Zou, T., Wang, T., Zhen, F., Dong, S., Gong, B., & Zhang, H. | Biomedical Reports | March 14, 2022 | 16, 40 | https://doi.org/10.3892/br.2022.1523
Abstract
Retinitis pigmentosa (RP) belongs to a family of retinal disorders that is characterized by the progressive degeneration of rod and cone photoreceptors. The aim of the present study was to screen for possible disease‑causing genetic variants in a non‑consanguineous Chinese family with non‑syndromic autosomal recessive RP. Whole‑exome sequencing (WES) was performed in samples from the affected individual (the proband) and those from the two children of the proband. A novel compound heterozygous variant of c.C958T (p.R320X) and c.G1355A (p.R452H) in the Cytochrome P450 family 4 subfamily V member 2 (CYP4V2) gene was identified through WES. Subsequently, this variant was validated by direct Sanger sequencing. This compound heterozygous variant was found to be absent from other unaffected family members and 400 ethnically‑matched healthy control individuals. In addition, this compound variant was co‑segregated with the RP phenotype in an autosomal recessive manner. In silico analysis revealed that both c.C958T (p.R320X) and c.G1355A (p.R452H) could compromise the protein function of CYP4V2. These results strongly suggest this compound variant to be a disease‑causing variant, which expands upon the spectrum of currently known CYP4V2 genetic variants associated with retinal diseases.
Introduction
Retinitis pigmentosa (RP; OMIM no. 268000) is a group of highly heterogeneous but related retinal disorders that cause progressive vision loss (1-3). Typically, RP manifests as night blindness in the early stages. As this disease progresses, the extent of visual field loss becomes gradually more apparent, with impaired color vision and fundus degeneration during the advanced stages. The prevalence of RP is ~1/4000 in China (4,5). RP can be classified as syndromic or non-syndromic. Usher syndrome and Bardet-Biedl syndrome, which also affect multiple organs, are the most common forms of syndromic RP. By contrast, non-syndromic RP is typically inherited and can manifest in an autosomal-recessive (50-60% of cases), autosomal-dominant (30-40% of cases), X-linked (5-15% of cases) or mitochondrial manner (6-8). In the pathophysiology of all types of RP, the majority of mutant genes reported are expressed exclusively in rod cells. Although a small number of mutants are specifically expressed in the retinal pigment epithelium, none are cone-specific (https://sph.uth.edu/retnet/). Despite this, RP can cause the degeneration of both rod and cone photoreceptors, which mediate achromatic night vision and high acuity central vision, respectively (9-14).
One of the reasons for the heterogeneity of RP is the >80 disease-causing genes that have been identified (https://sph.uth.edu/retnet/). Additionally, variations in these genes can cause a wide range of clinical symptoms that are distinct from typical RP, including cone-rod dystrophy (CORD), Leber's congenital amaurosis (LCA) and stationary night blindness. For example, whilst a number of variants in the cone-rod homeobox (CRX) gene have been reported to be associated with RP, other variants of CRX can also trigger CORD and LCA (15-18). In another example, although the majority of Cytochrome P450 family 4 subfamily V member 2 (CYP4V2) variants are associated with Bietti crystalline dystrophy (BCD), other variants in the gene can also cause RP. BCD is an autosomal recessive chorioretinal degenerative disease that is characterized by numerous glistening yellow-white crystalline retinal micro-deposits, progressive atrophy of the retinal pigment epithelium (RPE) and choroidal sclerosis (19).
In the present study, whole-exome sequencing (WES) was applied to screen for potential disease-causing variants in a non-consanguineous Chinese family with autosomal recessive RP. A novel compound heterozygous variant in CYP4V2 was identified in a patient with RP.
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