Extending the allelic spectrum at noncoding risk loci of orofacial clefting

Thieme F, Henschel L, Hammond NL, Ishorst N, Hausen J, Adamson AD, Biedermann A, Bowes J, Zieger HK, Maj C, Kruse T, Buness A, Hoischen A, Gilissen C, Kreusch T, Jaeger A, Gölz L, Braumann B, Aldhorae K, Rojas-Martinez A, Krawitz PM, Mangold E, Dixon MJ, Ludwig KU (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Human Mutation Wiley-Blackwell

DOI: 10.1002/humu.24219

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.

Authors with CRIS profile

Lina Gölz Lehrstuhl für Zahn-, Mund- und Kieferheilkunde, insbesondere Kieferorthopädie

Involved external institutions

Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) University of Manchester GB United Kingdom (GB) Radboud University Nijmegen NL Netherlands (NL) Universität zu Köln DE Germany (DE) Asklepios Kliniken DE Germany (DE) Thamar University YE Yemen (YE) Tecnológico de Monterrey (ITESM) MX Mexico (MX)

How to cite

APA:

Thieme, F., Henschel, L., Hammond, N.L., Ishorst, N., Hausen, J., Adamson, A.D.,... Ludwig, K.U. (2021). Extending the allelic spectrum at noncoding risk loci of orofacial clefting. Human Mutation. https://doi.org/10.1002/humu.24219

MLA:

Thieme, Frederic, et al. "Extending the allelic spectrum at noncoding risk loci of orofacial clefting." Human Mutation (2021).

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