ArticleCell2025
Genetic modifiers and ascertainment drive variable expressivity of complex disorders.
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Article in Cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12citing papers in PubMed
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Who cites it
12 citing papers in PubMed.
- Protocol for identifying genetic modifiers of phenotypes in individuals with disease-associated variants.STAR protocols · 2026Article
- Functional impact of genetic background on variable expressivity in neurodevelopmental disorders.Nature communications · 2026Article
- CHOPS Syndrome: A Rare Malformation Syndrome with de novo AFF4 Gene Variant.Molecular syndromology · 2026Article
- Evolutionary instability drives structural diversity and disease susceptibility at the 16p12.2 locus.bioRxiv : the preprint server for biology · 2026Article
- Suppressive Genetic Interactions Between Haploinsufficient Mitochondrial Genes Encoded in the 22q11.2 Microdeletion Locus Define Brain and Cardiac Phenotypes.bioRxiv : the preprint server for biology · 2026Article
- Case Report: A novel variant in fibrillin-2 identified in a congenital contractural arachnodactyly family with phenotypic heterogeneity.Frontiers in medicine · 2026Article
- A Novel Splice Variant in theHuman mutation · 2026Article
- Integrating rare and common variation in epilepsy genetics: from genetic architecture to penetrance and clinical expressivity.Frontiers in genetics · 2026Review
- Identification of a NovelDiagnostics (Basel, Switzerland) · 2025Article
- Quantifying the impact of genetic mutations on enhancer dynamics.bioRxiv : the preprint server for biology · 2025Article
- Article
- An integrated framework for functional dissection of variable expressivity in genetic disorders.medRxiv : the preprint server for health sciences · 2025Article
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Authors and funding
72 authors.
Matthew JensenDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Corrine SmolenDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Anastasia TyryshkinaDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Lucilla PizzoDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Jiawan SunDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Serena NossDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Deepro BanerjeeDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Matthew OetjensAutism & Developmental Medicine Institute, Geisinger, Lewisburg, PA 17837, USA.
Hermela ShimelisAutism & Developmental Medicine Institute, Geisinger, Lewisburg, PA 17837, USA.
Cora M TaylorAutism & Developmental Medicine Institute, Geisinger, Lewisburg, PA 17837, USA.
Vijay Kumar PounrajaDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Hyebin SongDepartment of Statistics, Pennsylvania State University, University Park, PA 16802, USA.
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.
Laila El KhattabiParis Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Hôpital Pitié Salpêtrière, 75013 Paris, France.
Ingrid van de LaarDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3000 Rotterdam, the Netherlands.
Rafik TadrosDepartment of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, 1081 Amsterdam, the Netherlands.
Connie R BezzinaDepartment of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, 1081 Amsterdam, the Netherlands.
Marjon van SlegtenhorstDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3000 Rotterdam, the Netherlands.
Janneke KammeraadDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3000 Rotterdam, the Netherlands.
Paolo PronteraMedical Genetics Unit, Hospital Santa Maria della Misericordia, 06156 Perugia, Italy.
Jean-Hubert CabergCentre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart Tilman, 4000 Liège, Belgium.
Harry FraserDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK.
Siddharth BankaDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester University Hospitals, NHS Foundation Trust Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK.
Anke Van DijckDepartment of Medical Genetics, University and University Hospital Antwerp, 2650 Edegem, Belgium.
Charles SchwartzGreenwood Genetic Center, Greenwood, SC 29646, USA.
Els VoorhoeveDepartment of Human Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, the Netherlands.
Patrick CallierLaboratoire de Genetique Chromosomique et Moleculaire, CHU Dijon, 21000 Dijon, France.
Anne-Laure Mosca-BoidronLaboratoire de Genetique Chromosomique et Moleculaire, CHU Dijon, 21000 Dijon, France.
Nathalie MarleLaboratoire de Genetique Chromosomique et Moleculaire, CHU Dijon, 21000 Dijon, France.
Mathilde LefebvreLaboratoire de Genetique Chromosomique et Moleculaire, CHU Dijon, 21000 Dijon, France.
Kate PopeBruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
Penny SnellBruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
Amber BoysBruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
Paul J LockhartBruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3010, Australia.
Myla AshfaqDepartment of Pediatrics, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA.
Elizabeth McCreadyDepartment of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
Margaret NowacyzkDepartment of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
Lucia CastigliaResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, 94018 Troina, Italy.
Ornella GalesiResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, 94018 Troina, Italy.
Emanuela AvolaResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, 94018 Troina, Italy.
Teresa MattinaSection of Clinical Biochemistry and Medical Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine, 95131 Catania, Italy.
Marco FicheraResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, 94018 Troina, Italy; Section of Clinical Biochemistry and Medical Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine, 95131 Catania, Italy.
Maria Grazia BruccheriResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, 94018 Troina, Italy.
Giuseppa Maria Luana MandaràMedical Genetics, ASP Ragusa, 97100 Ragusa, Italy.
Francesca MariMedical Genetics Unit of the General Hospital of Siena, University of Siena, 53100 Siena, Italy.
Flavia PriviteraMedical Genetics Unit of the General Hospital of Siena, University of Siena, 53100 Siena, Italy.
Ilaria LongoMedical Genetics Unit of the General Hospital of Siena, University of Siena, 53100 Siena, Italy.
Aurora CurróMedical Genetics Unit of the General Hospital of Siena, University of Siena, 53100 Siena, Italy.
Alessandra RenieriMedical Genetics Unit of the General Hospital of Siena, University of Siena, 53100 Siena, Italy.
Boris KerenDepartment of Genetics, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, 75013 Paris, France.
Perrine CharlesDepartment of Genetics, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, 75013 Paris, France.
Silvestre CuinatMedical Genetics Department, CHU Nantes, 44093 Nantes, France.
Mathilde NizonMedical Genetics Department, CHU Nantes, 44093 Nantes, France.
Olivier PichonMedical Genetics Department, CHU Nantes, 44093 Nantes, France.
Claire BénéteauMedical Genetics Department, CHU Nantes, 44093 Nantes, France.
Radka StoevaDepartment of Medical Genetics, Le Mans Hospital, 72037 Le Mans, France.
Dominique Martin-CoignardDepartment of Medical Genetics, Le Mans Hospital, 72037 Le Mans, France.
Sophia BlessonDepartment of Genetics, Bretonneau University Hospital, 37000 Tours, France.
Cedric Le CaignecDepartment of Medical Genetics, CHU Toulouse, 31300 Toulouse, France; Toulouse Neuro Imaging Center, Inserm, UPS, Université de Toulouse, 31300 Toulouse, France.
Sandra MercierMedical Genetics Department, CHU Nantes, 44093 Nantes, France.
Marie VincentMedical Genetics Department, CHU Nantes, 44093 Nantes, France.
Christa L MartinAutism & Developmental Medicine Institute, Geisinger, Lewisburg, PA 17837, USA.
Katrin MannikInstitute of Genomics, University of Tartu, 50090 Tartu, Estonia; Health2030 Genome Center, Fondation Campus Biotech, 1202 Geneva, Switzerland.
Alexandre ReymondCenter for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland.
Laurence FaivreCenter for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes, CHU Dijon, 21000 Dijon, France.
Erik SistermansDepartment of Human Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, the Netherlands.
R Frank KooyDepartment of Medical Genetics, University and University Hospital Antwerp, 2650 Edegem, Belgium.
David J AmorBruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3010, Australia.
Corrado RomanoResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, 94018 Troina, Italy; Section of Clinical Biochemistry and Medical Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine, 95131 Catania, Italy.
Joris AndrieuxInstitut de Genetique Medicale, Hopital Jeanne de Flandre, CHRU de Lille, 59000 Lille, France.
Santhosh GirirajanDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA. Electronic address: sxg47@psu.edu.
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
$1.2MCellular Basis for Genetic Susceptibility to Neurodevelopmental DisordersR21NS122398 · NINDS · PENNSYLVANIA STATE UNIVERSITY, THE · PI GIRIRAJAN, SANTHOSH · 2021 to 2021
$428kNIGMS NIH HHS R01 GM121907NIGMS NIH HHS T32 GM102057NINDS NIH HHS R21 NS122398NLM 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 on the clinical outcomes of 2,455 individuals with primary variants. Among 124 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risks for specific developmental features, including short tandem repeats for neurological defects. Network analysis suggested distinct mechanisms involving 16p12.1 genes and secondary variants specific to each proband. Within disease and population cohorts of 976 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants on clinical features across ascertainments. Additional analysis of 1,479 probands with other primary variants, such as the 16p11.2 deletion and CHD8 variants, and 1,528 probands without primary variants showed that phenotypic associations differed by primary variant context and were influenced by synergistic interactions between primary and secondary variants. Our study provides a paradigm to dissect the personalized genomic architecture of complex disorders.
Indexed as
Genes, ModifierChromosome DeletionChromosomes, Human, Pair 16DNA-Binding ProteinsFemaleGenetic Predisposition to DiseaseHumansMalePhenotypeTranscription FactorsCHD8 protein, humanDNA-Binding ProteinsTranscription Factorsascertainmentautism spectrum disordercomplex diseasecopy-number variantsmodifiersmulti-hit modelneurodevelopmentalrare variantsvariable expressivity
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.