Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores
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 heritabili...
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Wiley
2023-03-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.2109 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Nina Ishorst |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T00:49:25Z |
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| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-04-10T00:49:25Z |
| publishDate | 2023-03-01 |
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| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-205be1f83d914d678ac7257527a61a582023-03-13T12:14:56ZengWileyMolecular Genetics & Genomic Medicine2324-92692023-03-01113n/an/a10.1002/mgg3.2109Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scoresNina Ishorst0Leonie Henschel1Frederic Thieme2Dmitriy Drichel3Sugirthan Sivalingam4Sarah L. Mehrem5Ariane C. Fechtner6Julia Fazaal7Julia Welzenbach8André Heimbach9Carlo Maj10Oleg Borisov11Jonas Hausen12Ruth Raff13Alexander Hoischen14Michael Dixon15Alvaro Rada‐Iglesias16Michaela Bartusel17Augusto Rojas‐Martinez18Khalid Aldhorae19Bert Braumann20Teresa Kruse21Christian Kirschneck22Gerrit Spanier23Heiko Reutter24Stefanie Nowak25Lina Gölz26Michael Knapp27Andreas Buness28Peter Krawitz29Markus M. Nöthen30Michael Nothnagel31Tim Becker32Kerstin U. Ludwig33Elisabeth Mangold34Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyCologne Center for Genomics University of Cologne Cologne GermanyCore Unit for Bioinformatic Analysis, Medical Faculty University of Bonn Bonn GermanyInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyInstitute for Genomic Statistics and Bioinformatics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyInstitute for Genomic Statistics and Bioinformatics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyCore Unit for Bioinformatic Analysis, Medical Faculty University of Bonn Bonn GermanyInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyDepartment of Human Genetics Radboud University Medical Center Nijmegen The NetherlandsFaculty of Biology, Medicine & Health University of Manchester Manchester UKInstitute of Biomedicine and Biotechnology of Cantabria (IBBTEC) CSIC/University of Cantabria Santander SpainCenter for Molecular Medicine Cologne (CMMC) University of Cologne Cologne GermanyTecnologico de Monterrey Escuela de Medicina y Ciencias de la Salud Monterrey MexicoDepartment of Orthodontics, College of Dentistry Thamar University Thamar YemenFaculty of Medicine and University Hospital Cologne, Department of Orthodontics University of Cologne Cologne GermanyFaculty of Medicine and University Hospital Cologne, Department of Orthodontics University of Cologne Cologne GermanyDepartment of Orthodontics University of Regensburg Regensburg GermanyDepartment of Cranio‐Maxillofacial Surgery University Hospital Regensburg Regensburg GermanyInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyDepartment of Orthodontics University of Erlangen‐Nürnberg Erlangen GermanyInstitute of Medical Biometry, Informatics and Epidemiology University Hospital Bonn Bonn GermanyCore Unit for Bioinformatic Analysis, Medical Faculty University of Bonn Bonn GermanyInstitute for Genomic Statistics and Bioinformatics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyCologne Center for Genomics University of Cologne Cologne GermanyInstitute of Community Medicine University of Greifswald Greifswald GermanyInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn Bonn GermanyAbstract 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.https://doi.org/10.1002/mgg3.2109candidate genesde novo variantsexome sequencingnonsyndromic cleft lip with/without cleft palatepolygenic risksingle‐molecule molecular inversion probes |
| spellingShingle | 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 Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores Molecular Genetics & Genomic Medicine candidate genes de novo variants exome sequencing nonsyndromic cleft lip with/without cleft palate polygenic risk single‐molecule molecular inversion probes |
| title | Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores |
| title_full | Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores |
| title_fullStr | Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores |
| title_full_unstemmed | Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores |
| title_short | Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores |
| title_sort | identification of de novo variants in nonsyndromic cleft lip with without cleft palate patients with low polygenic risk scores |
| topic | candidate genes de novo variants exome sequencing nonsyndromic cleft lip with/without cleft palate polygenic risk single‐molecule molecular inversion probes |
| url | https://doi.org/10.1002/mgg3.2109 |
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