Presence of autism, hyperserotonemia, and severe expressive language impairment in Williams-Beuren syndrome

Tordjman et al. Molecular Autism 2013, 4:29 http://www.molecularautism.com/content/4/1/29 RESEARCH Open Access Presence of autism, hyperserotonemia, and severe expressive language impairment in Williams-Beuren syndrome Sylvie Tordjman1,2*, George M Anderson3, David Cohen4, Solenn Kermarrec1, Michèle Carlier5, Yvan Touitou6, Pascale Saugier-Veber7, Céline Lagneaux8, Claire Chevreuil1 and Alain Verloes8,9 Abstract Background: Deletion of the Williams-Beuren syndrome (WBS) critical region (WBSCR), at 7q11.23, causes a developmental disorder commonly characterized by hypersociability and excessive talkativeness and often considered the opposite behavioral phenotype to autism. Duplication of the WBSCR leads to severe delay in expressive language. Gene–dosage effects on language development at 7q11.23 have been hypothesized. Methods: Molecular characterization of the WBSCR was performed by fluorescence in situ hybridization and high-resolution single-nucleotide polymorphism array in two individuals with severe autism enrolled in a genetic study of autism who showed typical WBS facial dysmorphism on systematic clinical genetic examination. The serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4) was genotyped. Platelet serotonin levels and urinary 6-sulfatoxymelatonin excretion were measured. Behavioral and cognitive phenotypes were examined. Results: The two patients had common WBSCR deletions between proximal and medial low copy repeat clusters, met diagnostic criteria for autism and displayed severe impairment in communication, including a total absence of expressive speech. Both patients carried the 5-HTTLPR ss genotype and exhibited platelet hyperserotonemia and low melatonin production. Conclusions: Our observations indicate that behaviors and neurochemical phenotypes typically associated with autism can occur in patients with common WBSCR deletions. The results raise intriguing questions about phenotypic heterogeneity in WBS and regarding genetic and/or environmental factors interacting with specific genes at 7q11.23 sensitive to dosage alterations that can influence the development of social communication skills. Thus, the influence of WBSCR genes on social communication expression might be dramatically modified by other genes, such as 5-HTTLPR, known to influence the severity of social communication impairments in autism, or by environmental factors, such as hyperserotonemia, given that hyperserotonemia is found in WBS associated with autism but not in WBS without autism. In this regard, WBS provides a potentially fruitful model with which to develop integrated genetic, cognitive, behavioral and neurochemical approaches to study genotype–phenotype correlations, possible gene–environment interactions and genetic background effects. The results underscore the importance of considering careful clinical and molecular genetic examination of individuals diagnosed with autism. Keywords: 7q11.23, Autistic disorder, Serotonin, Gene–environment interactions, Gene–phenotype correlations, Genetic background * Correspondence: 1 Department of Child and Adolescent Psychiatry, Centre Hospitalier Guillaume Regnier and Medical School of the University of Rennes 1, Rennes 35000, France 2 Laboratoire de la Psychologie de la Perception, CNRS UMR 8158, Centre Biomédical des Saints Pères, 75006 Paris, France Full list of author information is available at the end of the article © 2013 Tordjman et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Tordjman et al. Molecular Autism 2013, 4:29 http://www.molecularautism.com/content/4/1/29 Background Williams-Beuren syndrome (WBS) is a developmental disorder caused by a hemizygous recurrent deletion of the WBS critical region (WBSCR) at chromosomal band 7q11.23, which includes ELN (gene coding for elastin) and 27 additional coding genes [1]. The common deletion results from recombination between misaligned low copy repeat (LCR) sequences flanking the critical region. Three LCR clusters have been delineated: centromeric, medial and telomeric. Each LCR cluster is broken down in highly homologous subregions (blocks A, B and C). The deletions arise as a consequence of a nonallelic homologous recombination. The deletion occurs between proximal and medial LCRs in about 95% of WBS cases, and it occurs between proximal and distal LCRs in the remaining cases. The size of the deletion is approximately 1.55 Mb for the small deletion and approximately 1.84 Mb for the larger one [1-5]. However, the precise size depends upon the exact position of the breakpoints in each block. The physical WBS phenotype includes typical facial dysmorphism (elfin-like face), vascular stenoses (most commonly aortic stenosis), infantile hypercalcemia, dental problems, kidney abnormalities, feeding and sleep disturbances, abnormal gait and developmental delay with short stature [6,7]. The characteristic cognitive and behavioral profile includes some strengths in socialization (overfriendliness and enhanced social interest) and communication (excessive talkativeness and hyperverbal speech) with relatively good short-term verbal memory, contrasting with a common mild to moderate intellectual disability (it is noteworthy that some patients with WBS have been reported to show severe intellectual disability [8]) and severe impairment in visuospatial abilities associated with hyperacusis, peer interaction difficulties, general anxiety and behavioral problems such as hyperactivity [9-13]. The roles played by most genes deleted in the WBSCR are largely unknown. However, deletion of the elastin gene (ELN) is clearly involved in the vascular anomalies [14], and the LIMK1, GTF2I and GTFIIRD1 genes have been implicated in cognitive developmental delay and visuospatial deficiency [3,7,15]. Recently, duplication of the WBSCR has been reported to be associated with intellectual disability, severe delay in expressive language and autism spectrum disorders, suggesting that specific genes within WBSCR can influence language and social development through gene–dosage effects [16-19]. Here we report on two unrelated Caucasian individuals with typical WBSCR deletion and severe autistic disorder, including a total absence of expressive language, found during a systematic clinical genetic examination of a cohort of 71 individuals with autistic disorder enrolled for a genetic study of autism. The existence of such individuals raises questions about the common idea that WBS (regarding its characteristics of overfriendliness and Page 2 of 10 excessive talkativeness) represents the opposite phenotype of autism (a developmental disorder characterized by social and communication deficits and stereotypies) and suggests that geneti (...truncated)