Leber congenital amaurosis (LCA) and early‐onset retinal degeneration (EORD) are inherited retinal diseases (IRD) characterized by early‐onset vision impairment. Herein, we studied 15 Saudi families by whole exome sequencing (WES) and run‐of‐homozygosity (ROH) detection via AutoMap in 12/15 consanguineous families. This revealed (likely) pathogenic variants in 11/15 families (73%). A potential founder variant was found in RPGRIP1. Homozygous pathogenic variants were identified in known IRD genes (ATF6, CRB1, CABP4, RDH12, RIMS2, RPGRIP1, SPATA7). We established genotype‐driven clinical reclassifications for ATF6, CABP4, and RIMS2. Specifically, we observed isolated IRD in the individual with the novel RIMS2 variant, and we found a retina‐enriched RIMS2 isoform conserved but not annotated in mouse. The latter illustrates potential different phenotypic consequences of pathogenic variants depending on the particular tissue/cell‐type specific isoforms they affect. Lastly, a compound heterozygous genotype in GUCY2D in one non‐consanguineous family was demonstrated, and homozygous variants in novel candidate genes ATG2B and RUFY3 were found in the two remaining consanguineous families. Reporting these genes will allow to validate them in other IRD cohorts. Finally, the missing heritability of the two unsolved IRD cases may be attributed to variants in non‐coding regions or structural variants that remained undetected, warranting future WGS studies.

中文翻译：

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在患有早发性视网膜疾病的近亲队列中进行的 Autozygome 引导的外显子组优先研究发现了一种孤立的 RIMS2 表型和一种富含视网膜的 RIMS2 亚型

莱伯先天性黑蒙（LCA）和早发性视网膜变性（EORD）都是以早发性视力障碍为特征的遗传性视网膜疾病（IRD）。在此，我们通过全外显子组测序 (WES) 和通过 AutoMap 对 12/15 个近亲家庭进行纯合性运行 (ROH) 检测来研究 15 个沙特家庭。这揭示了（可能）11/15 个家族（73%）的致病变异。发现了一个潜在的创始人变体RPGRIP1。在已知的 IRD 基因中鉴定出纯合致病变异（ATF6,CRB1,CABP4,RDH12,RIMS2,RPGRIP1,斯巴达7)。我们建立了基因型驱动的临床重新分类ATF6,CABP4， 和RIMS2。具体来说，我们在患有小说的个体中观察到孤立的IRDRIMS2变体，我们发现了视网膜丰富的RIMS2同种型在小鼠中保守但未注释。后者说明了致病变异潜在的不同表型后果，具体取决于它们影响的特定组织/细胞类型的特定亚型。最后，复合杂合基因型GUCY2D在一个非近亲家庭中得到证实，并且新候选基因中存在纯合变异ATG2B和鲁菲3在剩下的两个近亲家庭中被发现。报告这些基因将有助于在其他 IRD 队列中验证它们。最后，两个未解决的 IRD 病例的遗传性缺失可能归因于未检测到的非编码区变异或结构变异，这需要未来的全基因组测序研究。