Genotypes and phenotypes of genes associated with achromatopsia: A reference for clinical genetic testing

Abstract

Purpose: Achromatopsia is a congenital autosomal recessive cone disorder, and it has been found to be associated with six genes. However, pathogenic variants in these six genes have been identified in patients with various retinal dystrophies with the exception of achromatopsia. Thus, this study aims to investigate the contribution of these genes in hereditary retinal diseases and the potential genotype-phenotype correlations.

Methods: Biallelic variants in six achromatopsia-related genes, namely, CNGA3, CNGB3, GNAT2, ATF6, PDE6C, and PDE6H, were analyzed based on data obtained from 7,195 probands with different eye conditions. A systematic genotype-phenotype analysis of these genes was performed based on these data, along with the data reported in the literature.

Results: Biallelic potential pathogenic variants (PPVs) in five of the six genes were identified in 119 probands with genetic eye diseases. The variants in CNGA3 were the most common and accounted for 81.5% (97/119). Of the 119 probands, 62.2% (74/119) have cone-rod dystrophy, whereas only 25.2% (30/119) have achromatopsia. No biallelic pathogenic variants in these genes were identified in patients with rod-dominant degeneration. A systematic review of genotypes and phenotypes revealed certain characteristics of each of the six genes, providing clues for the pathogenicity evaluation of the variants of the genes.

Conclusions: PPVs in the six genes were identified in various inherited retinal degeneration diseases, most of which are cone-dominant diseases but no rod-dominant diseases based on the data from a cohort of 7,195 probands with different eye conditions. The systematic genotype-phenotype analysis of these genes will be useful in drafting guidelines for the clinical genetic diagnostic application for the investigated genes.

Figure 1

The available ERG data of newly recruited probands. The proband IDs and their genotypes are indicated to the left. The electroretinogram (ERG) recordings from the probands all show severely reduced or even extinguished cone responses with different rod responses.

Figure 2

Spectrum of PPV types of the six investigated genes. Only the potential pathogenic variants (PPVs) in CNGA3 were predominately missense, whereas those in the other five genes were predominately truncation variants.

Figure 3

Variant locations in CNGA3 and CNGB3. The blue bar above and the green bar below represent the missense and truncation variants, respectively. B and E represent the functional domains of CNGA3 and CNGB3, respectively. C represents the two alternative transcripts of CNGA3. The NM_001298.2 transcript above is longer than the NM_001079878.1 transcript, which lacks exon 4. S1–6, six transmembrane helix domains; E, exon. The vertical axis represents the number of families.

Figure 4

Proportion of diseases associated with the six genes. A: ACHM is the most common disease in families carrying potential pathogenic variants (PPVs) in the six genes. B: Frequency of each gene in families with different diseases. PPVs in CNGB3 were the most common in families with ACHM. PPVs in CNGA3 were most common in families with CORD. ACHM, achromatopsia; CORD, cone-rod dystrophy; UN, unclassified retinopathy; LCA, Leber congenital amaurosis, OT, oligocone trichromacy; MD, macular degeneration; RP, retinitis pigmentosa; eoHM, early-onset high myopia; CSNB, congenital stationary night blindness.

Figure 5

Frequencies of variants in the six genes in Caucasian and Asian patients. A: Potential pathogenic variants (PPVs) in CNGA3 were the most common among Asians and involved the common achromatopsia (ACHM) and cone-rod dystrophy (CORD), as well as the rare Leber congenital amaurosis (LCA), unclassified retinopathy (UN), and retinitis pigmentosa (RP). B: Among Caucasians, PPVs in CNGB3 were the most common, and these variants are associated with ACHM, which is the most common disease, as well as with CORD, UN, LCA, oligocone trichromacy (OT), and macular dystrophy (MD).

Figure 6

Distribution of available visual acuity in patients with PPVs in the investigated genes.