Deciphering the Pathogenic Nature of Two de novo Sequence Variations in a Patient with Shprintzen-Goldberg Syndrome.

Shprintzen-Goldberg syndrome (SGS) is autosomal dominant disorder with features of craniosynostosis, distinctive craniofacial features, skeletal abnormalities, marfanoid body habitus, aortic dilatation, and intellectual disability. SGS is caused by mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFβ activity. We present the unusual molecular findings in a 12-year-old female child with SGS. There was co-occurrence of 2 heterozygous missense variations, c.346G>A (p.Gly116Arg) and c.687G>C (p.Lys229Asn), in exon 1 (hotspot) of the SKI gene, which makes this propositus different from all other patients reported in the literature. Both variants were found to be de novo. In silico analysis revealed that both of them are pathogenic, but later on, Gly116Arg was proven to be more pathogenic by various in silico prediction tools. c.687G>C (p.Lys229Asn) was found as a single report in ExAC in the South Asian population, but c.346G>A (p.Gly116Arg) is not reported anywhere, thereby making it a novel sequence variant in the SKI gene, giving rise to SGS. This case illustrates the issues regarding the importance and difficulties associated with the determination of the causative variations in a single-gene disorder.