Expanding the genotypic and phenotypic spectra with a novel variant in the ciliopathy gene, CFAP410, associated with selective cone degeneration

Abstract

Purpose : CFAP410 (Cilia and Flagella Associated Protein 410) encodes a protein that has an important role in the development and function of cilia. In ophthalmology, pathogenic variants in CFAP410 typically manifest as retinitis pigmentosa, macular staphyloma and in association with systemic abnormalities such as skeletal dysplasia. Here we report a consanguineous family with a novel homozygous c.335_346del del variant of CFAP410 with cone only degeneration and no systemic features.

Methods : Retrospective analysis of ophthalmic history, examination, retinal imaging, electrophysiology and microperimetry. Genetic testing by Next Generation Sequencing (NGS) and Whole Genome Sequencing (WGS). In silico pathogenicity predictions (SIFT Indel, Mutation Taster, Splice AI).

Results : A 28-year-old female of Pakistani ethnicity, consanguineous parents with no relevant family history presented with childhood-onset poor central vision and photophobia and is systemically well. Best-corrected visual acuity and colour vision were reduced at 0.5logMAR, 6/17plates (right) and 0.6logMAR, 3/17plates (left). Fundus examination showed no pigmentary retinopathy, no macular staphyloma and autofluorescence was unremarkable. Macular optical coherence tomography, showed subtle signs of mottling and intermittently disrupted ellipsoid zone. Microperimetry demonstrated reduction in central retinal sensitivity. Electrodiagnostics confirmed reduction in cone-driven responses. Genetic testing by NGS and additional deep sequencing of achromatopia genes revealed no pathogenic variants. Subsequent WGS identified an in-frame deletion of 12 base pairs at c.335_346del in CFAP410. The variant was found in the homozygous state and affects the downstream leucine-rich repeat C-terminal (LRRCT) removing 4 amino acid residues p.(Leu112_Leu115) in this highly conserved protein motif. Previous reports of variants within this region result in decreased protein expression and lead to cone-dominating phenotypes, suggesting that c.335_346del is a loss of function variant, preferentially affecting cone photoreceptors.

Conclusions : The non-syndromic cone-specific phenotype reported herein expands the genotypic and phenotypic spectra of CFAP410-associated ciliopathies and highlights the need for deep characterisation of affected cases in the light of potential future genetic therapies.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.