Elsevier

Ophthalmology

Volume 118, Issue 3, March 2011, Pages 558-563
Ophthalmology

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

https://doi.org/10.1016/j.ophtha.2010.07.029Get rights and content

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. Approximately 60% of cases harbor OPA1 mutations, whereas OPA3 mutations have been reported in only 2 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 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 polymerase chain reaction-based sequencing methods. The presence of large-scale OPA1 and OPA3 genomic rearrangements was assessed further with a targeted comparative genomic hybridization microarray platform. The 3 primary Leber hereditary optic neuropathy (LHON) mutations, m.3460G→>A, m.11778G→A, and m.14484T→C, also were 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

Twenty-one different OPA1 mutations were found in 27 (14.4%) of the 188 probands screened. The mutations included 6 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 black girl with optic atrophy and peripheral sensorimotor 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 the patient cohort, and additional molecular investigations did not reveal any large-scale OPA1 rearrangements or OPA3 genetic defects. The mean baseline visual acuity for the OPA1-positive group was 0.48 logarithm of the minimum angle of resolution (units 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.

Financial Disclosure(s)

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Section snippets

Optic Atrophy Cohort

The study cohort consisted of 188 patients with bilateral optic atrophy referred for molecular investigations to the Emory Genetics Laboratory, a tertiary diagnostic facility with College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA) accreditations. All affected individuals had been assessed by experienced neuro-ophthalmologists (VB, NRM, NJN) over a 6-year period from January 1, 2004, through December 31, 2009. A comprehensive examination was performed

OPA1 Mutations Identified

Using the PCR-based sequencing methods, 21 different OPA1 mutations were identified in 27 (14.4%) of the 188 probands screened: (1) missense (8/21; 38.1%), (2) deletion (7/21; 33.3%), (3) nonsense (4/21; 19.0%), (4) duplication (1/21; 4.8%), and (5) splice site mutations (1/21; 4.8%; Table 1, available at http://aaojournal.org). The mutational yield rate was significantly higher among individuals with a positive family history of visual failure (19/38; 50.0%) compared with presumed singleton

Discussion

OPA1 comprises 30 coding exons spread over 100 Kb of genomic DNA. It is a highly polymorphic gene with more than 200 pathogenic variants known to cause disease.18, 19 This study further extended the mutational spectrum of OPA1 and identified 6 novel mutations in families with nonsyndromic optic atrophy. The first OPA1 initiation codon mutation, c.1A→T was also identified, which is a rare molecular occurrence, but has been reported in other inherited ocular disorders.20, 21, 22, 23

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    Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

    Supported in part by the National Institutes of Health, Bethesda, Maryland (core grant nos.: P30 EY 06360 and NIH R01 EY11916 [Department of Ophthalmology]; and an unrestricted grant from Research to Prevent Blindness, Inc, New York, New York. Dr Yu-Wai-Man is an Medical Research Council (MRC, UK) Clinical Research Fellow in Neuro-Ophthalmology, and Dr Newman is the recipient of a Research to Prevent Blindness Lew R. Wasserman Merit Award.

    Manuscript no. 2010-587.

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