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Original article
Genetic factors contributing to autism spectrum disorder in Williams-Beuren syndrome
  1. Marta Codina-Sola1,2,
  2. Mar Costa-Roger1,
  3. Debora Pérez-García1,
  4. Raquel Flores1,
  5. Maria Gabriela Palacios-Verdú1,3,
  6. Ivon Cusco1,2,
  7. Luis Alberto Pérez-Jurado1,4
  1. 1 Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universitat Pompeu Fabra Departament de Ciences Experimentals i de la Salut, Barcelona, Spain
  2. 2 Clinical and Molecular Genetics Area, Vall Hebrón Hospital Research Institute (VHIR), Hospital Vall d'Hebron, Barcelona, Spain
  3. 3 Fundacio Dexeus Salut de la Dona, Barcelona, Spain
  4. 4 SA Clinical Genetics, Women’s and Children’s Hospital, South Australian Health and Medical Research Institute (SAHMRI) and University of Adelaide, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
  1. Correspondence to Dr Ivon Cusco, Clinical and Molecular Genetics Area, Vall Hebrón Hospital Research Institute (VHIR), Hospital de la Vall d’Hebron, Hospital Vall d'Hebron, Barcelona 08035, Spain; icusco{at}


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.

  • autism spectrum disorders
  • Williams-Beuren syndrome
  • comorbidity
  • exome sequencing
  • neurobehavioural phenotype

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  • MC-S and MC-R are joint first authors.

  • Contributors MC-S and MC-R analysed the exome data, performed the experiments and drafted the manuscript. DP-G and MGP-V contributed with the clinical and phenotypic information. RF contributed with detailed molecular characterisation of deletions. IC and LAP-J conceived the study and participated in the design and data interpretation, and helped in drafting the manuscript. All authors read and approved the manuscript.

  • 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).

  • Competing interests LAP-J is scientific advisor of qGenomics SL. The remaining authors declare no conflict of interest.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the Clinical Research Ethics Committee of the Parc Salut Mar.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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