A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder

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...

Descripción completa

Guardado en:
Detalles Bibliográficos
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
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
Descripción
Sumario: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.

Ejemplares similares