Ishorst, Nina, Henschel, Leonie, Thieme, Frederic, Drichel, Dmitriy, Sivalingam, Sugirthan, Mehrem, Sarah L., Fechtner, Ariane C., Fazaal, Julia, Welzenbach, Julia, Heimbach, Andre, Maj, Carlo, Borisov, Oleg, Hausen, Jonas, Raff, Ruth, Hoischen, Alexander ORCID: 0000-0002-8072-4476, Dixon, Michael, Rada-Iglesias, Alvaro, Bartusel, Michaela, Rojas-Martinez, Augusto, Aldhorae, Khalid, Braumann, Bert, Kruse, Teresa, Kirschneck, Christian, Spanier, Gerrit, Reutter, Heiko, Nowak, Stefanie, Goelz, Lina, Knapp, Michael, Buness, Andreas, Krawitz, Peter, Noethen, Markus M., Nothnagel, Michael, Becker, Tim, 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. Mol. Genet. Genom. Med., 11 (3). HOBOKEN: WILEY. ISSN 2324-9269

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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: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ishorst, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henschel, LeonieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thieme, FredericUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Drichel, DmitriyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sivalingam, SugirthanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mehrem, Sarah L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fechtner, Ariane C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fazaal, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Welzenbach, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heimbach, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maj, CarloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borisov, OlegUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hausen, JonasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raff, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoischen, AlexanderUNSPECIFIEDorcid.org/0000-0002-8072-4476UNSPECIFIED
Dixon, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rada-Iglesias, AlvaroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartusel, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rojas-Martinez, AugustoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aldhorae, KhalidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braumann, BertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kruse, TeresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kirschneck, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spanier, GerritUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reutter, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nowak, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goelz, LinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knapp, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buness, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krawitz, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noethen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nothnagel, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ludwig, Kerstin U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mangold, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-694491
DOI: 10.1002/mgg3.2109
Journal or Publication Title: Mol. Genet. Genom. Med.
Volume: 11
Number: 3
Date: 2023
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 2324-9269
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; ORAL CLEFTS; MUTATIONS; LOCI; IDENTIFY; 8Q24.3; FOXE1; IRF6Multiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69449

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