ArticlemedRxiv : the preprint server for health sciences2024
Genetic modifiers and ascertainment drive variable expressivity of complex disorders.
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Article in medRxiv : the preprint server for health sciences, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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70 authors.
Matthew JensenDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.ORCID 0000-0002-5153-8543
Corrine SmolenDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.ORCID 0000-0001-5951-5365
Anastasia TyryshkinaDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.ORCID 0000-0001-8710-5590
Lucilla PizzoDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.ORCID 0000-0001-9325-7283
Deepro BanerjeeDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.ORCID 0000-0003-4877-0920
Matthew OetjensAutism & Developmental Medicine Institute, Geisinger, Lewisburg, PA 17837, USA.ORCID 0000-0003-0955-9356
Hermela ShimelisAutism & Developmental Medicine Institute, Geisinger, Lewisburg, PA 17837, USA.ORCID 0000-0003-1284-8909
Cora M TaylorAutism & Developmental Medicine Institute, Geisinger, Lewisburg, PA 17837, USA.ORCID 0000-0002-3813-873X
Vijay Kumar PounrajaDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.ORCID 0000-0002-9710-189X
Hyebin SongDepartment of Statistics, Pennsylvania State University, University Park, PA 16802, USA.ORCID 0000-0003-1875-5009
Laura RohanDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Emily HuberDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.ORCID 0000-0003-0123-7141
Laila El KhattabiInstitut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France.ORCID 0000-0003-1546-5276
Ingrid van de LaarDepartment of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam, Rotterdam, The Netherlands.ORCID 0000-0002-2523-1230
Rafik TadrosDepartment of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam, Rotterdam, The Netherlands.ORCID 0000-0002-1472-0258
Connie BezzinaDepartment of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam, Rotterdam, The Netherlands.ORCID 0000-0002-0633-3514
Marjon van SlegtenhorstDepartment of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam, Rotterdam, The Netherlands.
Janneke KammeraadDepartment of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam, Rotterdam, The Netherlands.ORCID 0000-0002-1556-9422
Paolo PronteraMedical Genetics Unit, Hospital Santa Maria della Misericordia, Perugia, Italy.ORCID 0000-0003-4960-9223
Jean-Hubert CabergCentre Hospitalier Universitaire de Liège. Domaine Universitaire du Sart Tilman, Liège, Belgium.ORCID 0000-0003-4083-3907
Harry FraserDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.ORCID 0000-0002-2732-5994
Siddhartha BankaDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Anke Van DijckDepartment of Medical Genetics, University and University Hospital Antwerp, Antwerp, Belgium.ORCID 0000-0002-6713-2943
Charles SchwartzGreenwood Genetic Center, Greenwood, SC 29646, USA.
Els VoorhoeveDepartment of Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands.ORCID 0000-0002-7426-395X
Patrick CallierCenter for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes, CHU Dijon, Dijon, France.ORCID 0000-0002-9794-1848
Anne-Laure Mosca-BoidronCenter for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes, CHU Dijon, Dijon, France.ORCID 0000-0002-9130-1495
Nathalie MarleCenter for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes, CHU Dijon, Dijon, France.ORCID 0000-0003-0690-0790
Mathilde LefebvreLaboratoire de Genetique Chromosomique et Moleculaire, CHU Dijon, France.ORCID 0009-0008-4761-1462
Kate PopeBruce Lefroy Centre, Murdoch Children's Research Institute, Melbourne, Australia.ORCID 0000-0002-6232-3759
Penny SnellBruce Lefroy Centre, Murdoch Children's Research Institute, Melbourne, Australia.ORCID 0000-0002-9821-5282
Amber BoysBruce Lefroy Centre, Murdoch Children's Research Institute, Melbourne, Australia.ORCID 0000-0003-0802-1351
Paul J LockhartBruce Lefroy Centre, Murdoch Children's Research Institute, Melbourne, Australia.ORCID 0000-0003-2531-8413
Myla AshfaqDepartment of Pediatrics, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA.ORCID 0000-0002-0502-5659
Elizabeth McCreadyDepartment of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.ORCID 0000-0002-7952-2279
Margaret NowacyzkDepartment of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Lucia CastigliaResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy.ORCID 0000-0002-3261-8847
Ornella GalesiResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy.ORCID 0000-0002-7877-938X
Emanuela AvolaResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy.ORCID 0000-0002-6740-665X
Teresa MattinaResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy.ORCID 0000-0001-6143-6682
Marco FicheraResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy.ORCID 0000-0002-8225-6880
Maria Grazia BruccheriResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy.
Giuseppa Maria Luana MandaràMedical Genetics, ASP Ragusa, Ragusa, Italy.ORCID 0000-0003-3927-0908
Francesca MariLaboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute, Milan, Italy.ORCID 0000-0003-1992-1654
Flavia PriviteraLaboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute, Milan, Italy.ORCID 0000-0002-0316-4903
Ilaria LongoLaboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute, Milan, Italy.ORCID 0000-0003-2056-8763
Aurora CurróLaboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute, Milan, Italy.ORCID 0000-0002-7321-9148
Alessandra RenieriLaboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute, Milan, Italy.ORCID 0000-0002-4882-9083
Boris KerenDépartement de Génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, 75019 Paris, France.ORCID 0000-0001-6172-8247
Perrine CharlesDépartement de Génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, 75019 Paris, France.ORCID 0000-0002-3108-2171
Silvestre CuinatCHU Nantes, Medical Genetics Department, Nantes, France.ORCID 0000-0002-0763-5661
Mathilde NizonCHU Nantes, Medical Genetics Department, Nantes, France.ORCID 0000-0003-2170-4210
Olivier PichonCHU Nantes, Medical Genetics Department, Nantes, France.ORCID 0000-0001-6764-0713
Claire BénéteauCHU Nantes, Medical Genetics Department, Nantes, France.ORCID 0000-0002-1682-523X
Radka StoevaCHU Nantes, Medical Genetics Department, Nantes, France.ORCID 0000-0002-6383-8201
Dominique Martin-CoignardService de Cytogenetique, CHU de Le Mans, Le Mans, France.
Sophia BlessonDepartment of Genetics, Bretonneau University Hospital, Tours, France.
Cedric Le CaignecCHU Toulouse, Department of Medical Genetics, Toulouse, France.ORCID 0000-0002-0598-653X
Sandra MercierDepartment of Genetics, Bretonneau University Hospital, Tours, France.ORCID 0000-0002-6627-8748
Marie VincentDepartment of Genetics, Bretonneau University Hospital, Tours, France.ORCID 0000-0003-1010-5618
Christa MartinAutism & Developmental Medicine Institute, Geisinger, Lewisburg, PA 17837, USA.ORCID 0000-0002-8071-5780
Katrin MannikInstitute of Genomics, University of Tartu, Estonia.ORCID 0000-0001-7819-4536
Alexandre ReymondCenter for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Switzerland.ORCID 0000-0003-1030-8327
Laurence FaivreCenter for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes, CHU Dijon, Dijon, France.ORCID 0000-0001-9770-444X
Erik SistermansDepartment of Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands.ORCID 0000-0001-7187-4563
R Frank KooyDepartment of Medical Genetics, University and University Hospital Antwerp, Antwerp, Belgium.ORCID 0000-0003-2024-0485
David J AmorDepartment of Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands.ORCID 0000-0001-7191-8511
Corrado RomanoResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy.ORCID 0000-0003-1049-0683
Joris AndrieuxInstitut de Genetique Medicale, Hopital Jeanne de Flandre, CHRU de Lille, Lille, France.
Santhosh GirirajanDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.ORCID 0000-0003-0598-4945
Funding
Genomic basis of phenotypic variability of genomic disordersR01GM121907 · NIGMS · PENNSYLVANIA STATE UNIVERSITY, THE · PI GIRIRAJAN, SANTHOSH · 2017 to 2025
$5.2MComputation, Bioinformatics, and Statistics (CBIOS) Training ProgramT32GM102057 · NIGMS · PENNSYLVANIA STATE UNIVERSITY, THE · PI CHIAROMONTE, FRANCESCA, GIRIRAJAN, SANTHOSH · 2013 to 2022
$2.7MPenn State Biomedical Big Data to Knowledge (B2D2K) Training ProgramT32LM012415 · NLM · PENNSYLVANIA STATE UNIVERSITY, THE · PI BROACH, JAMES R., HONAVAR, VASANT G. · 2016 to 2020
$1.2MNIGMS NIH HHS R01 GM121907NIGMS NIH HHS T32 GM102057NLM NIH HHS T32 LM012415
Abstract
Variable expressivity of disease-associated variants implies a role for secondary variants that modify clinical features. We assessed the effects of modifier variants towards clinical outcomes of 2,252 individuals with primary variants. Among 132 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risk for specific developmental features, including short tandem repeats for neurological defects and SNVs for microcephaly, while additional disease-associated variants conferred multiple genetic diagnoses. Within disease and population cohorts of 773 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants towards clinical features across ascertainments. Additional analysis of 1,479 probands with other primary variants, such as 16p11.2 deletion and
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