Genotypic Profile and Clinical Characteristics of CRX-Associated Retinopathy in Koreans

Abstract

This study aimed to investigate the clinical characteristics of Korean patients with retinal dystrophy associated with pathogenic variants of cone rod homeobox-containing gene (CRX). We retrospectively enrolled Korean patients with CRX-associated retinal dystrophy (CRX-RD) who visited two tertiary referral hospitals. Pathogenic variants were identified using targeted panel sequencing or whole-exome sequencing. We analyzed clinical features and phenotypic spectra according to genotype. Eleven patients with CRX-RD were included in this study. Six patients with cone-rod dystrophy (CORD), two with macular dystrophy (MD), two with Leber congenital amaurosis (LCA), and one with retinitis pigmentosa (RP) were included. One patient (9.1%) had autosomal recessive inheritance, and the other ten patients (90.9%) had autosomal dominant inheritance. Six patients (54.5%) were male, and the mean age of symptom onset was 27.0 ± 17.9 years. At the first presentation, the mean age was 39.4 ± 20.6 years, and best-corrected visual acuity (BCVA) (logMAR) was 0.76 ± 0.90 in the better eye. Negative electroretinography (ERG) was observed in seven (63.6%) patients. Nine pathogenic variants were identified, including two novel variants, c.101-1G>A and c.898T>C:p.(*300Glnext*118). Taken together with the variants reported in prior studies, all variants within the homeodomain are missense variants, whereas most variants downstream of the homeodomain are truncating variants (88%). The clinical features of pathogenic variants within the homeodomain are either CORD or MD with bull’s eye maculopathy, whereas variants downstream of the homeodomain cause more diverse phenotypes, with CORD and MD in 36%, LCA in 40%, and RP in 24%. This is the first case series in Korea to investigate the CRX-RD genotype–phenotype correlation. Pathogenic variants downstream of the homeodomain of the CRX gene are present as RP, LCA, and CORD, whereas pathogenic variants within the homeodomain are mainly present as CORD or MD with bull’s eye maculopathy. This trend was similar to previous genotype–phenotype analyses of CRX-RD. Further molecular biologic research on this correlation is required.

Atypic Retinitis Pigmentosa Clinical Features Associated with a Peculiar CRX Gene Mutation in Italian Patients

“…One study reported that all mutations within the homeodomain were missense mutations, with most showing a phenotype of cone-rod dystrophy or macular degeneration. On the other hand, most mutations in other regions of the gene were frame-shift mutations resulting in truncating proteins (88%), associated with different phenotypic presentations (cone-rod dystrophy and macular degeneration in 36%, Leber congenital amaurosis in 40%, and RP in 24%) [17]. Moreover, most mutations occur de novo in the absence of a positive family history [8].…”

Occult Macular Dysfunction Syndrome: Identification of Multiple Pathologies in a Clinical Spectrum of Macular Dysfunction with Normal Fundus in East Asian Patients: EAOMD Report No. 5

“…CRX, a cone-rod homeobox-containing gene (OMIM: 602225), encodes a homeodomain transcription factor crucial for the development and survival of photoreceptors [85,86]. CRX-retinopathy encompasses severe AR-LCA, AR-RP, AD-CORD, AD-COD, and AD-MD; AD-MD shows a mild phenotype [39,[87][88][89][90][91][92][93][94][95][96][97][98][99][100][101]. The relatively mild phenotype of patients with CRX-OMD is consistent with the previous AD-CRX cases [87], although there are no reported CRX cases with the identical variant.…”