OPA1 analysis in an international series of probands with bilateral optic atrophy.

Petra Liskova,Stepanka Svecova,Hana Kolarova,Lubica Dudakova,Marcela Votruba,Tomas Honzik,Marketa Tesarova,Sharon Seto

doi:10.1111/aos.13285

Petra Liskova, Stepanka Svecova + Show 6 more

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https://doi.org/10.1111/aos.13285

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Abstract

To determine the molecular genetic cause in previously unreported probands with optic atrophy from the United Kingdom, Czech Republic and Canada. OPA1 coding regions and flanking intronic sequences were screened by direct sequencing in 82 probands referred with a diagnosis of bilateral optic atrophy. Detected rare variants were assessed for pathogenicity by in silico analysis. Segregation of the identified variants was performed in available first degree relatives. A total of 29 heterozygous mutations evaluated as pathogenic were identified in 42 probands, of these seven were novel. In two probands, only variants of unknown significance were found. 76% of pathogenic mutations observed in 30 (71%) of 42 probands were evaluated to lead to unstable transcripts resulting in haploinsufficiency. Three probands with the following disease-causing mutations c.1230+1G>A, c.1367G>A and c.2965dup were documented to suffer from hearing loss and/or neurological impairment. OPA1 gene screening in patients with bilateral optic atrophy is an important part of clinical evaluation as it may establish correct clinical diagnosis. Our study expands the spectrum of OPA1 mutations causing dominant optic atrophy and supports the fact that haploinsufficiency is the most common disease mechanism.

Highlights

Autosomal dominant optic atrophy (DOA, OMIM 165500) is the most common hereditary optic neuropathy with an estimated prevalence of 1:12 000–1:50 000 (Lyle 1990; Kjer et al 1996)
32 rare sequence changes in a heterozygous state were detected in optic atrophy gene 1 (OPA1) coding region and intron–exon boundaries in 44 probands, of 82 tested
We report on rare OPA1 sequence variants identified in a large cohort of international patients with bilateral optic atrophy

Summary

Introduction

Autosomal dominant optic atrophy (DOA, OMIM 165500) is the most common hereditary optic neuropathy with an estimated prevalence of 1:12 000–1:50 000 (Lyle 1990; Kjer et al 1996). The disease is genetically heterogeneous, with five mapped loci (Votruba et al 1997; Kerrison et al 1999; Anikster et al 2001; Barbet et al 2005; Carelli et al 2011). OPA1 is the most frequently mutated gene causing DOA accounting for up to 60% of cases with inherited optic atrophies (Yu-Wai-Man et al 2009). Autosomal dominant optic atrophy (DOA) shows highly variable expression, onset and progression. DOA plus phenotype is found, characterized by variable presence of sensorineural hearing loss, ataxia, axonal sensory-motor polyneuropathy, multiple sclerosis-like phenotype, chronic progressive external ophthalmoplegia and mitochondrial myopathy (Amati-Bonneau et al 2009; Yu-Wai-Man et al 2010; Liskova et al 2013). Most recently association of OPA1 mutations with a multisystem disorder characterized by age-related parkinsonian features as well as cognitive deterioration has been described (Carelli et al 2015)

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