Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery

Raman Kumar, Alison Gardner, Claire C. Homan, Evelyn Douglas, Heather Mefford, Dagmar Wieczorek, Hermann Josef Lüdecke, Zornitza Stark, Simon Sadedin, Catherine Bearce Nowak, Jessica Douglas, Gretchen Parsons, Paul Mark, Lourdes Loidi, Gail E. Herman, Theresa Mihalic Mosher, Meredith K. Gillespie, Lauren Brady, Mark Tarnopolsky, Irene MadrigalJesús Eiris, Laura Domènech Salgado, Raquel Rabionet, Tim M. Strom, Naoko Ishihara, Hidehito Inagaki, Hiroki Kurahashi, Tracy Dudding-Byth, Elizabeth E. Palmer, Michael Field, Jozef Gecz, The Broad CMG

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans.

Original languageEnglish
Pages (from-to)1126-1138
Number of pages13
JournalHuman mutation
Issue number8
Publication statusPublished or Issued - Aug 2018


  • THOC2
  • XLID
  • mRNA export
  • partial loss-of-function variants
  • protein stability

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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