Department of Child and Adolescent Psychiatry, Centre Hospitalier Guillaume Regnier and Medical School of the University of Rennes 1, Rennes 35000, France.
Mol Autism. 2013 Aug 23;4(1):29. doi: 10.1186/2040-2392-4-29.
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.
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.
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.
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.
威廉姆斯-比伦综合征（WBS）关键区域（WBSCR）缺失，位于 7q11.23，引起一种常见的发育障碍，其特征通常为过度社交和过度健谈，通常被认为是自闭症的相反行为表型。WBSCR 的重复导致表达性语言严重延迟。人们假设 7q11.23 上的基因剂量效应对语言发育有影响。
通过荧光原位杂交和高分辨率单核苷酸多态性微阵列对两名患有严重自闭症的个体进行 WBSCR 的分子特征分析，这两名个体参加了自闭症的遗传研究，在系统的临床遗传学检查中表现出典型的 WBS 面部畸形。对 5-羟色胺转运体启动子多态性（5-HTTLPR，SLC6A4 基因座）进行基因分型。测量血小板 5-羟色胺水平和尿 6-硫酸褪黑素排泄。检查行为和认知表型。
两名患者近端和内侧低拷贝重复簇之间存在常见的 WBSCR 缺失，符合自闭症的诊断标准，并表现出严重的沟通障碍，包括完全缺乏表达性语言。两名患者均携带 5-HTTLPR ss 基因型，表现出血小板 5-羟色胺过多和褪黑素生成减少。
我们的观察表明，通常与自闭症相关的行为和神经化学表型可发生在具有常见 WBSCR 缺失的患者中。结果提出了关于 WBS 表型异质性以及与 7q11.23 上特定基因相互作用的遗传和/或环境因素的有趣问题，这些基因对社会沟通技能的发展敏感于剂量改变，可影响其发育。因此，WBSCR 基因对社会交流表达的影响可能会被其他基因（如已知会影响自闭症中社会交流障碍严重程度的 5-HTTLPR 基因）或环境因素（如在自闭症相关的 WBS 中发现的高血清素血症，但在没有自闭症的 WBS 中未发现）显著改变。在这方面，WBS 提供了一个有前途的模型，可用于制定综合的遗传、认知、行为和神经化学方法，以研究基因型-表型相关性、可能的基因-环境相互作用和遗传背景效应。结果强调了在诊断为自闭症的个体中仔细进行临床和分子遗传学检查的重要性。
