Genetic factors contributing to autism spectrum disorder in Williams-Beuren syndrome
Codina Solà, Marta (Hospital Universitari Vall d'Hebron)
Costa-Roger, Mar (Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut)
Pérez-García, Debora (Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut)
Flores, Raquel (Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut)
Palacios-Verdú, Maria Gabriela (Fundacio Dexeus Salut de la Dona)
Cusco, Ivon (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Pérez-Jurado, Luis Alberto (South Australian Health and Medical Research Institute (SAHMRI))

Data:	2019
Resum:	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.
Ajuts:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2017-SRG-01974 Ministerio de Educación, Cultura y Deporte FPU16/06907 Ministerio de Economía y Competitividad MDM-2014-0370 Ministerio de Economía y Competitividad FIS/PI16/00369 Instituto de Salud Carlos III FI11/00656
Nota:	Funding this work was funded by grants from the Spanish Ministry of economy and competiveness (FiS Pi16/00369 and Pi1302481 cofunded by FeDer, and 'Programa de excelencia María de Maeztu' MDM-2014-0370), and the generalitat de catalunya (2017Srg01974 and icrea-acadèmia program). Mc-r had a predoctoral fellowship of Ministry of education, culture and Sport (FPU16/06907) and DP-g had a predoctoral fellowship from the instituto de Salud carlos iii (Fi11/00656).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Journal of medical genetics, Vol. 56 Núm. 12 (january 2019) , p. 801-808, ISSN 1468-6244

DOI: 10.1136/jmedgenet-2019-106080
PMID: 31413120

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