A novel missense TUBB4B variant outside of the canonical hotspot is associated with cone-rod dystrophy and sensorineural hearing loss.

INTRODUCTION: Pathogenic variants in TUBB4B, which encodes the β-tubulin 4B isotype of microtubule subunits, have been associated with Leber congenital amaurosis with early-onset deafness (LCAEOD), an autosomal dominant condition characterized by early and severe loss of photoreceptor and cochlear cells. The majority of reported cases feature early disease onset and are caused by missense mutations in the R390/R391 hotspot. METHODS: Multimodal evaluation included ultra-widefield pseudocolor and autofluorescence fundus photography, spectral-domain optical coherence tomography, full-field electroretinography, Goldmann kinetic perimetry, audiography, and genetic testing with next-generation sequencing. RESULTS: We report seven individuals from three unrelated families affected by cone-rod dystrophy and sensorineural hearing loss associated with a novel variant in TUBB4B (c.784C > T, p.R262W). Cone-rod dystrophy associated with this variant generally features a later age of onset compared to the Leber congenital amaurosis caused by variants in the canonical hotspot. DISCUSSION: This report expands the mutation spectrum and phenotypic range of TUBB4B-associated retinopathies beyond the R390/R391 hotspot and may offer insight into the pathogenesis of this rare tubulinopathy.

Duke Scholars

Author Ramiro Maldonado Ophthalmology, Vitreoretinal Diseases & Surgery