Heterozygous alterations of GTF2I at the Williams-Beuren syndrome's locus cause a neurodevelopmental disorder.

Purpose: Williams-Beuren syndrome (WBS) is a well-known neurodevelopmental disorder caused by a copy-number loss at the 7q11.23 locus. Although the 1.5-1.8 Mb recurrent deletion carries several genes of interest, no single gene has been identified in which pathogenic variants cause a neurodevelopmental phenotype. At this locus, GTF2I, encoding the general transcription factor II-I, has been considered as the main candidate gene for the cognitive and behavioural phenotype of WBS, based on clinical observations of cases with atypical 7q.11.23 deletions and functional studies in humans and mice.

Methods: Individuals with a neurodevelopmental disorder were identified through a multicentre collaboration using GeneMatcher and the ERN-ITHACA network. They remained undiagnosed following genome/exome sequencing. Clinical evaluations were performed in each participating centre.

Results: We identified seven unrelated individuals with de novo variants in GTF2I (two non-sense, two splice-site, one missense, one indel and one intragenic deletion). We also identified one individual with a WBS phenotype and low GTF2I expression identified by RNA sequencing. All eight individuals presented with global developmental delay and facial dysmorphic features, with speech delay and/or autistic features in seven cases. The effect of the two splice-site variants was confirmed by RNA sequencing.

Conclusion: Pathogenic heterozygous GTF2I variants cause a neurodevelopmental disorder characterised by global developmental delay with facial dysmorphic features, partly resembling the phenotype observed in individuals affected with WBS.