Submission Details

The THOC6 gene is located on chromosome 16 at 16p13.3 and encodes for a 341-amino acid protein named THOC6, a subunit of the multi-protein THO complex, which is involved in coordination between transcription and mRNA processing. THOC6 was first reported in relation to autosomal recessive Beaulieu-Boycott-Innes Syndrome (BBIS) in 2013 (Beaulieu et al., PMID: 23621916), a neurodevelopmental condition with microcephaly and dysmorphic facial features. 10 variants (missense, nonsense, frameshift) that have been reported in at least 13 probands in 7 publications (PMIDs: 23621916, 26739162, 27102954, 30238602, 30476144, 31421288, 33739554) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (functional alteration evidence, expression-level evidence, mouse model; PMIDs: 23621916, 38388531). Functional alteration evidence in HeLa cells showed an increase in apoptosis when knockdown of THOC6 occurred. Expression evidence showed THOC6 was expressed in zebrafish brains during development. A mouse model showed reduced size, delayed development, and early lethality in the mutant mice compared to the wild-type. In summary, there is definitive evidence supporting the relationship between THOC6 and autosomal recessive BBIS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date March 15, 2024 (SOP Version 10).