Codina i Solà, Marta, 1988-Costa-Roger, MarPérez García, Débora, 1985-Flores Peirats, RaquelPalacios Verdú, María Gabriela, 1983-Cuscó Martí, Ivon, 1973-Pérez Jurado, Luis Alberto2020-02-142020-02-142019Codina-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-2019-1060800022-2593http://hdl.handle.net/10230/43599Background: 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.application/pdfengCopyright © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1136/jmedgenet-2019-106080Williams-Beuren syndromeAutism spectrum disordersComorbidityExome sequencingNeurobehavioural phenotypeinfo:eu-repo/semantics/openAccess