The mutation spectrum of a large Brazilian inherited retinal disease cohort

Abstract

Purpose: The purpose of this study was to examine the mutation spectrum of a largely unstudied ethnicity which comprises the world’s fifth most populous nation in order to assign a molecular diagnosis to patients, enable access to clinical trials and emerging treatments, and to report the identified pathogenic variants to the retinal disease community to advance the study of retinal diseases.

Methods: Brazilian consenting patients were recruited starting in July 2012. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the local ethics committee. 1492 patients are available in this cohort with various diseases including Retinitis Pigmentosa (RP), Stargardt (STGD)/STGD-like disease, Usher syndrome, and Leber Congenital Amaurosis (LCA). Genomic DNA was extracted from patients’ blood samples and genotyped by capture sequencing of 224 known retinal disease genes using next-generation sequencing (NGS). Captured DNA was sequenced on the Illumina HiSeq platform and NGS data was processed by an in-house bioinformatics pipeline leading to annotated variant calls. Patients with negative results from our panel sequencing were further analyzed by whole exome sequencing. The results of the first 300 patients are being reported herein.

Results: A molecular diagnosis was able to be assigned in 80% of LCA, 60% of RP, 35% of STGD/STGD-like, and 80% of Usher syndrome. Approximately 70% of causative variants identified in this study were novel when compared to variants reported to be pathogenic in the Human Gene Mutation Database.

Conclusions: The solving rates obtained for each disease cohort are similar to published cohorts of other ethnicities found in literature, however the distribution of which genes are affected differs. In Caucasian LCA patients CEP290 is the most widely affected gene, while in Brazilians CRB1 accounts for the majority of disease. In Brazilian RP patients RHO, EYS, and PRPH2 are the most frequently mutated genes, while in Chinese and Caucasian RP patients USH2A and ABCA4 are two of the most frequently mutated. Discovering the genetic basis of retinal disease in unstudied ethnicities remains an important method to expand our knowledge about the different causes of retinal disease which can help lead to treatments.