Ciliopathies are a group of genetic dystrophies causing syndromic and non-syndromic retinal degeneration. We identified CFAP410 as the causative gene in a patient with childhood-onset retinal dystrophy without other systemic symptoms at the age of 20. This 20-year-old man presented with cone-rod dystrophy and CFAP410 homozygous in-frame duplication variants (c.340_351dup). His clinical features included early subnormal vision, posterior pole staphyloma, and short stature. Unlike the previously reported features of retinal ciliopathy, our patient showed no obvious retinal pigmentation and only a slight hyper-autofluorescent parafoveal ring at the 16-year follow up. This case report aims to characterize the clinical features in a patient with novel, homozygous and likely pathogenic in-frame duplication variants in the CFAP410 gene. Ultimately, this report will help contribute to the understanding of CFAP410-associated ciliopathies.

Ciliopathies are a broad range of inherited developmental and degenerative diseases associated with structural or functional defects in motile or primary non-motile cilia. There are around 200 known ciliopathy disease genes and whilst genetic testing can provide an accurate diagnosis, 24-60% of ciliopathy patients who undergo genetic testing do not receive a genetic diagnosis. This is partly because following current guidelines from the American College of Medical Genetics and the Association for Molecular Pathology, it is difficult to provide a confident clinical diagnosis of disease caused by missense or non-coding variants, which account for more than one-third of cases of disease. Mutations in PRPF31 are the second most common cause of the degenerative retinal ciliopathy autosomal dominant retinitis pigmentosa. Here, we present a high-throughput high-content imaging assay providing quantitative measure of effect of missense variants in PRPF31 which meets the recently published criteria for a baseline standard in vitro test for clinical variant interpretation. This assay utilizes a new PRPF31+/- human retinal cell line generated using CRISPR gene editing to provide a stable cell line with significantly fewer cilia in which novel missense variants are expressed and characterised. We show that high-content imaging of cells expressing missense variants in a ciliopathy gene on a null background can allow characterisation of variants according to the cilia phenotype. We hope that this will be a useful tool for clinical characterisation of PRPF31 variants of uncertain significance, and can be extended to variant classification in other ciliopathies.