The purpose of this study was to detect the missing heritability of patients with KIF11-related retinopathy and to describe their clinical and genetic characteristics. We enrolled 10 individuals from 7 unrelated families harboring a pathogenic monoallelic variant in KIF11. All subjects underwent ophthalmic assessment and extraocular phenotype evaluations, as well as comprehensive molecular genetic analyses using next-generation sequencing. Minigene assays were performed to observe the effects of one novel deep intron variant (DIV) and one novel synonymous variant on pre-mRNA splicing. We detected 6 novel different disease-causing variants of KIF11 in the seven pedigrees. Co-segregation analysis and ultra-deep sequencing results indicated that 5 variants arose de novo in 5 families (71%). Functional validation revealed that the synonymous variant leads to an exon skip, while the DIV causes a pseudoexon (PE) inclusion. The patients presented with high variations in their phenotype, and two families exhibited incomplete penetrance. Ocular manifestations and characteristic facial features were observed in all patients, as well as microcephaly in seven patients, intellectual disability in five patients, and lymphedema in one patient. The key retinal features for KIF11-related retinopathy were retinal folds, tractional retinal detachment, and chorioretinal dysplasia. All seven probands had more severe visual detects than other affected family members. Our findings widen the genetic spectrum of KIF11 variants. DIV explained rare unresolved cases with KIF11-related retinopathy. The patients displayed a variable phenotype expressivity and incomplete penetrance, indicating the importance of genetic analysis for patients with KIF11-related retinopathy.
Keywords: KIF11; deep intronic variant; familial exudative vitreoretinopathy; lymphedema; microcephaly with or without chorioretinopathy; minigene assay; or mental retardation.