org/0000-0003-1693-9699UNSPECIFIED
Kreusch, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jaeger, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goelz, LinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braumann, BertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aldhorae, KhalidUNSPECIFIEDorcid.org/0000-0002-5920-8004UNSPECIFIED
Rojas-Martinez, AugustoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krawitz, Peter M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mangold, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dixon, Michael J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ludwig, Kerstin U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-597556
DOI: 10.1002/humu.24219
Journal or Publication Title: Hum. Mutat.
Volume: 42
Number: 8
Page Range: S. 1066 - 1079
Date: 2021
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1098-1004
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MOLECULAR INVERSION PROBES; REGULATORY ELEMENTS; RARE VARIANTS; ORAL CLEFTS; GENOME; LIP; PALATE; IDENTIFICATION; GENE; IRF6Multiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59755

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item