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

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. 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. 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 &gt; 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. 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.编码微管亚基β微管蛋白4B同型的TUBB4B基因致病变异，已与Leber先天性黑蒙伴早发性耳聋（Leber congenital amaurosis with early-onset deafness, LCAEOD）相关联，该疾病为常染色体显性遗传病，特征为光感受器细胞与耳蜗细胞早期且严重丢失。目前已报道的多数病例发病较早，多由R390/R391热点区域的错义突变所致。 本研究采用的多模态评估手段包括超宽域伪彩色及自发荧光眼底照相、光谱域光学相干断层扫描、全视野视网膜电图、戈德曼动态视野检查、听力图检测，以及下一代测序基因检测。 本文报告了来自3个无亲缘关系家系的7名患者，均患有锥杆营养不良及感音神经性听力损失，其致病关联为TUBB4B基因上的一处新变异位点（c.784C>T, p.R262W）。相较于经典热点区域变异所致的Leber先天性黑蒙，该变异相关的锥杆营养不良通常发病年龄更晚。 本报告拓展了TUBB4B相关视网膜病的突变谱与表型范围，突破了R390/R391热点区域的局限，或可为该罕见微管蛋白病的发病机制研究提供新的见解。