Expanding the genetic spectrum of achromatopsia: novel CNGA3 and CNGB3 variants.

Purpose: Achromatopsia is a rare autosomal recessive disorder characterised by congenital pendular nystagmus, photophobia, decreased visual acuity, and impaired colour vision. Variants in the CNGA3 (Achromatopsia 2, MIM#216900) and CNGB3 (Achromatopsia 3, MIM#262300) genes account for the majority (more than 2/3) of cases, but genotype-phenotype correlations remain incompletely understood.

Methods: This study aims to expand the clinical and genetic spectrum of achromatopsia by analysing five patients from three families, including two novel variants in the CNGA3 and CNGB3. Comprehensive ophthalmological and genetic evaluations were performed, including best corrected visual acuity, electroretinography, optical coherence tomography, and clinical exome sequencing. Segregation analysis was conducted to confirm the inheritance pattern.

Results: We identified a novel missense variant in CNGA3 (c.1710C > A p.(Ser570Arg)) and a novel frameshift variant in CNGB3 (c.739_754del p.(Ala247Thrfs*27)).

Conclusion: Molecular dynamics simulations suggest that the CNGA3 c.1710C > A p.(Ser570Arg) variant may act as a gain-of-function variant, leading to altered cyclic nucleotide-gated channel activity in cone photoreceptors. This finding provides new insights into the functional consequences of CNGA3 variants in the pathophysiology of achromatopsia. Our findings provide new insights into genotype-phenotype correlations in achromatopsia and highlight the importance of early genetic diagnosis in improving disease management and genetic counselling. The identification of novel variants enhances our understanding of the genetic basis of achromatopsia and highlights the clinical utility of next-generation sequencing in the diagnosing of inherited retinal diseases.