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Prioritization of non-coding elements involved in non-syndromic cleft lip with/without cleft palate through genome-wide analysis of de novo mutations

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Item Type:Article
Title:Prioritization of non-coding elements involved in non-syndromic cleft lip with/without cleft palate through genome-wide analysis of de novo mutations
Creators Name:Zieger, H.K. and Weinhold, L. and Schmidt, A. and Holtgrewe, M. and Juranek, S.A. and Siewert, A. and Scheer, A.B. and Thieme, F. and Mangold, E. and Ishorst, N. and Brand, F.U. and Welzenbach, J. and Beule, D. and Paeschke, K. and Krawitz, P.M. and Ludwig, K.U.
Abstract:Non-syndromic cleft lip with/without cleft palate (nsCL/P) is a highly heritable facial disorder. To date, systematic investigations of the contribution of rare variants in non-coding regions to nsCL/P etiology are sparse. Here, we re-analyzed available whole-genome sequence (WGS) data from 211 European case-parent trios with nsCL/P and identified 13,522 de novo mutations (DNMs) in nsCL/P cases, 13,055 of which mapped to non-coding regions. We integrated these data with DNMs from a reference cohort, with results of previous genome-wide association studies (GWASs), and functional and epigenetic datasets of relevance to embryonic facial development. A significant enrichment of nsCL/P DNMs was observed at two GWAS risk loci (4q28.1 (p = 8 × 10(−4)) and 2p21 (p = 0.02)), suggesting a convergence of both common and rare variants at these loci. We also mapped the DNMs to 810 position weight matrices indicative of transcription factor (TF) binding, and quantified the effect of the allelic changes in silico. This revealed a nominally significant overrepresentation of DNMs (p = 0.037), and a stronger effect on binding strength, for DNMs located in the sequence of the core binding region of the TF Musculin (MSC). Notably, MSC is involved in facial muscle development, together with a set of nsCL/P genes located at GWAS loci. Supported by additional results from single-cell transcriptomic data and molecular binding assays, this suggests that variation in MSC binding sites contributes to nsCL/P etiology. Our study describes a set of approaches that can be applied to increase the added value of WGS data.
Keywords:Orofacial Clefting, Rare Variants, Non-Coding Genome, Birth Defect, Muscle Development, Transcription Factor Binding, Allelic Spectrum
Source:Human Genetics and Genomics Advances
Publisher:Cell Press
Page Range:100166
Date:12 January 2023
Official Publication:https://doi.org/10.1016/j.xhgg.2022.100166
PubMed:View item in PubMed

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