Genetic Screening for OPA1 and OPA3 Mutations in Patients with Suspected Inherited Optic Neuropathies

• Type of Material: Article
• Authors: Patrick Yu-Wai-Man, Emory University; Suma Shankar, Emory University; Valerie Biousse, Emory University; Neil R. Miller, Johns Hopkins University; Lora H Bean, Emory University; Brad Coffee, Emory University; Madhuri Hegde, Emory University; Nancy J. Newman, Emory University
• Language: English
• Date: 2011-03
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 American Academy of Ophthalmology, Inc. Published by Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ophtha.2010.07.029
• Title of Journal or Parent Work: Ophthalmology
• ISSN: 0014-4169
• Volume: 118
• Issue: 3
• Start Page: 558
• End Page: 563
• Grant/Funding Information: PYWM is an MRC Clinical Research Fellow in Neuro-Ophthalmology, and NJN is the recipient of a Research to Prevent Blindness Lew R. Wasserman Merit Award.; This work was supported in part by core grants NIH P30 EY 06360 and NIH R01 EY11916 (Department of Ophthalmology) from the National Institutes of Health (Bethesda, MD), and an unrestricted grant from Research to Prevent Blindness (New York, NY).
• Research Categories: Health Sciences, Opthamology; Biology, Neuroscience; Biology, Genetics

Abstract

Purpose: Autosomal-dominant optic atrophy (DOA) is one of the most common inherited optic neuropathies, and it is genetically heterogeneous, with mutations in both OPA1 and OPA3 known to cause disease. About 60% of cases harbor OPA1 mutations, whereas OPA3 mutations have only been reported in two pedigrees with DOA and premature cataracts. The aim of this study was to determine the yield of OPA1 and OPA3 screening in a cohort of presumed DOA cases referred to a tertiary diagnostic laboratory. Design: Retrospective case series. Participants: One hundred and eighty-eight probands with bilateral optic atrophy referred for molecular genetic investigations at a tertiary diagnostic facility: 38 patients with an autosomal-dominant pattern of inheritance and 150 sporadic cases. Methods: OPA1 and OPA3 genetic testing was initially performed using PCR-based sequencing methods. The presence of large-scale OPA1 and OPA3 genomic rearrangements was further assessed with a targeted comparative genomic hybridization (CGH) microarray platform. The three primary Leber hereditary optic neuropathy (LHON) mutations, m.3460G>A, m.11778G>A, and m.14484T>C, were also screened in all patients. Main Outcome Measures: The proportion of patients with OPA1 and OPA3 pathogenic mutations. The clinical profile observed in molecularly confirmed DOA cases. Results: We found 21 different OPA1 mutations in 27 of the 188 (14.4%) probands screened. The mutations included six novel pathogenic variants and the first reported OPA1 initiation codon mutation at c.1A>T. An OPA1 missense mutation, c.239A>G (p.Y80C), was identified in an 11-year-old African-American girl with optic atrophy and peripheral sensori-motor neuropathy in her lower limbs. The OPA1 detection rate was significantly higher among individuals with a positive family history of visual failure (50.0%) compared with sporadic cases (5.3%). The primary LHON screen was negative in our patient cohort, and additional molecular investigations did not reveal any large-scale OPA1 rearrangements or OPA3 genetic defects. The mean baseline visual acuity for our OPA1-positive group was 0.48 logarithm of the minimum angle of resolution (LogMAR) (Mean Snellen equivalent = 20/61, range = 20/20–20/400, 95% confidence interval = 20/52–20/71), and visual deterioration occurred in 54.2% of patients during follow-up. Conclusions: OPA1 mutations are the most common genetic defects identified in patients with suspected DOA, whereas OPA3 mutations are very rare in isolated optic atrophy cases.