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THOC6 is implicated in an autosomal recessive neurodevelopmental disorder characterized by intellectual disability, microcephaly, and distinctive facial dysmorphism. Multiple independent case reports, including a female proband from an Irish Traveller family presenting with severe intellectual disability, renal anomalies, dental caries, and global developmental delay (PMID:27295358), as well as additional cases from India and China, have delineated a relatively homogeneous clinical phenotype. These studies consistently report features such as abnormal kidney morphology, feeding difficulties, and cardiac anomalies, underscoring the clinical importance of considering THOC6 in the differential diagnosis of syndromic intellectual disability.
Genetic analyses across these reports have uncovered several variant classes in THOC6. In one seminal study, three linked homozygous missense variants – including the representative variant c.824G>A (p.Gly275Asp) – were identified in a proband, establishing a molecular diagnosis of Beaulieu-Boycott-Innes syndrome (PMID:27295358). Similar missense and truncating variants were reported in additional families, further supporting a strong gene–disease link with autosomal recessive inheritance (PMID:31421288; PMID:35084103). In aggregate, more than 12 probands from distinct families have been documented with consistent segregation of biallelic pathogenic variants. These data provide robust genetic evidence that pathogenic THOC6 variants underlie the disorder.
Beyond the genetic data, functional studies have clarified the underlying disease mechanism. Multiple in vitro and in vivo models demonstrate that mutant THOC6 protein shows mislocalization from the nucleus to the cytoplasm, impairing normal TREX complex formation and mRNA processing (PMID:23621916; PMID:38388531). Such molecular defects are consistent with the neurodevelopmental abnormalities observed in patients, reinforcing the biological plausibility of the association between THOC6 dysfunction and the clinical syndrome.
The convergence of genetic evidence – with multiple missense and loss‑of‑function variants identified in over 12 unrelated probands – and consistent functional findings across patient-derived cells and animal models provides a coherent narrative for a strong gene–disease association. Small numbers in each study are supplemented by multi‐family segregation and experimental concordance, and although additional patients have been evaluated, the current overall evidence exceeds the minimum required for clinical diagnostic use.
In summary, the comprehensive evaluation of both genetic and functional data supports a strong association between THOC6 and THOC6‑related developmental delay-microcephaly‑facial dysmorphism syndrome. This evidence is critical for diagnostic decision‑making, commercial genetic testing, and future publication.
Gene–Disease AssociationStrongAt least 12 unrelated probands from distinct families have been reported (PMID:35084103), with consistent segregation and supporting experimental data (PMID:27295358). Genetic EvidenceStrongMultiple missense and loss‑of‑function variants have been documented in over 12 probands (PMID:31421288; PMID:35084103), establishing a robust genetic association. Functional EvidenceModerateFunctional studies demonstrate aberrant cellular localization of mutant THOC6 and impaired TREX complex function, consistent with neurodevelopmental dysfunction (PMID:23621916; PMID:38388531). |