- DLG4-related synaptopathy presents variably with intellectual disability, ASD, epilepsy, hypotonia, sensory disturbances and marfanoid musculoskeletal features.
- Case: 21-year-old man with chronic pain, sensory hypersensitivity, tremors, cognitive decline, ASD traits, psychotic manifestations and multiple autonomic and gastrointestinal complaints.
- Whole-exome sequencing identified heterozygous DLG4 missense variant p.Tyr50Phe classified as a variant of uncertain significance, limiting definitive genotype phenotype correlation.
Cureus. 2026 Aug 13;18(8):e114477. doi: 10.7759/cureus.114477. eCollection 2026 Aug.
ABSTRACT
DLG4-related synaptopathy is a rare neurodevelopmental condition caused by pathogenic variants in the DLG4 gene, which encodes the postsynaptic density protein 95 (PSD-95). The disorder is characterized by a broad clinical spectrum that may include intellectual disability, autism spectrum disorder (ASD), epilepsy, hypotonia, sleep disturbances, and marfanoid manifestations. Most reported cases arise from de novo variants, although autosomal dominant inheritance with variable phenotypic expressivity has also been described. This report describes a 21-year-old man presenting with chronic musculoskeletal pain, sensory hypersensitivity, tremors, cognitive decline, ASD traits, psychotic manifestations, and marfanoid features. Additional symptoms included gastroesophageal reflux, dysphagia, constipation, urinary hesitancy with interrupted urinary stream, nocturnal polyuria, visual complaints, and impaired sleep quality. Cytogenetic analysis demonstrated a normal male karyotype (46,XY). Whole-exome sequencing identified a heterozygous missense variant of uncertain significance (VUS) (c.149A>T; p.Tyr50Phe) in the DLG4 gene. Although the patient’s phenotype shows significant overlap with previously described presentations of DLG4-related synaptopathy, the variant is currently classified as a VUS and its clinical significance remains undetermined. He continues to undergo multidisciplinary follow-up and remains on pregabalin therapy for symptomatic pain control. This report further broadens the recognized phenotypic spectrum potentially associated with DLG4-related synaptopathy, highlighting the disorder’s clinical heterogeneity while acknowledging that the identified variant remains of uncertain significance and therefore limits definitive genotype-phenotype correlation. Clinicians should consider this diagnosis in individuals presenting with neurodevelopmental manifestations, sensory disturbances, and marfanoid features. Early recognition and comprehensive genetic evaluation may support diagnostic clarification, guide management, and improve clinical outcomes.
PMID:42732390 | PMC:PMC13570606 | DOI:10.7759/cureus.114477
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