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X-linked cone–rod dystrophy 3 (CORDX3) is a progressive retinal disorder characterized by early-onset nyctalopia, reduced visual acuity, and nystagmus. CACNA1F encodes the Cav1.4 L-type calcium channel α1F subunit, essential for photoreceptor neurotransmission. A hemizygous stop-gain variant, c.4051C>T (p.Arg1351Ter), was identified in a 57-year-old male and his 2-month-old grandson presenting with nyctalopia, nystagmus, high myopia, and retinoschisis, expanding the known CORDX3 spectrum to include inner retinal splitting ([PMID:38474172]).
This truncating variant abolishes channel function via a loss-of-function mechanism, consistent with other CACNA1F allelic disorders (CSNB2A, AIED). The phenotypic overlap and absence of genotype–phenotype correlations suggest additional modifiers influence disease severity. Genetic testing for CACNA1F truncating variants is recommended for males with early-onset cone–rod dystrophy, guiding diagnosis, prognosis, and genetic counseling.
Gene–Disease AssociationLimitedVariant identified in two related males in one family ([PMID:38474172]); no additional unrelated cases reported Genetic EvidenceLimitedHemizygous truncating c.4051C>T (p.Arg1351Ter) in two related individuals; no unrelated probands ([PMID:38474172]) Functional EvidenceLimitedTruncating CACNA1F variants are predicted loss-of-function consistent with channel deficiency, but no specific assay for Arg1351Ter reported |