Genetic modifiers and ascertainment drive variable expressivity of complex disorders.

Autor:	Jensen M; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.; Bioinformatics and Genomics Graduate program, Pennsylvania State University, University Park, PA 16802, USA., Smolen C; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.; Bioinformatics and Genomics Graduate program, Pennsylvania State University, University Park, PA 16802, USA., Tyryshkina A; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA., Pizzo L; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA., Banerjee D; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA., Oetjens M; Autism & Developmental Medicine Institute, Geisinger, Lewisburg, PA 17837, USA., Shimelis H; Autism & Developmental Medicine Institute, Geisinger, Lewisburg, PA 17837, USA., Taylor CM; Autism & Developmental Medicine Institute, Geisinger, Lewisburg, PA 17837, USA., Pounraja VK; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.; Bioinformatics and Genomics Graduate program, Pennsylvania State University, University Park, PA 16802, USA., Song H; Department of Statistics, Pennsylvania State University, University Park, PA 16802, USA., Rohan L; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA., Huber E; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA., El Khattabi L; Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France., van de Laar I; Department of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam, Rotterdam, The Netherlands., Tadros R; Department of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam, Rotterdam, The Netherlands., Bezzina C; Department of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam, Rotterdam, The Netherlands., van Slegtenhorst M; Department of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam, Rotterdam, The Netherlands., Kammeraad J; Department of Clinical Genetics, Erasmus MC, Univ. Medical Center Rotterdam, Rotterdam, The Netherlands., Prontera P; Medical Genetics Unit, Hospital Santa Maria della Misericordia, Perugia, Italy., Caberg JH; Centre Hospitalier Universitaire de Liège. Domaine Universitaire du Sart Tilman, Liège, Belgium., Fraser H; Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Banka S; Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester University Hospitals, NHS Foundation Trust Manchester Academic Health Sciences Centre, Manchester, UK., Van Dijck A; Department of Medical Genetics, University and University Hospital Antwerp, Antwerp, Belgium., Schwartz C; Greenwood Genetic Center, Greenwood, SC 29646, USA., Voorhoeve E; Department of Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands., Callier P; Center for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes, CHU Dijon, Dijon, France., Mosca-Boidron AL; Center for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes, CHU Dijon, Dijon, France., Marle N; Center for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes, CHU Dijon, Dijon, France., Lefebvre M; Laboratoire de Genetique Chromosomique et Moleculaire, CHU Dijon, France., Pope K; Bruce Lefroy Centre, Murdoch Children's Research Institute, Melbourne, Australia., Snell P; Bruce Lefroy Centre, Murdoch Children's Research Institute, Melbourne, Australia., Boys A; Bruce Lefroy Centre, Murdoch Children's Research Institute, Melbourne, Australia., Lockhart PJ; Bruce Lefroy Centre, Murdoch Children's Research Institute, Melbourne, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Ashfaq M; Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA., McCready E; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada., Nowacyzk M; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada., Castiglia L; Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy., Galesi O; Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy., Avola E; Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy., Mattina T; Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy., Fichera M; Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy.; Section of Clinical Biochemistry and Medical Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine, Catania, Italy., Bruccheri MG; Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy., Mandarà GML; Medical Genetics, ASP Ragusa, Ragusa, Italy., Mari F; Laboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute, Milan, Italy., Privitera F; Laboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute, Milan, Italy., Longo I; Laboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute, Milan, Italy., Curró A; Laboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute, Milan, Italy., Renieri A; Laboratory of Clinical Molecular Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute, Milan, Italy., Keren B; Département de Génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, 75019 Paris, France., Charles P; Département de Génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, 75019 Paris, France., Cuinat S; CHU Nantes, Medical Genetics Department, Nantes, France., Nizon M; CHU Nantes, Medical Genetics Department, Nantes, France., Pichon O; CHU Nantes, Medical Genetics Department, Nantes, France., Bénéteau C; CHU Nantes, Medical Genetics Department, Nantes, France., Stoeva R; CHU Nantes, Medical Genetics Department, Nantes, France., Martin-Coignard D; Service de Cytogenetique, CHU de Le Mans, Le Mans, France., Blesson S; Department of Genetics, Bretonneau University Hospital, Tours, France., Le Caignec C; CHU Toulouse, Department of Medical Genetics, Toulouse, France.; Toulouse Neuro Imaging, Center, Inserm, UPS, Université de Toulouse, Toulouse, France., Mercier S; Department of Genetics, Bretonneau University Hospital, Tours, France., Vincent M; Department of Genetics, Bretonneau University Hospital, Tours, France., Martin C; Autism & Developmental Medicine Institute, Geisinger, Lewisburg, PA 17837, USA., Mannik K; Institute of Genomics, University of Tartu, Estonia.; Health2030 Genome Center, Fondation Campus Biotech, Geneva, Switzerland., Reymond A; Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Switzerland., Faivre L; Center for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes, CHU Dijon, Dijon, France.; Laboratoire de Genetique Chromosomique et Moleculaire, CHU Dijon, France., Sistermans E; Department of Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands., Kooy RF; Department of Medical Genetics, University and University Hospital Antwerp, Antwerp, Belgium., Amor DJ; Department of Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands., Romano C; Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy.; Section of Clinical Biochemistry and Medical Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine, Catania, Italy., Andrieux J; Institut de Genetique Medicale, Hopital Jeanne de Flandre, CHRU de Lille, Lille, France., Girirajan S; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.; Bioinformatics and Genomics Graduate program, Pennsylvania State University, University Park, PA 16802, USA.; Department of Anthropology, Pennsylvania State University, University Park, PA 16802, USA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Aug 28. Date of Electronic Publication: 2024 Aug 28.
DOI:	10.1101/2024.08.27.24312158
Abstrakt:	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 CHD8 variants, and 1,084 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 genomic architecture of complex disorders towards personalized treatment. Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.
Databáze:	MEDLINE
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