Abstract
Purpose :
To examine the mutation spectrum of a Brazilian cohort of patients with Achromatopsia (ACHM) in order to assign a molecular diagnosis to patients, hereby confirming the clinical diagnosis, enable access to clinical trials and emerging treatments, and to report the identified pathogenic variants.
Methods :
Brazilian consenting patients were recruited between August 2014 through February 2017. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the local ethics committee. Genomic DNA was extracted from patients’ blood samples or oral swabs and genotyped by sequential target analysis (19 patients) or multigene panel sequencing of 226 (4 patients) or 300 genes (18 patients). The patients with negative multigene panel results (1 patient tested with 226 genes panel and 2 patients tested with 300 genes panel) were retested with targeted analysis.
All of the participants underwent detailed ophthalmologic examinations, including BCVA, biomicroscopy, dilated-pupil fundus examination, full-field ERG, optical coherence tomography, fundus photography, and autofluorescence.
Results :
The cohort was composed of 34 patients with ACHM from 32 families. Pathogenic variants for all the 34 patients (100%) were identified. CNGA3 and CNGB3 were the most frequently mutated genes. We could identify 12 novel variants, including 5 novel missense and 1 novel nonsense variants in the CNGA3, 1 stopgain, 3 intronic and 1 novel nonsense variants in the CNGB3 and 1 novel stopgain variant in the PDE6C gene.
A total of 3 patients - from 3 different families and cities - with CNGA3 mutations harbored the same novel mutated allele (c.332_333delinsAA p.Ser111*) heterozygously, which therefore might be considered a founder mutation in the Brazilian population. Another recurrent CNGA3 variant in our cohort is the c.1495C>T p.Arg499* found heterozygously in 2 non-related patients. In addition, 2 patients were shown to carry the only recently published deep intronic variant c.1663-1205G>A<;p.G555Lfs*33, 1 hetero- and 1 homozygously - up to now the variant had only been reported in European patients.
Conclusions :
Variants in CNGB3 and CNGA3 account for 62% and 35% of ACHM in Brazilian patients, respectively, including known and novel variants. Knowing the molecular profile of the disease in an unstudied population, we can better design molecular diagnosis and follow research achievements.
This is a 2020 ARVO Annual Meeting abstract.