The mutation spectrum of a large Brazilian inherited retinal disease cohort.

Porto, Fernanda B.O.2, 3; Jones, Evan M.1; Soens, Zachry1; Sampaio, Shirley A.2; Sena, Isadora FG 4 ; Magalhaes, Kenia CS 4; Li, Yumei1; Xu, Shan1; Simoes, Renata T.4; Chen, Rui1

Inherited retinal dystrophies (IRDs) affect roughly 1 in 2,000 individuals. These disorders range in most severe cases of congenital blindness to more delayed cases of progressive visual and retinal degeneration in later adulthood. A significant amount of clinical and genetic heterogeneity among these disorders makes diagnosis difficult without comprehensive sequencing of potentially causative genes. IRDs, moreover, can manifest in autosomal dominant, autosomal recessive, and X-linked inheritance patterns, which adds to the complexity. Cohort studies in populations such as Caucasian and Chinese have highlighted distinct genetic effects based on population. Here we characterize the molecular cause of IRDs in a large Brazilian cohort, a prominent world population that has largely remained unstudied. We report on the molecular diagnosis of 231 individuals in an available cohort of 1,492 Brazilians affected by IRDs. Through targeted capture and next-generation sequencing of 224 known retinal disease genes, we identify the leading molecular causes of retinitis pigmentosa (RP), Leber’s congenital amaurosis (LCA), Stargardt’s disease, and Usher syndrome among numerous other IRDs in our cohort. The solving rates for IRDs found within our cohort are slightly higher than generally reported rates in the current literature. This is likely in part a result of improved access to reported pathogenic variants in numerous publicly accessible databases. Roughly 35% of pathogenic variants in our cohort have been previously reported to cause retinal disease. The other 65% are novel variants likely to be pathogenic as either putative loss-of-function variants such as stop-gain or predicted damaging variants in a gene associated with the expected diagnosis. Notably, 11% of RP individuals were found to have pathogenic or likely pathogenic variants in GPR98. This is a much higher percentage than what is seen in other populations and may highlight the presence of a founder mutation. Furthermore, in LCA individuals the most common genes were CRB1 (12%) and ABCA4 (12%) with less than 1% of individuals affected by CEP290 variants, differing significantly from that observed in Caucasian populations. These findings highlight the need for a precise and population-based molecular diagnosis of IRDs. With the development of current gene therapies for diseases such as LCA an accurate molecular diagnosis is essential for appropriate genetic counseling and informed treatment recommendations. 

1. Human Genome Sequencing Center Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States. 2. INRET - Clínica e Centro de Pesquisa, Belo Horizonte, Minas Gerais, Brazil. 3. Departamento de Retina e Vítreo, Centro Oftalmológico de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. 4. Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, Minas Gerais, Brazil.