Gene dosage and williams syndrome
Segmental duplications play an important role in disease by creating instability that leads to genomic rearrangements in important regions. The consequences can be dosage imbalance of gene(s) critical for normal human development. Abnormal gene dosage is involved in the aetiology of the microdeletion disorder Williams-Beuren Syndrome (WBS) which displays characteristic cardiovascular, craniofacial and neurological phenotypes (strong language skills alongside deficient visuospatial ones). To advance our understanding of the complex mechanisms involved in craniofacial and cognitive brain development firm associations between the 28 or more genes heterozygously deleted and the phenotypes displayed are necessary but are scarce. Our multidisciplinary approach to advance these studies investigates rare individuals with atypical deletions in the WBS region, supplemented by mouse models. We carry out clinical, psychological and 3D-face morphometric analyses alongside detailed molecular profiling of patients with atypical WBS, displaying partial features of the classic spectrum. 3D dense surface models (DSMs) of the full face using pattern recognition algorithms can separate controls from WS individuals with ~96% accuracy and have classified the facial gestalt of these atypical patients in relation to the WBS model. Psychological testing has uncovered cognitive impairments that are different to the classic WBS profile. One patient with a partial deletion shows mildly dysmorphic features and serious deficits in spatial cognition, but not as severe as in classical WBS. Another patient with a de novo duplication including the WBS critical region has craniofacial abnormalities unlike those of WBS and speech dyspraxia. It, therefore,appears that specific gene(s) in the WBS region are exquisitely sensitive to dosage changes and upsetting the balance can affect human speech and language as well as visuospatial capabilities. The main candidates for the main aspects of WBS are CYLN2 and members of the TFII-I (or GTF2I) gene family. Indeed, lack of Gtf2ird1 in mice causes craniofacial abnormalities which implicates these transcription factors in normal human craniofacial as well as neurological development.