Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability

Francesca Mattioli, Bertrand Isidor, Omar Abdul-Rahman, Andrew Gunter, Lijia Huang, Raman Kumar, Chandree Beaulieu, Jozef Gecz, Micheil Innes, Jean Louis Mandel, Amelie Piton

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6 Citations (Scopus)


THOC6 encodes a subunit of the THO complex that is part of a highly-conserved TREX complex, known to have roles in mRNA processing and export. Few homozygous or compound heterozygote variants have been identified in the THOC6 gene in patients with a syndromic form of intellectual disability (ID) (Beaulieu-Boycott-Innes syndrome, BBIS MIM# 613680). Here we report two additional individuals affected with BBIS originating from the north of Europe and sharing an haplotype composed by threevery rare missense changes in the THOC6gene: p.(Trp100Arg; Val234Leu; Gly275Asp). The first individual is a boy who is homozygous for the three-variant haplotype, due to a maternal uniparental disomy event. The second is a girl, who is compound heterozygote for this haplotype and a previously reported p.(Gly190Glu) missense variant. We analyzed the impact of these different amino acid changes on THOC6 protein expression,cellular localization, and interaction with the other THO complex subunits. We show that the different THOC6 variants alter the physiological nuclear localization of the protein and its interaction with at least two THO subunits, THOC1 and THOC5. Two amino acid changes from the three-variant-haplotype have alone specific effects and might contribute to the pathogenicity of the haplotype. Overall, we expanded the cohort of currently known BBIS affected individuals by reporting two individuals carrying the same recurrent European haplotype composed of three amino acid changes, affecting THOC6 localization and interaction with THO protein partners.

Original languageEnglish
Pages (from-to)952-960
Number of pages9
JournalHuman Molecular Genetics
Issue number6
Early online date21 Nov 2018
Publication statusPublished - 1 Jan 2019


  • Journal Article

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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