Genomic deletions in OPA1 in Danish patients with autosomal dominant optic atrophy

Abstract

Background: Autosomal dominant optic atrophy (ADOA, Kjer disease, MIM #165500) is the most common form of hereditary optic neuropathy. Mutations in OPA1 located at chromosome 3q28 are the predominant cause for ADOA explaining between 32 and 89% of cases. Although deletions of OPA1 were recently reported in ADOA, the frequency of OPA1 genomic rearrangements in Denmark, where ADOA has a high prevalence, is unknown. The aim of the study was to identify copy number variations in OPA1 in Danish ADOA patients.

Methods: Forty unrelated ADOA patients, selected from a group of 100 ADOA patients as being negative for OPA1 point mutations, were tested for genomic rearrangements in OPA1 by multiplex ligation probe amplification (MLPA). When only one probe was abnormal results were confirmed by additional manually added probes. Segregation analysis was performed in families with detected mutations when possible.

Results: Ten families had OPA1 deletions, including two with deletions of the entire coding region and eight with intragenic deletions. Segregation analysis was possible in five families, and showed that the deletions segregated with the disease.

Conclusion: Deletions in the OPA1 gene were found in 10 patients presenting with phenotypic autosomal dominant optic neuropathy. Genetic testing for deletions in OPA1 should be offered for patients with clinically diagnosed ADOA and no OPA1 mutations detected by DNA sequencing analysis.

Figure 1

Deletions and duplications identified in the OPA1 gene. Black boxes illustrate exons and light grey boxes illustrate alternative spliced exons. Arrows above the gene show the functional domains. Arrows below the gene show localization of deletions identified in the present study (blue arrows) and deletions (green arrows) and duplication (red arrow) identified by Fuhrmann et al. (2009) [23].

Figure 2

Pedigrees of three ADOA families A. Family DOA105, B. Family DOA110 C. Family DOA108. Index patients are indicated with an arrow. Filled symbols are individuals affected with ADOA, open symbols are either unaffected or not known. Individuals investigated by deletion analysis are shown with a "+del" (deletion present) or "-del" (no deletion) below symbol.