Functional characterization of SOX5 variant causing Lamb-Shaffer syndrome and literature review of variants in the...

Lamb-Shaffer syndrome (LAMSHF, OMIM 616803) is a neurodevelopmental disorder caused by mutations in the SRY-box transcription factor 5 (SOX5) gene. The SOX5 protein is a conserved transcription factor with a high-mobility-group domain that enhances the expression of various extracellular matrix genes by promoting SOX9 binding to a distant enhancer of the target gene.

We reported a 7-year-old boy with severe intellectual disability, seizures, autism, strabismus, and myopia, who carries a novel SOX5 gene variant (c.1769T > C, p.Leu590Ser) inherited from his mother, who has a milder phenotype. We conducted in vitro assays to evaluate the effects of this variant and performed a literature review to explore the clinical and genetic spectrum of LAMSHF.

In silico and in vitro data suggest that the SOX5 missense variant (c.1769T > C, p.Leu590Ser) may be pathogenic due to reduced transcriptional activation activity. Common characteristics of LAMSHF include intellectual disability, language delay, hypotonia, strabismus, autism spectrum disorder, seizures, and dysmorphic facial features. Although no clear genotype-phenotype association was found in LAMSHF, variable expressivity was noted.

Our findings expand the genetic spectrum of LAMSHF and highlight the intrafamilial variability in severity among affected individuals. This study provides a comprehensive overview of the clinical manifestations of LAMSHF, aiding in diagnosis and genetic counseling.