Molecular investigation, using chromosomal microarray and whole exome sequencing, of six patients affected by Williams Beuren syndrome and Autism Spectrum Disorder

Williams Beuren syndrome (WBS) is a multiple malformations/intellectual disability (ID) syndrome caused by 7q11.23 microdeletion and clinically characterized by a typical neurocognitive profile including excessive talkativeness and social disinhibition, often defined as “overfriendliness” and “hyersociability”. WBS is generally considered as the polar opposite phenotype to Autism Spectrum Disorder (ASD). Surprisingly, the prevalence of ASD has been reported to be significantly higher in WBS (12%) than in general population (1%). Our study aims to investigate the molecular basis of the peculiar association of ASD and WBS. We performed chromosomal microarray analysis and whole exome sequencing in six patients presenting with WBS and ASD, in order to evaluate the possible presence of chromosomal or gene variants considered as pathogenic. Our study shows that the presence of ASD in the recruited WBS patients is due to i) neither atypically large deletions; ii) nor the presence of pathogenic variants in genes localized in the non-deleted 7q11.23 allele which would unmask recessive conditions; iii) moreover, we did not identify a second, indisputable independent genetic diagnosis, related to pathogenic Copy Number Variations or rare pathogenic exonic variants in known ID/ASD causing genes, although several variants of unknown significance were found. Finally, imprinting effect does not appear to be the only cause of autism in WBS patients, since the deletions occurred in alleles of both maternal and paternal origin. The social disinhibition observed in WBS does not follow common social norms and symptoms overlapping with ASD, such as restricted interests and repetitive behavior, can be observed in “typical” WBS patients: therefore, the terms “overfriendliness” and “hypersociability” appear to be a misleading oversimplification. The etiology of ASD in WBS is likely to be heterogeneous. Further studies on large series of patients are needed to clarify the observed variability in WBS social communication, ranging from excessive talkativeness and social disinhibition to absence of verbal language and social deficit. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13023-019-1094-5) contains supplementary material, which is available to authorized users.