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Periventricular nodular heterotopia (PNH) is a neuronal migration disorder characterized by ectopic neuronal nodules along the lateral ventricles. NEDD4L encodes an E3 ubiquitin ligase expressed in the fetal brain cortex and ventricular zone, with critical roles in regulating signaling pathways that govern neurogenesis and neuronal positioning (PMID:32117442).
Missense variants in NEDD4L have been identified in nine unrelated individuals with PNH often accompanied by polymicrogyria, syndactyly, and cleft palate, clustering in substrate‐recognition domains ([PMID:32117442]). A recurrent variant, c.623G>A (p.Arg208Gln), affects the WW domain and has been observed in a four‐member pedigree and as a de novo event in an unrelated patient ([PMID:32117442]).
Segregation analysis in the familial case showed co‐segregation of c.623G>A (p.Arg208Gln) with PNH in three additional affected relatives, demonstrating autosomal dominant inheritance with variable penetrance ([PMID:32117442]).
Functional studies of HECT‐domain mutations, including c.2690G>A (p.Arg897Gln), reveal proteasome sensitivity of mutant proteins and deregulation of AKT/mTOR signaling. In utero electroporation of PNH‐associated NEDD4L mutants disrupts neuronal positioning and terminal translocation, recapitulating human PNH phenotypes in vivo (PMID:27694961).
These data support haploinsufficiency or dominant‐negative effects as the mechanism of pathogenicity, with loss of ubiquitin ligase activity leading to aberrant signaling and cortical development defects. No conflicting evidence has been reported.
Key Take-home: Pathogenic NEDD4L missense variants cause autosomal dominant periventricular nodular heterotopia with consistent functional disruption of AKT/mTOR‐dependent neuronal migration pathways, informing molecular diagnosis and potential therapeutic targeting.
Gene–Disease AssociationStrong9 probands, multi-family segregation in 4 members and functional concordance Genetic EvidenceStrongIdentification of pathogenic missense variants in nine individuals including recurrent c.623G>A (p.Arg208Gln) segregating in a four-member family and de novo in an unrelated patient Functional EvidenceModerateHECT-domain mutations disrupt AKT/mTOR pathway and in utero electroporation models recapitulate neuronal migration defects |