| Autor: |
Nina Ishorst, Leonie Henschel, Frederic Thieme, Dmitriy Drichel, Sugirthan Sivalingam, Sarah L. Mehrem, Ariane C. Fechtner, Julia Fazaal, Julia Welzenbach, André Heimbach, Carlo Maj, Oleg Borisov, Jonas Hausen, Ruth Raff, Alexander Hoischen, Michael Dixon, Alvaro Rada‐Iglesias, Michaela Bartusel, Augusto Rojas‐Martinez, Khalid Aldhorae, Bert Braumann, Teresa Kruse, Christian Kirschneck, Gerrit Spanier, Heiko Reutter, Stefanie Nowak, Lina Gölz, Michael Knapp, Andreas Buness, Peter Krawitz, Markus M. Nöthen, Michael Nothnagel, Tim Becker, Kerstin U. Ludwig, Elisabeth Mangold |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Molecular Genetics & Genomic Medicine, Vol 11, Iss 3, Pp n/a-n/a (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2324-9269 |
| DOI: |
10.1002/mgg3.2109 |
| Popis: |
Abstract Background Nonsyndromic 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. Methods To 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. Conclusion In 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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