Ishorst, Nina and Henschel, Leonie and Thieme, Frederic and Drichel, Dmitriy and Sivalingam, Sugirthan and Mehrem, Sarah L. and Fechtner, Ariane C. and Fazaal, Julia and Welzenbach, Julia and Heimbach, Andre and Maj, Carlo and Borisov, Oleg and Hausen, Jonas and Raff, Ruth and Hoischen, Alexander and Dixon, Michael and Rada-Iglesias, Alvaro and Bartusel, Michaela and Rojas-Martinez, Augusto and Aldhorae, Khalid and Braumann, Bert and Kruse, Teresa and Kirschneck, Christian and Spanier, Gerrit and Reutter, Heiko and Nowak, Stefanie and Goelz, Lina and Knapp, Michael and Buness, Andreas and Krawitz, Peter and Noethen, Markus M. and Nothnagel, Michael and Becker, Tim and Ludwig, Kerstin U. and Mangold, Elisabeth (2023) Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores. MOLECULAR GENETICS & GENOMIC MEDICINE, 11 (3). ISSN 2324-9269,
Full text not available from this repository. (Request a copy)Abstract
BackgroundNonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome-wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. MethodsTo identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL/P patient/parent-trios with a low polygenic risk for the phenotype (discovery).We prioritized DNV-carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL/P patients of diverse ethnicities and 1574 population-matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome-wide association data, expression, protein-protein-interactions), were used for final prioritization. ConclusionIn the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL/P risk gene CDH1. Re-sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, MDN1 and PAXIP1 were prioritized as top candidates. Our findings demonstrate that DNV detection, including polygenic risk score analysis, is a powerful tool for identifying nsCL/P candidate genes, which can also be applied to other multifactorial congenital malformations.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GENOME-WIDE ASSOCIATION; ORAL CLEFTS; MUTATIONS; LOCI; IDENTIFY; 8Q24.3; FOXE1; IRF6; candidate genes; de novo variants; exome sequencing; nonsyndromic cleft lip with; without cleft palate; polygenic risk; single-molecule molecular inversion probes |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Kieferorthopädie Medicine > Lehrstuhl für Mund-, Kiefer- und Gesichtschirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 05 Mar 2024 11:13 |
| Last Modified: | 05 Mar 2024 11:13 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58395 |
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