Trichothiodystrophy 6, Nonphotosensitive

A number sign (#) is used with this entry because of evidence that trichothiodystrophy-6 (TTD6) is caused by homozygous mutation in the GTF2E2 gene (189964) on chromosome 8p12.

For a discussion of genetic heterogeneity of trichothiodystrophy, see 601675.

Clinical Features

Kuschal et al. (2016) reported a 10-year-old Asian boy and a 16-year-old Moroccan girl who both presented with short stature, microcephaly, brittle hair with 'tiger tail' banding on polarized microscopy, dry ichthyotic skin, and developmental delay with a happy personality. Laboratory studies showed low red blood cell mean corpuscular volume and elevated hemoglobin A2. Cells from both patients had normal post-UV DNA repair, with normal recruitment and efficiency of nucleotide excision repair (NER) proteins.

Molecular Genetics

In a 10-year-old Asian boy with nonphotosensitive trichothiodystrophy (TTD), who was negative for mutation in the MPLKIP gene (609188), Kuschal et al. (2016) performed whole-exome sequencing and identified homozygosity for a missense mutation in the GTF2E2 gene (A150P; 189964.0001). His unaffected parents were heterozygous for the mutation, and his healthy brother did not carry the variant. By targeted Sanger sequencing of both TFIIE subunits, GTF2E1 (189962) and GTF2E2, in a 16-year-old Moroccan girl with nonphotosensitive TTD, the authors identified homozygosity for a different missense mutation in GTF2E2 (D187Y; 189964.0002) that segregated with disease in her family. Sanger sequencing of GTF2E1 and GTF2E2 in 41 additional patients with clinically suspected TTD, who were negative for NER defects or mutation in MPLKIP, did not reveal any mutations, suggesting further genetic heterogeneity. Kuschal et al. (2016) noted that in their combined cohort of 125 TTD patients, mutations in GTF2E2 accounted for approximately 2% of cases.