A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder
Lívia O. Loureiro, Jennifer Howe, Miriam S. Reuter, Alana Iaboni, Kristina Calli, Delnaz Roshandel, Iva Pritišanac, Alan M Moses, Julie D. Forman‐Kay, Brett Trost, Mehdi Zarrei, Olivia Rennie, Lynette Lau, Christian R. Marshall, Siddharth Srivastava, Brianna Godlewski, Elizabeth D. Buttermore, Mustafa Şahin, Dean M. Hartley, Thomas Frazier, Jacob Vorstman, Stelios Georgiades, M. E. Suzanne Lewis, Péter Szatmári, Clarrisa A. Bradley, Anne‐Claude Tabet, Marjolaine Willems, Serge Lumbroso, Amélie Piton, James Lespinasse, Richard Delorme, Thomas Bourgeron, Evdokia Anagnostou, Stephen W. Scherer
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.