THOC2 – X-linked Intellectual Disability-Short Stature-Overweight Syndrome

X-linked recessive THOC2 variants have been reported in a single family with fetal arthrogryposis multiplex congenita (1 proband) harboring a canonical splice-site mutation, expanding the phenotype of MONDO:0010496 beyond intellectual disability (PMID:37945483). The variant segregates with disease in the family; no additional affected relatives have been described. Clinical validity is limited by the single family report and absence of broader segregation or replication.

Yeast and cellular studies of the THO/TREX complex demonstrate that THOC2 is essential for mRNA export, transcription elongation, and genome stability, supporting a loss-of-function mechanism via impaired mRNA metabolism (PMID:12093753; PMID:12871933). Human functional data directly linking THOC2 dysfunction to this syndrome are not yet available. Additional familial and experimental evidence is needed to reach higher ClinGen validity tiers. Key take-home: THOC2 splice-site variants may underlie an X-linked syndrome characterized by intellectual disability, short stature, overweight and, in rare cases, fetal arthrogryposis.

References

• Neuromuscular disorders : NMD • 2023 • Muscular phenotype description of abnormal THOC2 splicing. PMID:37945483
• The EMBO journal • 2002 • The yeast THO complex and mRNA export factors link RNA metabolism with transcription and genome instability. PMID:12093753
• The Journal of biological chemistry • 2003 • Molecular evidence that the eukaryotic THO/TREX complex is required for efficient transcription elongation. PMID:12871933

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