GTF2E2 – Trichothiodystrophy

The association between GTF2E2 and trichothiodystrophy is supported by a combined body of clinical, genetic, and functional evidence. Clinical reports include a BMJ case study describing PIBIDS syndrome in two Brazilian siblings, where one affected sibling represents an additional segregating case (PMID:30580289). Furthermore, multi‐patient studies have identified affected individuals with trichothiodystrophy carrying homozygous missense variants in GTF2E2.

Genetic evidence is robust. Two independent studies have delineated distinct homozygous missense mutations in GTF2E2, including the variant c.448G>C (p.Ala150Pro), observed in unrelated patients (PMID:26996949). This observation is consistent with an autosomal recessive mode of inheritance and is further reinforced by familial segregation data in the BMJ case report.

Detailed variant analysis identifies the reported mutation as c.448G>C (p.Ala150Pro). In the AJHG study, affected individuals harbor this variant alongside another missense change, c.559G>T (p.Asp187Tyr), underscoring the recurrence of pathogenic substitutions in GTF2E2. These mutations directly correlate with the corresponding trichothiodystrophy phenotype.

Functional assessments further validate the gene–disease link. Studies in patient‐derived cells have demonstrated that these missense mutations destabilize the TFIIE complex and impair transcription, thereby elucidating a mechanism of pathogenicity that is independent of nucleotide excision repair defects (PMID:26996949; PMID:28973399). This functional disruption parallels the clinical presentation, strengthening the overall evidence.

No significant contradictory evidence has been reported in the literature; all available data converge to support a strong association between GTF2E2 variants and trichothiodystrophy. The combined clinical and experimental findings exceed ClinGen scoring thresholds, although the curated score remains within the strong category given the current evidence volume.

Key Take‑home: The integration of clinical case reports, segregation data, and mechanistic functional studies solidifies the diagnostic utility of GTF2E2 variant screening in patients presenting with trichothiodystrophy.

References

• BMJ case reports • 2018 • PIBIDS syndrome in two Brazilian siblings PMID:30580289
• American journal of human genetics • 2016 • GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy PMID:26996949
• Human molecular genetics • 2017 • Trichothiodystrophy causative TFIIEβ mutation affects transcription in highly differentiated tissue PMID:28973399

Evidence Based Scoring (AI generated)