Genetic factors contributing to autism spectrum disorder in Williams-Beuren syndrome

Codina i Solà, Marta, 1988-; Costa-Roger, Mar; Pérez García, Débora, 1985-; Flores Peirats, Raquel; Palacios Verdú, María Gabriela, 1983-; Cuscó Martí, Ivon, 1973-; Pérez Jurado, Luis Alberto

doi:http://dx.doi.org/10.1136/jmedgenet-2019-106080

Genetic factors contributing to autism spectrum disorder in Williams-Beuren syndrome

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Codina-Sola M, Costa-Roger M, Pérez-García D, Flores R, Palacios-Verdú MG, Cusco I. et al. Genetic factors contributing to autism spectrum disorder in Williams-Beuren syndrome. J Med Genet. 2019 Dec;56(12):801-8. DOI: 10.1136/jmedgenet-2019-106080

Abstract

Background: The hallmark of the neurobehavioural phenotype of Williams-Beuren syndrome (WBS) is increased sociability and relatively preserved language skills, often described as opposite to autism spectrum disorders (ASD). However, the prevalence of ASD in WBS is 6-10 times higher than in the general population. We have investigated the genetic factors that could contribute to the ASD phenotype in individuals with WBS. Methods: We studied four males and four females with WBS and a confirmed diagnosis of ASD by the Autism Diagnostic Interview-Revised. We performed a detailed molecular characterisation of the deletion and searched for genomic variants using exome sequencing. Results: A de novo deletion of 1.55 Mb (6 cases) or 1.83 Mb (2 cases) at 7q11.23 was detected, being in 7/8 patients of paternal origin. No common breakpoint, deletion mechanism or size was found. Two cases were hemizygous for the rare T allele at rs12539160 in MLXIPL, previously associated with ASD. Inherited rare variants in ASD-related or functionally constrained genes and a de novo nonsense mutation in the UBR5 gene were identified in six cases, with higher burden in females compared with males (p=0.016). Conclusions: The increased susceptibility to ASD in patients with WBS might be due to additive effects of the common WBS deletion, inherited and de novo rare sequence variants in ASD-related genes elsewhere in the genome, with higher burden of deleterious mutations required for females, and possible hypomorphic variants in the hemizygous allele or cis-acting mechanisms on imprinting.