PDZD4 (PDZ domain containing 4) is an X-linked gene encoding a PDZ domain-containing protein with emerging roles in neurodevelopmental and metabolic diseases. Primary function: PDZD4 encodes a protein that localizes to the plasma membrane 1 and is normally expressed in fetal brain tissue 1. The protein contains PDZ domains, which typically mediate protein-protein interactions at cellular membranes. Mechanism and disease relevance: PDZD4 variants have been identified in neurodevelopmental disorders (NDDs) and autism spectrum disorder (ASD). Pathogenic PDZD4 variants were discovered through re-evaluation of exome sequencing data in NDD patients with skewed X-chromosome X patterns, suggesting X-linked inheritance 2. Biallelic PDZD4 variants were identified in Pakistani families with ASD, including homozygous missense mutations 3. Clinical significance: While PDZD4 deletions spanning exon 1 occur in contiguous deletion syndromes affecting X-chromosome X, evidence indicates that isolated PDZD4 deletions do not cause additional clinical manifestations beyond those from adjacent gene losses 4. However, PDZD4 appears relevant to prognosis in hepatocellular carcinoma, where it was identified as part of prognostic gene signatures associated with stromal/immune microenvironment features 56. In synovial sarcomas, PDZD4 overexpression promoted cell growth, suggesting oncogenic potential 1.