遗传性视网膜疾病（IRD）具有象征性的临床和遗传异质性。最常见的形式是色素性视网膜炎（RP），这是一种由80多种不同基因中的致病变异引起的杆-锥营养不良。更加复杂的是，同一个RP基因中的不同变异体也可以改变临床表型。USH2A是常见的自体隐性RP基因之一，也是最具挑战性的基因之一，因为其大小较大，因而具有大量的变异体。此外，USH2A变异体引起的无综合征性和综合征性RP，被称为乌舍综合征（USH）2型，与视力和听力损失有关。缺乏明确的基因型-表型相关性或预后模型使得诊断非常具有挑战性。我们在这里报道了一个期待已久的三种人类疾病特异性模型中非综合征性RP和USH表型的差异：成纤维细胞、诱导多能干细胞（iPSCs）和成熟iPSC衍生的视网膜器官样体。此外，我们在多个RP和USH个体的器官样体中鉴定了不同的视网膜表型，这些结果得到了等基因纠正对照的验证。非综合征性RP器官样体显示出受损的光感受器分化，而USH器官样体显示出令人惊讶的圆锥细胞表型。此外，补充的临床调查发现与RP相比，高比例的USH个体出现黄斑萎缩，进一步验证了我们的观察结果，即USH2A变异不同程度地影响圆锥细胞。总体而言，对多种模型中的非综合征性RP和USH表型的鉴定为测试USH2A变异体的致病性以及互补细胞类型的治疗方法的有效性提供了宝贵且可靠的指标。© 2023年作者们.

There is an emblematic clinical and genetic heterogeneity associated with inherited retinal diseases (IRDs). The most common form is retinitis pigmentosa (RP), a rod-cone dystrophy caused by pathogenic variants in over 80 different genes. Further complexifying diagnosis, different variants in individual RP genes can also alter the clinical phenotype. USH2A is the most prevalent gene for autosomal-recessive RP and one of the most challenging because of its large size and, hence, large number of variants. Moreover, USH2A variants give rise to non-syndromic and syndromic RP, known as Usher syndrome (USH) type 2, which is associated with vision and hearing loss. The lack of a clear genotype-phenotype correlation or prognostic models renders diagnosis highly challenging. We report here a long-awaited differential non-syndromic RP and USH phenotype in three human disease-specific models: fibroblasts, induced pluripotent stem cells (iPSCs), and mature iPSC-derived retinal organoids. Moreover, we identified distinct retinal phenotypes in organoids from multiple RP and USH individuals, which were validated by isogenic-corrected controls. Non-syndromic RP organoids showed compromised photoreceptor differentiation, whereas USH organoids showed a striking and unexpected cone phenotype. Furthermore, complementary clinical investigations identified macular atrophy in a high proportion of USH compared with RP individuals, further validating our observations that USH2A variants differentially affect cones. Overall, identification of distinct non-syndromic RP and USH phenotypes in multiple models provides valuable and robust readouts for testing the pathogenicity of USH2A variants as well as the efficacy of therapeutic approaches in complementary cell types.© 2023 The Authors.