SOX5 and Lamb-Shaffer Syndrome

Lamb-Shaffer syndrome (LSS; MONDO:0014778) is a rare autosomal dominant neurodevelopmental disorder caused by haploinsufficiency of the SRY-box transcription factor 5 (SOX5; HGNC:11201) gene (SOX5; Lamb-Shaffer syndrome). Patients typically present with global developmental delay, mild to moderate intellectual disability, delayed speech and language development, and characteristic facial features.

Extensive genetic studies have identified over 113 unrelated patients harboring heterozygous SOX5 alterations, including microdeletions, truncating and missense variants, with de novo occurrence in the majority of cases ([PMID:39075495]). A large series of 41 novel patients further expanded the genetic spectrum and confirmed variable expressivity across diverse populations ([PMID:31578471]). Additional cohorts, such as 20 Spanish patients, corroborate a recurrent mutation burden and highlight both single-nucleotide and copy-number variants ([PMID:37702321]).

The variant spectrum encompasses truncating alleles distributed throughout SOX5 and missense changes clustering in the pivotal high-mobility-group (HMG) DNA-binding domain. A recurrent loss-of-function variant, c.1477C>T (p.Arg493Ter), has been reported in multiple unrelated probands, all de novo, and associates consistently with language delay and scoliosis ([PMID:36759900]).

Segregation analysis across families demonstrates de novo occurrence in >30 cases and at least one pedigree with maternal transmission showing milder phenotype in the parent and more severe manifestations in the child, supporting dosage sensitivity of SOX5 (1 affected relative). Functional studies of selected HMG-domain missense variants reveal impaired DNA binding and loss of transactivation activity in luciferase assays, whereas variants outside this domain retain function ([PMID:31578471]).

In vivo and cellular models corroborate haploinsufficiency as the mechanism of pathogenicity. Drosophila knockdown of the SOX5 ortholog leads to disrupted neuronal morphology, dendritic arborization defects, and behavioral impairment, mirroring human neurodevelopmental phenotypes ([PMID:28186563]). Rescue experiments and protein stability assays confirm reduced SOX5 activity in patient-derived variants.

No studies to date have refuted the SOX5–LSS association; phenotypic variability likely reflects allelic heterogeneity and genetic background. Clinical diagnosis is supported by detection of heterozygous SOX5 variants in individuals with compatible presentations and can guide genetic counseling and management.

Key Take-Home: SOX5 haploinsufficiency is a definitive cause of Lamb-Shaffer syndrome; genetic testing for SOX5 should be prioritized in patients with developmental delay, intellectual disability, and speech impairment to enable accurate diagnosis and family planning.

References

• Genetics in Medicine • 2020 • Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency PMID:31578471
• Orphanet Journal of Rare Diseases • 2024 • Clinical cases series and pathogenesis of Lamb-Shaffer syndrome in China PMID:39075495
• Clinical Genetics • 2023 • Lamb-Shaffer syndrome: 20 Spanish patients and literature review expands the view of neurodevelopmental disorders caused by SOX5 haploinsufficiency PMID:37702321
• BMC Medical Genomics • 2023 • Clinical characterization of Lamb-Shaffer syndrome: a case report and literature review PMID:36759900
• Human Molecular Genetics • 2017 • Silencing of the Drosophila ortholog of SOX5 leads to abnormal neuronal development and behavioral impairment PMID:28186563

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