Submission Details

SKI was first reported in relation to Shprintzen-Goldberg syndrome (SGS) as early as 2012 (Doyle et al., Carmignac et al.; PMIDs: 23023332, 23103230). Clinical phenotypes of SGS include craniosynostosis and craniofacial features, motor and cognitive delays, mild-moderate intellectual disability, hypotonia, musculoskeletal anomalies, and cardiovascular problems such as aortic aneurysm. Variants in SKI have been identified in at least 40 probands with SGS (GeneReviews, Greally, 2020). Seven variants (missense and in-frame indel) reported in 13 probands in 4 publications (PMID: 23023332, 23103230, 24357594, 4736733) are included in this curation. Additionally, there is evidence that variants affecting amino acid position p.Thr180 may lead to phenotypes including thoracic aortic aneurysm and a marfanoid body habitus without intellectual disability, a feature which is often characteristic of SGS (PMID: 31980905). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is proposed to be dominant-negative (PMID: 23023332). Variants in SKI associated with SGS are concentrated in exon 1, a mutational hotspot, where variants exert a stabilizing effect on SKI protein function, attenuating the TGF-β signaling pathway (PMID: 33416497). This gene-disease association is also supported by experimental evidence including expression studies, animal models, and in vitro functional assays (PMID: 10906458, 23023332). In summary, SKI is definitively associated with Shprintzen-Goldberg syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was approved by the ClinGen Craniofacial Malformations Gene Curation Expert Panel on 10/29/20 (SOP Version 8). The evidence summary was updated by the Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease Gene Curation Expert Panel on 7/23/2024.