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Trichothiodystrophy (TTD; MONDO:0018053) is a multisystem autosomal recessive disorder defined by sulfur‐deficient, brittle hair and nails, ichthyosis, intellectual disability, and variable photosensitivity. Affected individuals often exhibit hair abnormalities by three months of age and may harbor occult learning disorders requiring early educational intervention (PMID:23960396). NER defects account for up to 83% of TTD cases and are primarily attributed to mutations in TFIIH subunits. ERCC3, encoding the XPB helicase component of TFIIH, plays a dual role in nucleotide excision repair and transcription initiation. Disruption of XPB impairs DNA unwinding at damaged sites and can contribute to systemic and neurodevelopmental features. The absence of skin cancer in TTD patients underscores a transcriptional mechanism distinct from xeroderma pigmentosum. ERCC3 thus represents a critical diagnostic target for molecular testing and multidisciplinary management.
Several clinical case reports have documented ERCC3 among genes implicated in TTD. A 13‐month‐old girl presented with hair fragility and hair loss since three months and was diagnosed with non–photosensitive TTD, underscoring early phenotypic overlap with other NER disorders (PMID:23960396). Photosensitive PIBIDS syndrome was described in two Brazilian siblings, involving ERCC3 and additional TFIIH subunits, with marked cysteine‐deficient brittle hair and neuroectodermal features (PMID:30580289). These pediatric presentations highlight the phenotypic heterogeneity of TTD and the importance of considering ERCC3 variants in differential diagnosis. However, variant information was not reported for ERCC3 in these case studies, limiting genotype–phenotype correlations at the individual level.
Multi‐patient studies have identified ERCC3 biallelic variants in TTD. Two unrelated patients with photosensitive TTD were assigned to XP complementation group B based on XPB functional assays and found to carry a homozygous NM_000122.2:c.355A>C (p.Thr119Pro) missense variant within the helicase domain (PMID:9012405). These probands exhibited characteristic brittle hair, ichthyosis, delayed sexual development, and intellectual disability without skin cancer. The exclusive involvement of ERCC3 in these cases defines a third TTD complementation group, termed XP‐B‐TDII. No additional ERCC3 variant classes, such as frameshifts or splice site mutations, have been reported in TTD to date.
ERCC3‐related TTD follows autosomal recessive inheritance, consistent with biallelic missense variants in affected patients. Segregation data are limited to reports of affected siblings, with no reports of affected carriers or incomplete penetrance. The variant c.355A>C (p.Thr119Pro) occurs in a region conserved across species, supporting pathogenicity. To date, the variant spectrum in TTD is restricted to missense substitutions impairing XPB function. No recurrent founder mutations have been described, and population frequencies are absent, reflecting the rarity of ERCC3‐related TTD.
Functional assays demonstrate that the p.Thr119Pro substitution in XPB compromises TFIIH activity in both NER and transcription contexts. Immunopurified TFIIH complexes from patient cells exhibit decreased promoter opening and impaired recruitment of NER factors to UV‐damaged DNA, leading to reduced repair synthesis (PMID:10064601). Western blot and enzymatic studies confirm that XPB alterations diminish TFIIH stability without affecting complex stoichiometry. Structural analyses of TFIIH components reveal alterations in complex architecture and stability in TTD cells (PMID:19808800). These concordant experimental findings provide mechanistic insight linking ERCC3 impairment to the TTD phenotype.
In summary, the gene–disease association for ERCC3 in TTD is classified as Moderate based on two probands with biallelic pathogenic variants and consistent functional evidence. Additional genetic studies, including identification of variant classes beyond missense substitutions and detailed family segregation analyses, are needed to strengthen clinical validity. The distinct molecular mechanism—transcriptional insufficiency combined with partial NER defect—explains the non–cancer‐prone TTD phenotype and guides therapeutic considerations. Key Take-home: ERCC3 testing should be integrated into diagnostic panels for TTD to enable timely diagnosis and multidisciplinary management.
Gene–Disease AssociationModerate2 unrelated probands with biallelic ERCC3 variants (PMID:9012405), functional concordance (PMID:10064601) Genetic EvidenceModerateAutosomal recessive inheritance with 2 probands harboring c.355A>C (p.Thr119Pro) in ERCC3 and supportive segregation Functional EvidenceModerateXPB variant impairs TFIIH-dependent transcription and NER promoter opening in vitro (PMID:10064601), consistent with TTD phenotype |