A novel mutation in KIF3B in a family with dominant retinitis pigmentosa and polydactyly

Abstract

Purpose : Whole-exome next-generation sequencing (NGS) was used to identify the cause of disease in a large family with a dominant form of retinitis pigmentosa.

Methods : Whole-exome NGS was performed on two affected female cousins. Sanger sequencing was used to confirm variants of interest. Linkage LOD scores were calculated based on results from eight affected family members.

Results : A large, six-generation family segregating both retinitis pigmentosa and polydactyly was tested as part of our large adRP cohort. Sanger sequencing of known adRP genes and NGS of a retinal gene panel had been performed previously by several laboratories on different family members and failed to identify a disease mutation. Exome sequencing of two cousins revealed a novel, potentially pathogenic variant in the KIF3B gene (NP_004789.1; p.Leu523Pro). All affected family members tested carried the variant; to date it has not been observed in any control population. The p.Leu523Pro mutation is predicted to be pathogenic and is located in the stalk between the motor domain and the tail of the kinesin protein. Linkage analysis in the extended family using the novel variant as a marker results in a LOD score of 4.2 at 0% recombination.

Conclusions : A novel mutation in the KIF3B gene is the likely cause of retinitis pigmentosa in a six-generation Ashkenazi Jewish family. All patients with the KIF3B mutation in the family exhibit classic symptoms of retinitis pigmentosa with an average age of onset in the first decade. Several affected members of the family have polydactyly; others are reported to have various forms of kidney dysfunction. Observation of these additional findings is suggestive of a ciliopathy and is consistent with a mutation in a kinesin gene. The KIF3B protein, along with KIF3A, is part of the heterotrimeric kinesin-2 complex and is required for anterograde transport along the connecting cilia of photoreceptors. Numerous genes critical for ciliary function and intraflagellar transport (IFT) have been identified as causes of retinal degeneration, both with and without additional ciliopathy findings.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.