Submission Details

The SKIC3 gene is located on chromosome 5 at 5q15 and encodes for Superkiller complex protein 3 (SKIC3) protein. SKIC3 protein, which is the main and largest scaffolding subunit, forms a SKI complex with SKIC2 helicase protein and two SKIC8 protein subunits. SKI complex assists the RNA-degrading exosome during the mRNA decay and quality-control pathways.

SKIC3 was first reported in relation to autosomal recessive trichohepatoenteric syndrome (THES) 1 in 2010 (Hartley et al., PMID: 20176027). THES is characterized by intractable diarrhea (usually during neonatal period, seen in almost all affected children), wooly hair (seen in most children), intrauterine growth restriction, facial dysmorphism, short stature, immunodeficiency, recurrent infections, skin abnormalities, and liver disease. Mild intellectual disability (ID) is seen in about 50% of affected individuals. Less common findings include congenital heart defects and platelet anomalies (Fabre et al 2018, PMID: 29334452). Nine different variants (nonsense, frameshift, missense) in SKIC3 (previously known as TTC37) that were found in 12 children from 11 unrelated families are included in this curation (Hartley et al., 2010 PMID: 20176027; Chong et al., 2015 PMID: 25976726; Bourgeois et al., 2018 PMID: 29527791). This gene-disease relationship is also supported by biochemical function, gene expression, protein interaction studies (Tomecki et al., 2023 PMID:37384835; Fabre et al., 2010 PMID: 21120949; Kögel et al., 2022 PMID: 35120588). In summary, the SKIC3 gene is definitively associated with autosomal recessive trichohepatoenteric syndrome (THES) 1. 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 GCEP on the meeting date April 23rd, 2024 (SOP Version 10).