Clinical cases series and pathogenesis of Lamb-Shaffer syndrome in China

Abstract Background Lamb-Shaffer syndrome (LAMSHF, OMIM: 616803) is a rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, poor expressive speech, which is attributed to haploinsufficiency by heterozygous variants of SOX5 gene (SRY-Box Transcription Factor 5, HGNC: 11201) on chromosome 12p12. A total of 113 cases have been reported in the world, however, only 3 cases have been reported. in China. Here, we aimed to report novel variants of SOX5 gene and provide examples for clinical diagnosis by reporting the clinical phenotype of a series of Chinese patients with LAMSHF. Methods This study retrospectively collected the information of families of LAMSHF patients in China. Whole Exome Sequencing (WES) were performed to confirm the diagnosis of 4 children with unexplained developmental delay or epilepsy. A minigene splicing assay was used to verify whether the splice variant affected splicing. Meanwhile, a literature review was conducted to analyze the clinical and genetic characteristics of patients with LAMSHF. Results Three of the LAMSHF patients had a de novo heterozygous mutation in the SOX5 gene respectively, c. 290delC (p. Pro97fs*30), chr12: 23686019₂4048958del, c. 1772-1C > A, and the remaining one had a mutation inherited from his father, c. 1411C > T (p. Arg471*). The main clinical manifestations of these children were presented with global developmental delays, and one of them also had seizures. And the results of the minigene experiment indicated that the splice variant, c. 1772-1C > A, transcribed a novel mRNA product which leaded to the formation of a truncated protein. Conclusions Through a comprehensive review and analysis of existing literature and this study showed intellectual disability, speech delay and facial dysmorphisms were common clinical manifestation, while the seizures and EEG abnormalities were rare (21/95, 22. 16%). Notably, we represent the largest sample size of LAMSHF in Asia that encompasses previously unreported SOX5 gene mutation, and a minigene testing have been conducted to validate the pathogenicity of the c. 1772-1C > A splice variant. The research further expands the phenotype and genotype of LAMSHF while offers novel insights for potential pathogenicity of genes locus.