Analysis of SSR4 gene variant in a child with congenital glycosylation type 1y in conjunct with congenital dysplasia of external auditory canal

Objective: To explore the genetic basis for a child with congenital disorder of glycosylation type 1y (CDG-1y) in conjunct with congenital dysplasia of external auditory canal.

Methods: Trio-whole exome sequencing (trio-WES) was carried out for the family. Candidate variant was verified by Sanger sequencing. Pathogenicity of the variant was predicted with a variety of bioinformatic tools.

Results: The proband, a 10-years-old boy, presented with mental retardation, microcephaly and dysplasia of external auditory canal. Trio-WES revealed that he has harbored a de novo frameshift variant c.302dupC (p.Y102Lfs*2) in exon 4 of SSR4 gene, which was unreported previously (PS2). The variant was absent in major allele frequency databases (PM2) and was predicted to be pathogenic by multiple bioinformatic tools (PP3). UCSF chimera software suggested that the c.302dupC (p.Y102Lfs*2) variant can induce significant alteration to the structure of SSR4 protein, resulting loss of function (PVS1+PM1). Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was classified as pathogenic (PVS1+PS2+PM1+PM2+PP3).

Conclusions: The de novo frameshift variant c.302dupC (p.Y102Lfs*2) of the SSR4 gene probably underlay the child's condition. Above finding has enriched the spectrum of SSR4 mutations and the phenotypic spectrum of CDG-1y.