Supplementary Material for: 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 <i>SKI</i> 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&gt;A (p.Gly116Arg) and c.687G&gt;C (p.Lys229Asn), in exon 1 (hotspot) of the <i>SKI</i> 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&gt;C (p.Lys229Asn) was found as a single report in ExAC in the South Asian population, but c.346G&gt;A (p.Gly116Arg) is not reported anywhere, thereby making it a novel sequence variant in the <i>SKI</i> 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.

施普林岑-戈德伯格综合征（Shprintzen-Goldberg syndrome, SGS）是一种常染色体显性遗传病，临床特征包括颅缝早闭、特征性颅面部表型、骨骼异常、马方样体型、主动脉扩张及智力障碍。该病由SKI基因突变引起，该基因编码癌蛋白SKI，后者是转化生长因子β（Transforming Growth Factor-β, TGFβ）活性的抑制因子。本文报道1例12岁女性SGS先证者，其携带罕见的分子学特征。该患儿SKI基因外显子1（突变热点区域）同时存在2种杂合错义变异：c.346G>A（p.Gly116Arg）与c.687G>C（p.Lys229Asn），这一特征使其区别于既往文献报道的所有SGS患者。上述两种变异均为新发变异。计算机模拟分析显示二者均具有致病性，后续多项计算机预测工具证实，p.Gly116Arg的致病性更强。c.687G>C（p.Lys229Asn）仅在ExAC数据库的南亚人群中被单次报道，而c.346G>A（p.Gly116Arg）此前未见任何文献报道，因此该变异属于SKI基因上的新型序列变异，可导致SGS。本案例阐明了单基因遗传病致病变异鉴定的重要性及相关难点。