July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Comprehensive molecular diagnosis of 118 Leber Congenital Amaurosis and Early Onset Severe Retinal Distrophy by targeted next generation sequencing
Author Affiliations & Notes
  • Fernanda Belga Ottoni Porto
    Retina Department, INRET Clínica e Centro de Pesquisa, Belo Horizonte, MINAS GERAIS, Brazil
    Retina Department, Centro Oftalmologico de Minas Gerais, Belo Horizonte, MINAS GERAIS, Brazil
  • Shirley Aparecida Madureira Sampaio
    Retina Department, INRET Clínica e Centro de Pesquisa, Belo Horizonte, MINAS GERAIS, Brazil
  • Evan Jones
    Human Genome Sequencing Center Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • Fernando Kok
    Mendelics Análise Genômica, Sao Paolo, SAO PAOLO, Brazil
  • Rui Chen
    Human Genome Sequencing Center Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • Renata Toscano Simoes
    Instituto de Ensino e Pesquisa da Santa Casa BH, Belo Horizonte, MINAS GERAIS, Brazil
  • Footnotes
    Commercial Relationships   Fernanda Porto, None; Shirley Sampaio, None; Evan Jones, None; Fernando Kok, None; Rui Chen, None; Renata Simoes, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 5419. doi:
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      Fernanda Belga Ottoni Porto, Shirley Aparecida Madureira Sampaio, Evan Jones, Fernando Kok, Rui Chen, Renata Toscano Simoes; Comprehensive molecular diagnosis of 118 Leber Congenital Amaurosis and Early Onset Severe Retinal Distrophy by targeted next generation sequencing. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5419.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The purpose of this study was to examine the mutation spectrum of a Brazilian cohort of patients with Leber congenital amaurosis (LCA) and early onset severe retinal distrophy (EOSRD) in order to assign a molecular diagnosis to patients, enable access to clinical trials and emerging treatments, and to report the identified pathogenic variants.

Methods : Brazilian consenting patients were recruited. 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 and genotyped by capture sequencing of 226 known retinal disease genes using next-generation sequencing (NGS). All of the participants underwent a comprehensive ophthalmologic examination. Patients were revisited to examine the potential phenotypic ambiguity at the time of initial diagnosis.

Results : Based on the ophthalmological assessment, the cohort was composed of 39 LCA and 79 EOSRD. Pathogenic mutations for 83/118 patients (70%) were identified, including 40% novel mutations. RPE65, CRB1, RPGRIP1, ABCA4 and CEP290 were the five most frequently mutated genes. 51/118 (40%) patients carried mutations in known LCA or EOSRD genes and exhibited corresponding phenotypes, while 32/118 (30%) carried mutations in retinal disease genes that were not consistent with their initial clinical diagnosis. We revisited patients in the latter case and found new genotype-phenotype relations; we reclassified the clinical diagnosis in 9 patients. A total of 6/11 patients - from three different families and cities - with RPE65 mutations harbored the same novel mutated allele (p.Gly187Glu), which was homozygous in all six patients.

Conclusions : We have identified a large number of new genotype-phenotype relation and novel mutations that are associated with LCA and EOSRD. RPE65, CRB1, RPGRIP1, ABCA4 and CEP290 were the five most frequently mutated genes. There may be a high frequency of RPE65 novel mutation in the Brazilian population of the State of Minas Gerais and a founder effect is suspected. Our findings of specific features in this population broaden the spectrum of novel mutations and new phenotype/genotype relations of LCA and EOSRD with ethnic and regional variations.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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