Autosomal Dominant Optic Atrophy (ADOA) or Optic Atrophy, Kjer-Type (OAK) and DOA Plus Syndrome (DOA+) via the OPA1 Gene

Autosomal Dominant Optic Atrophy (ADOA; OMIM# 165500) is the most prevalent inherited optic neuropathy besides Leber’s hereditary optic neuropathy (LHON). Both share a common pathological hallmark, the preferential loss of retinal ganglion cells (RGCs) (Carelli, V., et al. Biochim Biophys Acta 1787(5):518–528, 2009; Yu-Wai-Man, P., et al. Ophthalmology. 117(8):1538-1546, 2010). ADOA is clinically characterized by bilateral reduction in visual acuity that progresses insidiously from early childhood onwards (Yu-Wai-Man, P., et al. Ophthalmology. 118(3):558-563, 2011). Other symptoms include central or near central scotomas, tritanopia, variable degree of ptosis, central visual field defects and/or ophthalmalgia and optic nerve pallor. However, there is a marked inter-and intrafamilial variation in disease severity (Votruba, M., et al. Hum. Genet. 102(1): 79-86, 1998). Phenotype-genotype studies of optic atrophies found that 20% of DOA patients develop a more severe phenotype called “DOA plus” (DOA+, OMIM# 125250), which is characterized by extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts (Yu-Wai-Man, P., et al. 2010; Amati-Bonneau, P. et al. Int J Biochem Cell Biol 41(10):1855-1865, 2009). Disease prevalence is estimated as 3/100,000 in most populations in the world, but in Denmark it can reach to 1/10,000 due to a founder effect (Kjer, B. et al. Acta Ophthalmol Scand 74(1):3-7, 1996; Thiselton, DL. et al. Hum Genet 109(5):498-502, 2001).

Although heterogeneous, the majority of suspected hereditary optic neuropathy patients (>60%) harbor pathogenic mutations within OPA1; ~30% have mtDNA mutations; and ~3% have OPA3 mutations (Ferre et al. Hum Mutat 30(7): E692-705, 2009). OPA1 encodes mitochondrial dynamin-like GTPase, which localizes to the inner mitochondrial membrane and regulates several important cellular processes, which include the stability of the mitochondrial network, mitochondrial bioenergetic output, sequestration of proapoptotic cytochrome C oxidase molecules within the mitochondrial cristae spaces, control of apoptosis, maintenance of mitochondrial DNA and oxidative phosphorylation (Ferre et al., 2009; Yu-Wai-Man et al., 2010). OPA1 is composed of 30 coding exons that span ~90 kb of genomic DNA on chromosome 3q28-q29. Alternative splicing of exons 4, 4b, 5 and 5b leads to eight transcript isoforms shown to be expressed in a variety of tissues (Alavi, M.V. et al. Brain 130(Pt 4):1029-1042, 2007). Almost 50% of OPA1 mutations lead to haploinsufficiency due to complete deletion of the gene and nonsense mediated mRNA decay, which is believed to be the major pathomechanism underlying OPA1-associated ADOA (Pesch, U.E. et al. Hum Mol Genet 10(13):1359-1368, 2001). OPA1 genomic rearrangements account for ~13% cases of ADOA, suggesting that deletion and duplication analysis should be included in the routine genetic analysis of ADOA patients (Marchbank, N.J. et al. J Med Genet 39(8): e47, 2002 ; Fuhrmann, N. et al. J Med Genet 46(2):136-144, 2009 ; Almind, G.J. et al. BMC Med Genet 12:49, 2011). The haploinsufficiency has been shown to affect retinal ganglion cells, which have many mitochondria and especially high energy requirement due to their non-myelinated specialized extensions called axons that form the optic nerve. Based on Fuhrmann et al. (2009) genotyping results, ADOA penetrance was ~88%, which is consistent with previous reports (Toomes, C. et al. Hum Mol Genet 10(13):1369-1378, 2001; Cohn, A.C. et al. Am J Ophthalmol 143(4):656-662, 2007). Missense, nonsense, insertions, deletions and splicing mutations have been reported within OPA1 and are spread throughout the coding region, with most of them clustering over the cDNA region corresponding to the GTPase domain (Exons 8-16) and the 3' end of the coding region (exon 27-28) (Pesch, U.E. et al. 2001; Toomes, C. et al., 2001).

In a molecular screening of 980 cases of suspected hereditary optic neuropathy, 440 patients had molecular defects. Among these 440 patients, 295 had OPA1 mutations (67%) 131 patients had (30%) mtDNA mutations, and 14 patients (3%) had OPA3 mutations (Ferre, M., et al. Hum Mutat 30(7):E692-705, 2009). In another study done with ADOA patients, 75% of the cases had OPA1 mutations, whereas 1% of patients had OPA3 mutations (Lenaers, G. et al. Orphanet J Rare Dis 7:46, 2012).

This test provides full coverage of all coding exons of the OPA1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).