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Biallelic variants in CNPY3 have been identified in individuals with West syndrome, supporting an autosomal recessive mode of inheritance. Three affected individuals from two unrelated families harbored either compound-heterozygous or homozygous variants, with segregation of disease in a sibling pair (PMID:29394991). The reported variants include a splice-site change (c.495+1G>A) and a missense substitution (c.373G>C (p.Gly125Arg)), both predicted to disrupt CNPY3 function. Patients exhibited classical early-onset epileptic encephalopathy, infantile spasms (HP:0012469), and hippocampal malrotation on neuroimaging. Functional assays showed severely reduced CNPY3 protein levels in patient-derived lymphoblastoid cells, and Cnpy3-knockout mice recapitulated hyperactive EEG fast-wave oscillations akin to human disease.
The cumulative genetic evidence comprises three probands from two families, segregation of a recessive allele in a sibling pair, and two distinct pathogenic variant classes (missense and splicing) in CNPY3. Experimental concordance arises from loss-of-function protein assays and an animal model reproducing key electrophysiological features. No studies to date have reported conflicting evidence or alternative phenotypes for CNPY3 variants in West syndrome.
Given multiple unrelated affected individuals, observed segregation, and supportive functional data, the gene–disease association meets a Moderate ClinGen validity classification. Genetic evidence is rated Moderate based on biallelic pathogenic variants in three individuals, including familial segregation, and functional evidence is rated Moderate based on protein depletion assays and mouse knockout phenocopy.
Key Take-home: Biallelic loss-of-function variants in CNPY3 cause autosomal recessive West syndrome and should be included in diagnostic epilepsy gene panels.
Gene–Disease AssociationModerateThree affected individuals from two families, autosomal recessive inheritance, observed segregation and functional concordance Genetic EvidenceModerateThree probands with biallelic CNPY3 variants, segregation in a sibling pair, and multiple variant types Functional EvidenceModerateReduced CNPY3 protein in patient cells and electrophysiological recapitulation in knockout mice |