Identification of a Novel Splice-Site Variant in CACNA1F With Variable Phenotypic Expression in a Chinese Family

The calcium voltage-gated channel subunit alpha1 F (CACNA1F) gene-related retinal disorders have overlapping clinical symptoms and no definitive genotype-phenotype correlation, posing a challenge for diagnosis.

A comprehensive ocular examination was offered to a 6-year-old boy and his elder brother from a Chinese family. Exome sequencing and Sanger sequencing were applied to the family quads. A minigene assay was used to detect the aberrant splicing.

The 6-year-old boy presented with low visual acuity, congenital nystagmus, and reduced photopic and scotopic responses in electroretinography, suggesting a clinical diagnosis of cone-rod dystrophy type 3 (CORDX3). By contrast, his elder brother merely had high myopia. A hemizygous splice-site variant CACNA1F NM_005183.4:c.4422-1G>T, inherited from their heterozygous carrier mother, was identified in the two brothers. Minigene assay showed that the variant resulted in intron 37 retaining or exon 38 skipping, leading to frameshift translation and early termination. This variant was absent from the public population databases and classified as pathogenic according to the ACMG guidelines.

A novel splice-site variant in CACNA1F with familial expression variability was identified. This study increases our understanding of the genotypic and phenotypic spectrum of CACNA1F-related disorders.