GTF2H5 and trichothiodystrophy

The association between GTF2H5 and trichothiodystrophy is supported by multiple independent case reports and multi‐patient studies. Patients consistently present with core features such as brittle, sulfur‑deficient hair, ichthyosis, and neuroectodermal abnormalities including global developmental delay and alopecia (PMID:20075106).

Genetic evidence is robust, with several unrelated probands identified harboring distinct deleterious variants in GTF2H5. For example, one report described a neonate harboring a pathogenic variant, c.29T>A (p.Ile10Lys) (PMID:30359777). Additional families, including sibling pairs reported in independent studies (PMID:30580289), further reinforce segregation of pathogenic alleles along with consistent phenotypic findings.

Trichothiodystrophy due to GTF2H5 variants follows an autosomal recessive inheritance pattern. Segregation analysis in these families has revealed multiple affected relatives carrying biallelic variants, supporting the independent co‐segregation of the disorder (PMID:30359777).

Functional and experimental assessment has demonstrated that pathogenic mutations in GTF2H5 lead to destabilization of the TFIIH complex. In vitro and in vivo studies show altered transcription and impaired nucleotide excision repair, which concordantly reproduce the cellular defects seen in patient cells (PMID:15220921, PMID:25620205).

In summary, the convergence of clinical, genetic, and functional data across diverse studies robustly supports a strong association between GTF2H5 and trichothiodystrophy. This integrated evidence is compelling for diagnostic decision‑making, commercial testing, and future research publications.

Key Take‑home: Disruption of GTF2H5 leads to TFIIH instability and a consequent defect in DNA repair and transcription, establishing its strong clinical utility as a diagnostic marker for trichothiodystrophy.

References

• AJNR. American journal of neuroradiology • 2010 • Trichothiodystrophy with dysmyelination and central osteosclerosis PMID:20075106
• BMJ case reports • 2018 • PIBIDS syndrome in two Brazilian siblings PMID:30580289
• European journal of medical genetics • 2019 • A case of severe trichothiodystrophy 3 in a neonate due to mutation in the GTF2H5 gene: Clinical report PMID:30359777
• Nature genetics • 2004 • A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A PMID:15220921
• American journal of human genetics • 2015 • TFIIH subunit alterations causing xeroderma pigmentosum and trichothiodystrophy specifically disturb several steps during transcription PMID:25620205

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