Lamb-Shaffer syndrome (LAMSHF) is a rare neurodevelopmental disorder caused by pathogenic variants in the SRY-related high-mobility group box 5 (SOX5) gene. Clinical features are heterogeneous, and novel variants continue to be reported, expanding the genotypic and phenotypic spectrum of the disease. A 15-year-old male presented with short stature, mild intellectual disability, epilepsy, and multiple congenital anomalies, including facial dysmorphism and right thumb syndactyly. Whole-exome sequencing identified a novel heterozygous variant in the SOX5 gene, c.1160G>A (p.Ser387Asn), located at 12p12.1. Although initially classified as a variant of uncertain significance according to ACMG criteria, its strong correlation with the clinical phenotype supported the diagnosis of LAMSHF. The patient has been maintained on levetiracetam for epilepsy management and is receiving dental care for maxillofacial deformities. A multidisciplinary rehabilitation approach is recommended. Seizures are well-controlled with no recurrence. The patient demonstrates stable cognitive and functional status under current supportive care. This case reports a novel SOX5 variant associated with LAMSHF and highlights the importance of genetic confirmation in patients with unexplained neurodevelopmental features to guide appropriate management and avoid unnecessary interventions.

Haploinsufficiency of SOX5 causes Lamb-Shaffer syndrome, a rare condition with developmental delay, impaired language and intellectual disability and optic nerve abnormalities. Muscle involvement is poorly characterized. We report a 20-year-old woman with neonatal hypotonia, delayed motor milestones, proximal weakness and learning difficulties. Serum creatine kinase was normal. Electroneuromyography revealed a mild myogenic pattern. Muscle biopsy revealed myopathic changes, with cores and protein aggregates. Whole genome sequencing disclosed a heterozygous pathogenic variant in the SOX5 gene. This case expands the phenotypic spectrum of Lamb-Shaffer syndrome, confirming primary muscle involvement with core myopathy.

To explore the clinical phenotypes and genetic characteristics of five children with Lamb-Shaffer syndrome (LAMSHF). Five children with LAMSHF diagnosed at the Department of Pediatrics, the First Medical Center of Chinese PLA General Hospital from April 2021 to December 2024 were selected as study subjects. Clinical data of the children was collected. Genomic DNA was extracted from peripheral blood samples of the children and their parents. Whole exome sequencing (WES) was carried out to screen for variants. This study was approved by the Medical Ethics Committee of the Chinese PLA General Hospital (Ethics No.: S2025-411-01). All five children had presented with global developmental delay. Among them, two had manifestations of autism spectrum disorder, two had abnormal electroencephalogram findings, four had abnormal MRI results, and two had ocular abnormalities. WES has detected five novel variants in the SOX5 gene. Among these, c.1771G>C (p.Gly591Arg) was unreported previously. Sanger sequencing confirmed that none of the parents had carried the same variants, suggesting that they were all de novo variants. According to the guidelines from the American College of Medical Genetics and Genomics (ACMG), two nonsense variants and one missense variant were classified as pathogenic, whilst two missense variants were classified as likely pathogenic. This study has clarified the correlation between the clinical phenotypes of five children with LAMSHF and variants of the SOX5 gene, which expanded the mutational spectrum of the SOX5 gene and provided a basis for the clinical diagnosis and genetic counseling.

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.

The SOX5 gene has been identified as the pathogenic gene responsible for Lamb-Shaffer syndrome. In this study, we examined the SOX5 variant (c.221C > T, p.Thr74Met) within a Chinese family presenting with intellectual disability and evaluated the functional implications of SOX5 by in vitro experiment. The family underwent a clinical assessment of intellectual development, which included precise clinical exome sequencing to identify causative genetic variants. The potential deleterious effects and pathogenicity of the variant were predicted using bioinformatics tools such as Mutation Taster, PROVEAN, and SIFT. Additionally, protein stability was evaluated using I-Mutant, and 3D protein structures were modeled with I-TASSER. Western blots and QPCR were employed to assess gene expression and protein stability. Flow cytometry was utilized to compare the cell cycle dynamics between wild-type and mutant cells. A previously identified missense variant (c.221C > T) in the SOX5 gene was determined to be the underlying cause of intellectual disability in a Chinese family. Functional assays demonstrated that mutant cells exhibited increased levels of SOX5 mRNA and protein relative to wild-type cells, accompanied by enhanced protein stability. Additionally, the mutant SOX5 protein was found to alter the cell cycle and downregulate the mRNA expression levels of the ACAN, AXIN2, SOX9, and PDGFRA genes. We confirmed that the SOX5 p.Thr74Met variant is associated with intellectual disability in a second-generation Chinese family. This mutant protein potentially exhibits increased stability, influences the cell cycle, and downregulates genes related to bone and neural functions.