GTF2IRD2 – Williams syndrome

The association between GTF2IRD2 (HGNC:30775) and Williams syndrome (MONDO_0008678) is supported by multiple lines of evidence from large cohort studies and functional assessments. Several multi‑patient analyses have reported that deletions in the 7q11.23 region, which include GTF2IRD2, are present in patients with Williams syndrome. In one study, detailed clinical and molecular characterization of 96 patients (PMID:16532385) showed variability in deletion breakpoints affecting genes such as GTF2IRD2; similar findings were reported in additional cohorts of 47 (PMID:31204697) and 9 patients (PMID:31931504).

Genetic evidence indicates that deletions encompassing GTF2IRD2 contribute to the phenotypic spectrum of Williams syndrome. Although specific single‑nucleotide variants were not provided, copy number variation analyses across studies consistently implicate this gene. The correlation between the extent of the deletion and clinical manifestations such as altered craniofacial features (e.g. wide mouth (PMID:31931504)) and cardiovascular components (e.g. hypertension (PMID:16532385)) further substantiates its role in the condition.

Functional studies provide additional support for the role of GTF2IRD2 in Williams syndrome. Experimental evaluations have demonstrated that GTF2IRD2, a member of the TFII-I transcription factor family, may form both homo‑ and heterodimers with related proteins. Disruption of these transcriptional regulatory mechanisms, as documented in in vitro binding assays and protein structural analyses (PMID:15388857; PMID:15100712), supports a mechanistic link between its deletion and the neurodevelopmental and craniofacial features characteristic of Williams syndrome.

While none of the reports provided conventional segregation data from extended families, the recurrence of deletions affecting GTF2IRD2 across independent cohorts reinforces the genetic association. The convergence of these genetic findings with functional data underlines the biological relevance of GTF2IRD2 loss in the etiology of Williams syndrome.

Overall, the evidence supporting the association of GTF2IRD2 with Williams syndrome is robust. The multi‑patient cohort studies demonstrate a reproducible deletion of the gene in a substantial number of cases, while experimental studies confirm that disruption of its function leads to perturbations in transcriptional regulation. This convergence of data drives a strong confidence in its causative role in the disease.

Key take‑home: The deletion of GTF2IRD2 and its consequential impact on transcription factor activity make it a critical marker for Williams syndrome diagnosis and an attractive target for future therapeutic intervention.

References

• American journal of human genetics • 2006 • Hemizygosity at the NCF1 gene in patients with Williams-Beuren syndrome decreases their risk of hypertension PMID:16532385
• Journal of genetics • 2019 • Williams-Beuren syndrome in Mexican patients confirmed by FISH and assessed by aCGH PMID:31204697
• Cytogenetic and genome research • 2019 • Chromosomal Microarray Analysis in Taiwanese Patients with Williams-Beuren Syndrome PMID:31931504
• Protein science : a publication of the Protein Society • 2004 • Comparison of TFII-I gene family members deleted in Williams-Beuren syndrome PMID:15388857
• European journal of human genetics : EJHG • 2004 • Isolation and characterisation of GTF2IRD2, a novel fusion gene and member of the TFII-I family of transcription factors, deleted in Williams-Beuren syndrome PMID:15100712

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