GTF2I hemizygosity implicated in mental retardation in Williams syndrome: Genotype–phenotype analysis of five families with deletions in the Williams syndrome region

Most individuals with Williams syndrome (WS) have a 1.6 Mb deletion in chromosome 7q11.23 that encompasses the elastin (ELN) gene, while most families with autosomal dominant supravalvar aortic stenosis (SVAS) have point mutations in ELN. The overlap of the clinical phenotypes of the two conditions (cardiovascular disease and connective tissue abnormalities such as hernias) is due to the effect of haploinsufficiency of ELN. SVAS families often have affected individuals with some WS facial features, most commonly in infancy, suggesting that ELN plays a role in WS facial gestalt as well. To find other genes contributing to the WS phenotype, we studied five families with SVAS who have small deletions in the WS region. None of the families had mental retardation, but affected family members had the Williams Syndrome Cognitive Profile (WSCP). All families shared a deletion of LIMK1, which encodes a protein strongly expressed in the brain, supporting the hypothesis that LIMK1 hemizygosity contributes to impairment in visuospatial constructive cognition. While the deletions from the families nearly spanned the WS region, none had a deletion of FKBP6 or GTF2I, suggesting that the mental retardation seen in WS is associated with deletion of either the centromeric and/or telomeric portions of the region. Comparison of these five families with reports of other individuals with partial deletions of the WS region most strongly implicates GTF2I in the mental retardation of WS. © 2003 Wiley‐Liss, Inc.