Abstract

Background Williams–Beuren syndrome (WBS) is a developmental disorder with multisystemic manifestations mainly characterised by vascular stenoses, distinctive craniofacial features, mental retardation with a characteristic neurocognitive profile, and some endocrine and connective tissue abnormalities, caused by a recurrent deletion of 1.55 Mb including 26–28 genes at chromosomal region 7q11.23. The analysis of clinical–molecular correlations in a few reported atypical patients has been useful to propose several deleted genes as main contributors to specific aspects of the WBS phenotype.

Patients and methods Two additional families with partial phenotypes and atypical 7q11.23 deletions were studied. Deletions were precisely defined at the nucleotide level, and the expression levels of some affected and flanking genes were assessed in lymphoblastoid cell lines.

Results Affected individuals presented variable cardiovascular and connective tissue manifestations, subtle craniofacial features, normal visuospatial construction abilities with low average IQ and no endocrine abnormalities. The deletion in family NW1 encompassed 817 kb with 11 genes (CLDN3–GTF2IRD1), and 610 kb with 14 genes (VPS37D–RFC2) in family NW2. All deleted genes in typical and atypical deletions revealed low expression levels in lymphoblastoid cell lines, except for GTF2IRD1. CLIP2 was also underexpressed in all patients despite being outside the deletion in NW2, while no other flanking non-deleted gene showed significantly different expression compared to controls.

Conclusions Along with previously reported cases, clinical–molecular correlations in these two families further confirm that the functional hemizygosity for the GTF2I and GTF2IRD1 genes is the main cause of the neurocognitive profile and some aspects of the gestalt phenotype of WBS.