MPDZ is a multi-PDZ domain scaffolding protein that localizes to apical cell junctions and tight junctions, functioning as a key component of cell polarity complexes. At the synaptic level, MPDZ participates in NMDAR signaling and may regulate AMPAR potentiation and excitatory synaptic plasticity. During early neurodevelopment, MPDZ cooperates with DAPLE at apical junctions to promote cell constriction and neural tissue remodeling, processes critical for proper brain development 1. Biallelic MPDZ variants cause autosomal recessive disease with clinically heterogeneous manifestations. Congenital hydrocephalus is the most frequent phenotype 2, though the phenotypic spectrum now includes vision impairment, hearing impairment, cardiovascular defects, and spasticity 3. MPDZ variants have been identified in autosomal recessive nonsyndromic hearing impairment 4, retinal dystrophies with macular colobomas and chorioretinal atrophy 5, and complex neurodevelopmental syndromes with cardiac and respiratory involvement 6. At the population level, gnomAD v4.1 classifies MPDZ as loss-of-function tolerant (LOEUF=1.14); however, 133 pathogenic or likely pathogenic ClinVar variants document clinically meaningful pathogenicity in recessive disease contexts. In cancer biology, MPDZ expression correlates with worse prognosis in colorectal cancer and hepatocellular carcinoma, modulating immune infiltration and cell migration through YAP1 phosphorylation 78. In subjects of European ancestry, MPDZ sequence variation associates with alcohol dependence, though not alcohol withdrawal seizures 9, and transgenic and knockout models confirm its role in ethanol consumption behavior 10.