Abstract
BackgroundWilliams-Beuren Syndrome (WBS) is a rare neurodevelopmental disorder characterized by dysmorphic features, cardiovascular defects, cognitive deficits and developmental delay. WBS is caused by a segmental aneuploidy of chromosome 7 due to heterozygous deletion of contiguous genes at the long arm of chromosome 7q11.23. We aimed to apply array-CGH technique for the detection of copy number variants in suspected WBS patients and to determine the size of the deleted segment at chromosome 7q11.23 in correlation with the phenotype. The study included 24 patients referred to the CEGMR with the provisional diagnosis of WBS and 8 parents. The patients were subjected to conventional Cytogenetic (G-banding) analysis, Molecular Cytogenetic (Fluorescent In-Situ Hybridization), array-based Comparative Genomic Hybridization (array-CGH) and quantitative Real time PCR (qPCR) Techniques.ResultsNo deletions were detected by Karyotyping, however, one patient showed unbalanced translocation between chromosome 18 and 19, the karyotype was 45,XX, der(19) t(18;19)(q11.1;p13.3)-18. FISH technique could detect microdeletion in chromosome 7q11.23 in 10/24 patients. Array-CGH and qPCR confirmed the deletion in all samples, and could detect duplication of 7q11.23 in three patients and two parents. Furthermore, the size of the deletion could be detected accurately by both array-CGH and qPCR techniques. Three patients not showing the 7q11.23 deletion were diagnosed by array-CGH to have deletion in chr9p13.1-p11.2, chr18p11.32-p11.21 and chr1p36.13.ConclusionBoth FISH and array-CGH are reliable methods for the diagnosis of WBS; however, array-CGH has the advantage of detection of genome deletions/ duplications that cannot otherwise be detected by conventional cytogenetic techniques. Array-CGH and qPCR are useful for detection of deletion sizes and prediction of the interrupted genes and their impact on the disease phenotype. Further investigations are needed for studying the impact of deletion sizes and function of the deleted genes on chromosome 7q11.23.Trial registrationISRCTN ISRCTN73824458. MOCY-D-16-00041R1. Registered 28 September 2014. Retrospectively registered.
Highlights
Williams-Beuren Syndrome (WBS) is a rare neurodevelopmental disorder characterized by dysmorphic features, cardiovascular defects, cognitive deficits and developmental delay
Fluorescent in-Situ Hybridization (FISH) Analysis has shown the deletion on chromosome 7q11.23 in 10/24 (41.6 %) patients, but no deletion was observed in the parents
The size of deletion was confirmed by quantitative Real time polymerase chain reaction (PCR) (qPCR)
Summary
Williams-Beuren Syndrome (WBS) is a rare neurodevelopmental disorder characterized by dysmorphic features, cardiovascular defects, cognitive deficits and developmental delay. We aimed to apply array-CGH technique for the detection of copy number variants in suspected WBS patients and to determine the size of the deleted segment at chromosome 7q11.23 in correlation with the phenotype. A community-based National prevalence study of symptomatic CHDs reported a prevalence of 2.1/1000 children [4]. Williams’s syndrome (WS) or Williams-Beuren syndrome (WBS) (OMIM 194050) is a contiguous gene syndrome caused by hemizygous deletion of chromosome 7q11.23 and is often associated with a CHD. Affected children have distinctive facial features, congenital heart defects mainly supra valvular aortic stenosis, cognitive deficits, unique personality characteristics and infantile hypercalcemia [5, 6]. The disease occurrence is mostly sporadic with an estimated prevalence ranging between 1/7500 and 1/25,000 [9, 10]
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