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

Abstract

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.

Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor

“…Eight of these variants were novel and one recurrent (p.Arg77Cys) that was a maternally inherited in individual 8 as previously reported by us (detailed in Supplementary Data; Kumar et al, 2018). In our previous report, we designated p.Arg77Cys as a variant of uncertain clinical significance in the absence of functional studies at the time (Kumar et al, 2018). All families consented to publication of de-identified clinical information, neuroimaging and, for seven families, clinical photographs, in line with local ethics board regulations.…”

“…Through direct contact with clinicians, facilitated by the genotype-phenotype database DECIPHER and the Human Disease Gene Web series, where we moderate a THOC2related disorder site 1 , 10 individuals from 9 families were identified with rare (absent from gnomAD 2.1) missense variants or an intragenic microdeletion. Eight of these variants were novel and one recurrent (p.Arg77Cys) that was a maternally inherited in individual 8 as previously reported by us (detailed in Supplementary Data; Kumar et al, 2018). In our previous report, we designated p.Arg77Cys as a variant of uncertain clinical significance in the absence of functional studies at the time (Kumar et al, 2018).…”

“…We previously implicated missense and splicing-defective THOC2 variants in NDDs with a broad range of clinical features (Kumar et al, 2015(Kumar et al, , 2018. Here we report 10 previously unreported affected individuals with THOC2 variants, including the first case of a recurrent THOC2 variant (c.229C>T; p.Arg77Cys).…”

“…One such pathway-that has been the focus of our ongoing investigations-is of the highly conserved TREX (TRanscription-EXport) mRNA export pathway. Multiple TREX complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, and THOC7) have been implicated in NDDs and human disease (Kumar et al, 2015(Kumar et al, , 2018Heath et al, 2016;Amos et al, 2017;Mattioli et al, 2019). TREX-mediated mRNA export from the nucleus to the cytoplasm is a complex and highly conserved pathway in all eukaryotes.…”

“…The TREX complex has critical roles in developmental processes such as pluripotency maintenance and hematopoiesis as well as in gene regulation, 3 mRNA processing, stress responses, mitotic progression and genome stability in mammalian cells (Mancini et al, 2010;Yamazaki et al, 2010). We have previously reported genetic and molecular evidence implicating a large number of missense and splicing-defective variants in THOC2-which codes for the largest subunit of the TREX mRNA export complex-in NDDs (Mental retardation, X-linked 12/35 MIM 300957; Kumar et al, 2015Kumar et al, , 2018. Here we present genetic and molecular evidence on a set of novel THOC2 variants, and using aggregate data, refine the core clinical phenotype of THOC2 NDDs.…”