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Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores.
Ishorst, Nina; Henschel, Leonie; Thieme, Frederic; Drichel, Dmitriy; Sivalingam, Sugirthan; Mehrem, Sarah L; Fechtner, Ariane C; Fazaal, Julia; Welzenbach, Julia; Heimbach, André; Maj, Carlo; Borisov, Oleg; Hausen, Jonas; Raff, Ruth; Hoischen, Alexander; Dixon, Michael; Rada-Iglesias, Alvaro; Bartusel, Michaela; Rojas-Martinez, Augusto; Aldhorae, Khalid; Braumann, Bert; Kruse, Teresa; Kirschneck, Christian; Spanier, Gerrit; Reutter, Heiko; Nowak, Stefanie; Gölz, Lina; Knapp, Michael; Buness, Andreas; Krawitz, Peter; Nöthen, Markus M; Nothnagel, Michael; Becker, Tim; Ludwig, Kerstin U; Mangold, Elisabeth.
Afiliación
  • Ishorst N; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Henschel L; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Thieme F; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Drichel D; Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • Sivalingam S; Core Unit for Bioinformatic Analysis, Medical Faculty, University of Bonn, Bonn, Germany.
  • Mehrem SL; Institute for Genomic Statistics and Bioinformatics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Fechtner AC; Institute of Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Bonn, Germany.
  • Fazaal J; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Welzenbach J; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Heimbach A; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Maj C; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Borisov O; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Hausen J; Institute for Genomic Statistics and Bioinformatics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Raff R; Institute for Genomic Statistics and Bioinformatics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Hoischen A; Core Unit for Bioinformatic Analysis, Medical Faculty, University of Bonn, Bonn, Germany.
  • Dixon M; Institute for Genomic Statistics and Bioinformatics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Rada-Iglesias A; Institute of Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Bonn, Germany.
  • Bartusel M; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Rojas-Martinez A; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Aldhorae K; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Braumann B; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Kruse T; Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK.
  • Kirschneck C; Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/University of Cantabria, Santander, Spain.
  • Spanier G; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
  • Reutter H; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • Nowak S; Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico.
  • Gölz L; Centro de Investigacion y Desarrollo en Ciencias de la Salud, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico.
  • Knapp M; Department of Orthodontics, College of Dentistry, Thamar University, Thamar, Yemen.
  • Buness A; Department of Orthodontics, College of Dentistry, University of Ibn al-Nafis for Medical Sciences, Sanaa, Yemen.
  • Krawitz P; Faculty of Medicine and University Hospital Cologne, Department of Orthodontics, University of Cologne, Cologne, Germany.
  • Nöthen MM; Faculty of Medicine and University Hospital Cologne, Department of Orthodontics, University of Cologne, Cologne, Germany.
  • Nothnagel M; Department of Orthodontics, University of Regensburg, Regensburg, Germany.
  • Becker T; Department of Cranio-Maxillofacial Surgery, University Hospital Regensburg, Regensburg, Germany.
  • Ludwig KU; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Mangold E; Division of Neonatology and Pediatric Intensive Care, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany.
Mol Genet Genomic Med ; 11(3): e2109, 2023 03.
Article en En | MEDLINE | ID: mdl-36468602
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Labio Leporino / Fisura del Paladar Tipo de estudio: Diagnostic_studies / Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Mol Genet Genomic Med Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Labio Leporino / Fisura del Paladar Tipo de estudio: Diagnostic_studies / Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Mol Genet Genomic Med Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos