A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder

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 vari...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/54f8fe923ab549de9877b0baef9d1c16
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spelling	oai:doaj.org-article:54f8fe923ab549de9877b0baef9d1c162021-11-08T11:19:26ZA recurrent SHANK3 frameshift variant in Autism Spectrum Disorder10.1038/s41525-021-00254-02056-7944https://doaj.org/article/54f8fe923ab549de9877b0baef9d1c162021-11-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00254-0https://doaj.org/toc/2056-7944Abstract 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.Ala1227Glyfs69) 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.Ala1227Glyfs69 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.Livia O. LoureiroJennifer L. HoweMiriam S. ReuterAlana IaboniKristina CalliDelnaz RoshandelIva PritišanacAlan MosesJulie D. Forman-KayBrett TrostMehdi ZarreiOlivia RennieLynette Y. S. LauChristian R. MarshallSiddharth SrivastavaBrianna GodlewskiElizabeth D. ButtermoreMustafa SahinDean HartleyThomas FrazierJacob VorstmanStelios GeorgiadesSuzanne M. E. LewisPeter SzatmariClarrisa A. (Lisa) BradleyAnne-Claude TabetMarjolaine WillemsSerge LumbrosoAmélie PitonJames LespinasseRichard DelormeThomas BourgeronEvdokia AnagnostouStephen W. SchererNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 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 A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder
description	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.Ala1227Glyfs69) 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.Ala1227Glyfs69 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.
format	article
author	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
author_facet	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
author_sort	Livia O. Loureiro
title	A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder
title_short	A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder
title_full	A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder
title_fullStr	A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder
title_full_unstemmed	A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder
title_sort	recurrent shank3 frameshift variant in autism spectrum disorder
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/54f8fe923ab549de9877b0baef9d1c16
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A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder

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