Variants in CACNA2D4 were first associated with autosomal recessive inheritance of retinal cone dystrophy (RCD4) in 2006 (Wycisk et al., 17033974). Over eight probands reported four homozygous variants in this gene including one missense variant, and two large deletions covering multiple exons, as well as one stop gained.
This gene-disease association is supported by expression throughout the inner nuclear layer of the retina, photoreceptors and retinal periphery in model organism, zebrafish by RNA in situ hybridization (Schlegel et al., 31834350). Additional functional studies show alterations in Cacna2d4 in mice have significantly reduced transcript levels in the retina leading to structural and functional abnormalities of retinal ribbon synapses including substantial loss of photoreceptor activities and photoreceptor cell death (Wycisk et al., 16877424). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (12.0 pts.) has been reached.
In summary, CACNA2D4 is definitively associated with autosomal recessive inheritance of CACNA2D4-related retinopathy, and this has been has been upheld over time. This classification has been approved by the ClinGen Retina GCEP on March 2nd, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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