The clinical and genetic spectrum of cone-dominated retinal dystrophies with normal funduscopic appearance

Abstract

Purpose : There are several cone-dominated dystrophies (CDD) that show normal funduscopic appearance; however, the prevalence of each causative gene and the phenotypic overlap caused by each gene within the CDD are still uncertain. We illustrate the clinical/genetic spectrum of CDD with normal funduscopic appearance (CDD-NF) in a nationwide cohort.

Methods : 1302 patients with available genotype-phenotype correlation analysis results registered to the Japan Eye Genetic Consortium database were surveyed. Patients were classified into one of the three disease categories based on the electrophysiological findings: occult macular dysfunction syndrome (OMDS: confined macular dysfunction, including hereditary occult macular dystrophy (OMD) and occult maculopathy), cone (-rod) dystrophy with normal funduscopic appearance (CORD-NF: progressive generalized cone (-rod) dysfunction), and cone dysfunction syndrome (CDS: non-progressive generalized cone dysfunction). The clinical parameters were compared among the three disease categories, and the overlap of causative genes was investigated in genes identified in multiple families.

Results : 192 patients from 150 families with CDD-NF were recruited, including 76 families with OMDS, 43 families with CORD-NF, and 31 families with CDS. The median age of onset was 30.0 years for OMD, 30.0 years for CORD-NF, and 0.0 years for CDS, respectively. The median LogMAR visual acuity (VA) was 0.52 for OMD, 0.70 for CORD-NF, and 0.80 for CDS, respectively. The causative genes were RP1L1, GUCY2D, and CRX for OMD, POC1B, GUCY2D, CRX, PDE6C, and CRB1 for CORD-NF, and CNGA3, PDE6C, GNAT2, KCNV2, and RGS9BP for CDS. Out of eight genes identified in multiple families, four genes were found only in a single disease category: RP1L1 (OMD; Miyake disease), CNGA3 (CDS), GNAT2 (CDS), and KCNV2 (CDS); while four genes overlapped the disease categories; POC1B, PDE6C, GUCY2D, and CRX.

Conclusions : The clinical spectrum of CDD-NF was first identified in a large well-characterized cohort: OMD with later-onset and moderate VA decrease, CORD-NF with later-onset and severe VA impairment, and CDS with early-onset and more severe VA decline. The heterogeneous genetic background of CDD-NF was revealed; meanwhile distinct genotype-phenotype relations such as RP1L1-OMD, CNGA3-CDS, and GNAT2-CDS were confirmed.

This is a 2021 ARVO Annual Meeting abstract.