Williams Syndrome: Use of Chromosomal Microdeletions as a Tool to Dissect Cognitive and Physical Phenotypes

Abstract

In Williams syndrome (WS), a deletion of approximately 1.5 Mb on one copy of chromosome 7 causes specific physical, cognitive, and behavioral abnormalities. Molecular dissection of the phenotype may be a route to identification of genes important in human cognition and behavior. Among the genes known to be deleted in WS are ELN (which encodes elastin), LIMK1 (which encodes a protein tyrosine kinase expressed in the developing brain), STX1A (which encodes a component of the synaptic apparatus), and FZD3. Study of patients with deletions or mutations confined to ELN showed that hemizygosity for elastin is responsible for the cardiological features of WS. LIMK1 and STX1A are good candidates for cognitive or behavioral aspects of WS. Here we describe genetic and psychometric testing of patients who have small deletions within the WS critical region. Our results suggest that neither LIMK1 hemizygosity (contrary to a previous report) nor STX1A hemizygosity is likely to contribute to any part of the WS phenotype, and they emphasize the importance of such patients for dissecting subtle but highly penetrant phenotypes.

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits

“…However, the location of the breakpoints in nonhomologous or with low similarity sequences suggests that the most likely mechanism leading to this atypical rearrangements may be nonhomologous end joining or other processes that do not required high homology at the breakpoint, and support the proposal that other mechanisms predisposes to genomic instability of the WBS region 31 This study underscores the importance to map precisely the WBS deletion boundaries to revaluate the significance of the WBS genes hemizygosity in the pathogenesis of epilepsy, facial features, and neurological phenotypes. [32][33][34][35][36][37][38][39][40] CONFLICT OF INTEREST All patients and/or their parents gave written consent for the study, for genetic testing some gave consent for publication of photos. Ethics Committee approval was not required as this was not a specific study but a report of clinical investigation undertaken for four WBS patients, as part of their standard clinical care.…”

The genomic basis of the Williams – Beuren syndrome

“…Undoubtedly, haploinsufficiency of the ELN gene causes SVAS and other cardiovascular manifestations; further, it might contribute to connective tissue weakness (i.e. inguinal hernia) [187]. For the occurrence of the behavioural and the cognitive aspects in WBS patients (mental retardation, visual spatial impairment, overfriendliness and strength in verbal skills), several genes telomeric to the ELN gene are suspected of being responsible.…”

WBSCR14, a putative transcription factor gene deleted in Williams-Beuren syndrome: complete characterisation of the human gene and the mouse ortholog

“…To date, clinical-molecular correlations in some exceptional patients with partial deletions have suggested that the genes mainly responsible for abnormal cognition map to the telomeric interval of the deletion, whilst genes from FKBP6 to WBSCR14, at the centromeric edge of the deletion, might contribute to other phenotypic aspects including mental retardation. 10 However, these conclusions lack strong supportive evidence and additional clinical and molecular studies are required. WBSCR14 is included in the common interval deleted in WBS patients.…”

“…2,8 In addition, deletion of the gene encoding LIM-kinase 1 (LIMK1) has been proposed as a contributing factor to impaired visuo-spatial constructive cognition in WBS, 9 although this claim was not confirmed by clinical and molecular studies of three different patients with heterozygous LIMK1 deletions. 10 A total of 15 additional genes has been reported to be part of the common WBS deleted region although none of them has been related to any of the remaining phenotypic features of the WBS phenotype (see Francke 11 for a review). They include the single copy genes coding for the immunophilin FK-506 binding protein FKBP6, a Drosophila frizzled homolog (FZD9), the putative transcription factor WBSCR9 also known as WSTF, the homolog of a gene disrupted by a leukemic translocation breakpoint (BCL7B), a -transducin (TBL2 also named WS-TRP), the putative transcription factor WS-bHLH, the presynaptic vesicle protein syntaxin 1A (STX1A), the Clostridium perfringens enterotoxin receptors 1 and 2 (approved symbols CLDN4 and CLDN3), the eukaryotic initiation factor EIF4H also known as WBSCR1, the subunit 2 of the replication factor C (RFC2), the neuronal cytoplasmatic linker protein CYLN2, and the GTF2I-related protein GFT2IRD1/WBSCR11.…”