The SKIC2 gene is located on chromosome 6 at 6p21.33 and encodes the SKI2 subunit of superkiller complex, the cytoplasmic co-factor and regulator of the RNA-degrading exosome. SKIC2 was first reported in relation to autosomal recessive trichohepatoenteric syndrome 2 in 2012 (Fabre et al., PMID: 22444670). Trichohepatoenteric syndrome 2 is characterized by intrauterine growth restriction, facial dysmorphism, hair abnormalities, intractable diarrhea, and immunodeficiency. Twelve variants (five nonsense, three frameshift, three missense, and one indel ) that have been reported in nine probands in two publications (PMIDs: 22444670, 34414925) 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 functional alteration of patient cells and an animal model (PMIDs: 25064072, 35658009). In summary, there is definitive evidence supporting the relationship between SKIC2 and autosomal recessive trichohepatoenteric syndrome 2. 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 April 23rd, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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