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

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.