Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants |
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| Institution: | 1. Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA.;2. St.George’s University School of Medicine, Grenada, West Indies.;3. Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.;4. Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.;5. Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.;6. Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI, USA.;7. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.;8. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.;9. CHU Nantes, Medical genetics department, Nantes, France.;10. INSERM, UMR1238, Bone sarcoma and remodeling of calcified tissue, Nantes, France.;11. Department of Medical Genetics, University and University Hospital Antwerp, Antwerp, Belgium.;12. Department of Paediatrics, Royal Children’s Hospital, Murdoch Children’s Research Institute and University of Melbourne, Melbourne, Australia.;13. Department of Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands.;14. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.;15. Medical Genetics, University of Siena, Siena, Italy.;16. Medical Genetics, Azienda Ospedaliera Universitaria Senese, Siena, Italy.;17. Oasi Research Institute–IRCCS, Troina, Italy.;18. Medical Genetics, University of Catania School of Medicine, Catania, Italy.;19. Medical Genetics, ASP Ragusa, Ragusa, Italy.;20. Department of genetics, Bretonneau university hospital, Tours, France.;21. Service de Cytogenetique, CHU de Le Mans, Le Mans, France.;22. Laboratoire de Genetique Chromosomique et Moleculaire, CHU Dijon, France.;23. Centre Hospitalier Universitaire de Liège. Domaine Universitaire du Sart Tilman, Liège, Belgium.;24. McMaster University, Hamilton, Ontario, Canada.;25. Centre de Genetique. Hopital d’Enfants Dijon, Dijon, France.;26. Center for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes, CHU Dijon, Dijon, France.;27. Greenwood Genetic Center, Greenwood, SC, USA.;28. Hopital La Pitie Salpetriere, Paris, France.;29. Medical Genetics Unit, Hospital “Santa Maria della Misericordia”, Perugia, Italy.;30. Institut de Genetique Medicale, Hopital Jeanne de Flandre, CHRU de Lille, Lille, Franc |
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| Abstract: | PurposeTo assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants.MethodsWe analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants.ResultsThe number of rare likely deleterious variants in functionally intolerant genes (“other hits”) correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes.ConclusionAccurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified. |
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