LAUSR

Retinitis pigmentosa (RP) is a rare and heterogeneous group of inherited ocular diseases. However, the relationship between CACNA2D4 mutations and RP is not well understood. In this study, a Chinese autosomal recessive retinitis pigmentosa (arRP) pedigree was enrolled and targeted next-generation sequencing was employed for identifying the causative gene in the proband. These steps were followed by confirmatory Sanger sequencing and segregation analysis. RNA-sequencing (RNA-seq) data and semi-quantitative reverse transcription polymerase chain reaction analysis were then applied to examine the expressions in the human and mouse tissues. Novel compound heterozygous, deleterious missense variants of the CACNA2D4 gene, NM_172364.4: c.G955A (p.D319N) and c.A1822C (p.I608L), were identified in the arRP pedigree, co-segregating with the clinical phenotype in the patient. The CACNA2D4 protein is highly conserved among species. The CACNA2D4 mRNA expression showed the highest expression in the retina of humans and in the later four developmental stages/times of retinal tissues in mice, indicating its role in retina/eye functions and developments. This study is the first to identify novel compound heterozygous mutations c.G955A (p.D319N) and c.A1822C (p.I608L) in the CACNA2D4 gene. These might be disease-causing mutations, thereby extending the mutational spectra. The identification of pathogenic CACNA2D4 variants is expected to enhance our understanding of the genotype–phenotype correlations of arRP for disease diagnosis and genetic counseling. The relationship between the CACNA2D4 variants and diseases/phenotypes other than RP has also been reviewed and discussed in this paper.