RT Journal Article
SR Electronic
T1 Genetic factors contributing to autism spectrum disorder in Williams-Beuren syndrome
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 801
OP 808
DO 10.1136/jmedgenet-2019-106080
VO 56
IS 12
A1 Marta Codina-Sola
A1 Mar Costa-Roger
A1 Debora Pérez-García
A1 Raquel Flores
A1 Maria Gabriela Palacios-Verdú
A1 Ivon Cusco
A1 Luis Alberto Pérez-Jurado
YR 2019
UL http://jmg.bmj.com/content/56/12/801.abstract
AB 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.