Variants in TREX complex subunits (THOC2, ALYREF, THOC6, THOC7) define a neurodevelopmental disability spectrum.

THOC2, THOC6, THOC7, ALYREF

Partial loss-of-function variants in subunits of the TREX export complex (THOC2 and THOC6, known disease genes; THOC7 and ALYREF, candidate genes) that alter protein localisation, stability or interactions or delete functional domains, with accumulation of DNA damage

TREX (TRanscription EXport) is an evolutionarily conserved multifunctional complex with essential roles in regulating transcription, mRNA export, genome stability, cell differentiation and survival. Through international collaboration, the authors aggregated 40 individuals with high-impact variants in four genes encoding TREX subunits: THOC2 and THOC6, known disease genes, and THOC7 and ALYREF (THOC4), candidate disease genes. On a background of considerable heterogeneity, all variants affect cognitive functioning and development, speech and the respiratory system, and are accompanied by recognisable facial dysmorphism; five recurrent THOC2 variants give overlapping yet variable clinical presentations, including severe perinatal lethal arthrogryposis multiplex congenita. In cells from 13 affected individuals, the variants are generally partial loss of function, altering protein localisation, stability or interactions or deleting internal or C-terminal functional domains, and cells from all four subunits studied show a consistent yet variable accumulation of DNA damage. The authors conclude that a TREX spectrum disorder exists, due to functional variation across several subunits.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Bringing four genes of the same complex together as a single spectrum, with a shared cellular signature (partial loss of function, DNA damage), is a useful framing for interpreting neurodevelopmental exomes when speech, the respiratory sphere and recognisable facial dysmorphism point to this pathway. The reservation concerns THOC7 and ALYREF, which the authors themselves call candidate genes, and the 40 individuals spread across four genes, with no per-gene sample size given in the abstract: the strength of each association taken separately remains to be established. The clinical heterogeneity acknowledged by the authors also limits, for now, the value of the phenotype as an aid to variant prioritisation.

Analysis by Dr Thibaut Benquey