npj Genomic Medicine (Nov 2021)
A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder
- Livia O. Loureiro,
- Jennifer L. Howe,
- Miriam S. Reuter,
- Alana Iaboni,
- Kristina Calli,
- Delnaz Roshandel,
- Iva Pritišanac,
- Alan Moses,
- Julie D. Forman-Kay,
- Brett Trost,
- Mehdi Zarrei,
- Olivia Rennie,
- Lynette Y. S. Lau,
- Christian R. Marshall,
- Siddharth Srivastava,
- Brianna Godlewski,
- Elizabeth D. Buttermore,
- Mustafa Sahin,
- Dean Hartley,
- Thomas Frazier,
- Jacob Vorstman,
- Stelios Georgiades,
- Suzanne M. E. Lewis,
- Peter Szatmari,
- Clarrisa A. (Lisa) Bradley,
- Anne-Claude Tabet,
- Marjolaine Willems,
- Serge Lumbroso,
- Amélie Piton,
- James Lespinasse,
- Richard Delorme,
- Thomas Bourgeron,
- Evdokia Anagnostou,
- Stephen W. Scherer
Affiliations
- Livia O. Loureiro
- Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children
- Jennifer L. Howe
- Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children
- Miriam S. Reuter
- Canada’s Genomics Enterprise (CGEn), The Hospital for Sick Children
- Alana Iaboni
- Holland Bloorview Kids Rehabilitation Hospital
- Kristina Calli
- Department of Medical Genetics, BC Children’s Hospital Research Institute, University of British Columbia
- Delnaz Roshandel
- Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children
- Iva Pritišanac
- Program in Molecular Medicine, The Hospital for Sick Children
- Alan Moses
- Department of Cell & Systems Biology, University of Toronto
- Julie D. Forman-Kay
- Program in Molecular Medicine, The Hospital for Sick Children
- Brett Trost
- Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children
- Mehdi Zarrei
- Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children
- Olivia Rennie
- Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children
- Lynette Y. S. Lau
- Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children
- Christian R. Marshall
- Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children
- Siddharth Srivastava
- Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School
- Brianna Godlewski
- Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School
- Elizabeth D. Buttermore
- Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School
- Mustafa Sahin
- Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School
- Dean Hartley
- Autism Speaks
- Thomas Frazier
- Autism Speaks and Department of Psychology, John Carroll University
- Jacob Vorstman
- Department of Psychiatry, University of Toronto
- Stelios Georgiades
- Department of Psychiatry and Behavioural Neurosciences, McMaster University
- Suzanne M. E. Lewis
- Department of Medical Genetics, BC Children’s Hospital Research Institute, University of British Columbia
- Peter Szatmari
- Department of Psychiatry, University of Toronto
- Clarrisa A. (Lisa) Bradley
- Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children
- Anne-Claude Tabet
- Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris
- Marjolaine Willems
- Service de Génétique clinique, CH de Chambéry
- Serge Lumbroso
- Biochimie et Biologie Moléculaire, CHU Nimes, Univ. Montpellier
- Amélie Piton
- 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
- James Lespinasse
- Service de Génétique clinique, CH de Chambéry
- Richard Delorme
- Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris
- Thomas Bourgeron
- Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris
- Evdokia Anagnostou
- Holland Bloorview Kids Rehabilitation Hospital
- Stephen W. Scherer
- Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children
- DOI
- https://doi.org/10.1038/s41525-021-00254-0
- Journal volume & issue
-
Vol. 6,
no. 1
pp. 1 – 12
Abstract
Abstract 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.
