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Research has identified &gt;40 genome\u2010wide 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL\/P patient\/parent\u2010trios with a low polygenic risk for the phenotype (discovery).<\/jats:p><jats:p>We prioritized DNV\u2010carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL\/P patients of diverse ethnicities and 1574 population\u2010matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome\u2010wide association data, expression, protein\u2013protein\u2010interactions), were used for final prioritization.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL\/P risk gene <jats:italic>CDH1<\/jats:italic>. Re\u2010sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, <jats:italic>MDN1<\/jats:italic> and <jats:italic>PAXIP1<\/jats:italic> 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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.2109","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T11:43:31Z","timestamp":1670240611000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Identification of de novo variants in nonsyndromic cleft lip with\/without cleft palate patients with low polygenic risk scores"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9836-554X","authenticated-orcid":false,"given":"Nina","family":"Ishorst","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, University of Bonn School of Medicine &amp; University Hospital Bonn  Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonie","family":"Henschel","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Bonn School of Medicine &amp; University Hospital Bonn  Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9839-1764","authenticated-orcid":false,"given":"Frederic","family":"Thieme","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Bonn School of Medicine &amp; University Hospital Bonn  Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitriy","family":"Drichel","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics University of Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sugirthan","family":"Sivalingam","sequence":"additional","affiliation":[{"name":"Core Unit for Bioinformatic Analysis, Medical Faculty University of Bonn  Bonn Germany"},{"name":"Institute for Genomic Statistics and Bioinformatics, University of Bonn School of Medicine &amp; University Hospital Bonn  Bonn Germany"},{"name":"Institute of Medical Biometry, Informatics and Epidemiology University Hospital Bonn  Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah L.","family":"Mehrem","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Bonn School of Medicine &amp; 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