Pathogenesis Of Lamb-Shaffer Syndrome Induced By SOX5 Gene Variant

Objective:To analyze the pathogenic variant of SOX5 gene in a Chinese patient with Lamb-Shaffer Syndrome,and to provide reference for the study of the pathogenesis of Lamb-Shaffer Syndrome.Methods:Peripheral blood samples were collected from five members of the Lamb-Shaffer Syndrome proband and other members of the pedigree.The suspected pathogenic gene was screened out by whole exon sequencing.Sanger sequencing was applied to the proband and other members of the pedigree.The variation was analyzed conservatively and the pathogenicity was predicted.The wild-type and mutant expression vectors of SOX5 gene were constructed and transfected into HEK 293 T cells.The pathogenicity of the variant sites was studied by immunofluorescence,Western blot and q RT-PCR.Results:The proband was found to harbor a heterozygous c.1495 del A(p.Thr499Glnfs*5)frameshift variant of the SOX5 gene by WES.Sanger sequencing confirmed that the same variant was a denovo variant.The mutation was highly conserved across species.The Mutation Taster software prediction score was 1,indicating pathogenicity.Based on the ACMG guidelines,c.1495 del A(p.Thr499Glnfs*5)of the SOX5 gene was predicted to be pathogenic.The variant located in Exon 12 of SOX5 gene,is a frameshift mutation in which the loss of a base is introduced termination codon ahead of time to produce a truncated protein that causes the loss of the entire HMG domain.Conclusion:The heterozygous c.1495 del A(p.Thr499Glnfs*5)variant of the SOX5 gene probably underlies the Lamb-Shaffer Syndrome in this predigree.The detection of the new variant enriched the SOX5 gene variation spectrum of Lamb-Shaffer Syndrome.