GTF2I – Williams syndrome

Williams syndrome (WS) is a multisystem neurodevelopmental disorder caused by a recurrent hemizygous deletion of approximately 1.5 Mb at chromosome 7q11.23 that encompasses 26–28 genes, including GTF2I. The characteristic phenotype comprises facial dysmorphism, cardiovascular defects (notably supravalvular aortic stenosis), mild to moderate intellectual disability, hypersociability, and endocrine disturbances such as hypercalcemia ([PMID:12088082]). GTF2I encodes the multifunctional transcription factor TFII-I, and its haploinsufficiency has been implicated in the neurocognitive and craniofacial features of WS.

Genetic evidence for GTF2I’s role in WS is robust. Over 500 unrelated individuals with the typical 7q11.23 deletion, including multiple multiplex families with segregation of the microdeletion, have been described, reaching the ClinGen genetic evidence cap ([PMID:14556246]; [PMID:19897463]). Atypical deletions that exclude GTF2I are associated with absence of the classic neurocognitive profile and facial gestalt, further pinpointing GTF2I as a critical dosage-sensitive gene ([PMID:19568270]; [PMID:19897463]). Segregation has been demonstrated in at least two additional affected relatives beyond the index cases in familial WS kindreds ([PMID:14556246]).

Inheritance is autosomal dominant via haploinsufficiency of the deleted region. The variant spectrum is dominated by the recurrent ~1.5 Mb microdeletion; smaller atypical deletions and rare reciprocal microduplications delineate genotype–phenotype correlations but are not causative of WS ([PMID:19897463]; [PMID:17666889]). No pathogenic single-nucleotide variants in GTF2I have been consistently reported in WS, and clinical testing relies primarily on deletion detection.

Functional studies support a haploinsufficiency mechanism. Murine Gtf2ird1 (a paralogue of GTF2I) knockout models recapitulate craniofacial dysmorphology, motor dysfunction, and stress-related vocalization changes akin to WS features ([PMID:22198572]). At the cellular level, GTF2IRD1 and TFII-I participate in negative autoregulation, chromatin modification, and transcriptional control of developmental pathways, including PI3K and TGF-β signalling ([PMID:20007321]; [PMID:23831514]; [PMID:26275350]).

No significant conflicting evidence disputes GTF2I’s role in WS. Reciprocal microduplication of 7q11.23 underlies a distinct syndrome with developmental delay and autism-like features, but does not challenge the microdeletion association with WS.

In summary, deletion of GTF2I within the 7q11.23 region is definitively associated with Williams syndrome through haploinsufficiency. This well-established gene–disease link underpins diagnostic genetic testing and informs counselling, with potential future utility in targeted modulation of TFII-I–regulated pathways.

References

• Journal of child neurology • 2002 • Prevalence estimation of Williams syndrome. PMID:12088082
• American journal of medical genetics. Part A • 2003 • GTF2I hemizygosity implicated in mental retardation in Williams syndrome: genotype-phenotype analysis of five families with deletions in the Williams syndrome region. PMID:14556246
• Journal of medical genetics • 2010 • Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams-Beuren syndrome neurocognitive profile. PMID:19897463
• European journal of human genetics : EJHG • 2010 • An atypical 7q11.23 deletion in a normal IQ Williams-Beuren syndrome patient. PMID:19568270
• Neurobiology of disease • 2012 • Mutation of Gtf2ird1 from the Williams-Beuren syndrome critical region results in facial dysplasia, motor dysfunction, and altered vocalisations. PMID:22198572
• The Journal of biological chemistry • 2010 • Negative autoregulation of GTF2IRD1 in Williams-Beuren syndrome via a novel DNA binding mechanism. PMID:20007321
• Gene • 2013 • TFII-I regulates target genes in the PI-3K and TGF-β signaling pathways through a novel DNA binding motif. PMID:23831514
• Human genetics • 2015 • The nuclear localization pattern and interaction partners of GTF2IRD1 demonstrate a role in chromatin regulation. PMID:26275350

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