A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder.

Autor:	Loureiro LO; Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada., Howe JL; Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada., Reuter MS; Canada's Genomics Enterprise (CGEn), The Hospital for Sick Children, Toronto, ON, Canada., Iaboni A; Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada., Calli K; Department of Medical Genetics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada., Roshandel D; Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada., Pritišanac I; Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Cell & Systems Biology, University of Toronto, Toronto, ON, Canada., Moses A; Department of Cell & Systems Biology, University of Toronto, Toronto, ON, Canada., Forman-Kay JD; Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Biochemistry, University of Toronto, Toronto, ON, Canada., Trost B; Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada., Zarrei M; Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada., Rennie O; Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada., Lau LYS; Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada., Marshall CR; Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada., Srivastava S; Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Godlewski B; Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Buttermore ED; Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Sahin M; Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Hartley D; Autism Speaks, New York, NY, USA., Frazier T; Autism Speaks and Department of Psychology, John Carroll University, Cleveland, OH, USA., Vorstman J; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.; Department of Psychiatry, The Hospital for Sick Children, Toronto, ON, Canada., Georgiades S; Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada., Lewis SME; Department of Medical Genetics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada., Szatmari P; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.; Department of Psychiatry, The Hospital for Sick Children, Toronto, ON, Canada.; Centre for Addiction and Mental Health, Toronto, ON, Canada., Bradley CAL; Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada., Tabet AC; Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, F-75015, Paris, France.; Genetics Department, Cytogenetic Unit, Robert Debré Hospital, APHP, F-75019, Paris, France., Willems M; Service de Génétique clinique, CH de Chambéry, Chambéry, France., Lumbroso S; Biochimie et Biologie Moléculaire, CHU Nimes, Univ. Montpellier, Nimes, France., Piton A; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR7104, Institut National de la Santé et de la Recherche Médicale, U964, Université de Strasbourg, Illkirch, France.; Unité de Génétique Moléculaire, IGMA, Hôpitaux Universitaire de Strasbourg, Strasbourg, France.; Institut Universitaire de France, Paris, France., Lespinasse J; Service de Génétique clinique, CH de Chambéry, Chambéry, France., Delorme R; Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, F-75015, Paris, France.; Child and Adolescent Psychiatry Department, Robert Debré Hospital, APHP, F-75019, Paris, France., Bourgeron T; Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, F-75015, Paris, France., Anagnostou E; Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada.; Department of Paediatrics, University of Toronto, Toronto, ON, Canada., Scherer SW; Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada. stephen.scherer@sickkids.ca.; Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, ON, Canada. stephen.scherer@sickkids.ca.
Jazyk:	angličtina
Zdroj:	NPJ genomic medicine [NPJ Genom Med] 2021 Nov 04; Vol. 6 (1), pp. 91. Date of Electronic Publication: 2021 Nov 04.
DOI:	10.1038/s41525-021-00254-0
Abstrakt:	Autism Spectrum Disorder (ASD) is genetically complex with ~100 copy number variants and genes involved. To try to establish more definitive genotype and phenotype correlations in ASD, we searched genome sequence data, and the literature, for recurrent predicted damaging sequence-level variants affecting single genes. We identified 18 individuals from 16 unrelated families carrying a heterozygous guanine duplication (c.3679dup; p.Ala1227Glyfs*69) occurring within a string of 8 guanines (genomic location [hg38]g.50,721,512dup) affecting SHANK3, a prototypical ASD gene (0.08% of ASD-affected individuals carried the predicted p.Ala1227Glyfs*69 frameshift variant). Most probands carried de novo mutations, but five individuals in three families inherited it through somatic mosaicism. We scrutinized the phenotype of p.Ala1227Glyfs*69 carriers, and while everyone (17/17) formally tested for ASD carried a diagnosis, there was the variable expression of core ASD features both within and between families. Defining such recurrent mutational mechanisms underlying an ASD outcome is important for genetic counseling and early intervention. (© 2021. The Author(s).)
Databáze:	MEDLINE
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