Optic Atrophy and Neuropathy Panel

Optic Atrophy (OA) 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 et al. 2009; Yu-Wai-Man et al. 2010). OA is clinically characterized by bilateral reduction in visual acuity that progresses insidiously from early childhood onwards (Yu-Wai-Man et al. 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. The most common OA is inherited in an autosomal dominant mode (DOA). Phenotype-genotype studies found that 20% of DOA patients develop a more severe phenotype called “DOA plus” (DOA+), 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 et al. 2010; Amati-Bonneau et al. 2009). Disease prevalence is estimated as ~1/30,000 in most populations in the world, but in Denmark it can reach to 1/10,000 due to a founder effect (Kjer et al. 1996; Thiselton et al. 2001; Lenaers et al. 2012).

Although heterogeneous, the majority of suspected hereditary optic neuropathy patients (>60%) harbor pathogenic variants within OPA1, and ~3% have OPA3 pathogenic variants (Ferre et al. 2009). Optic nerve degeneration or optic atrophy is present in many disorders where mitochondrial impairment is the underlying cause for the RGC pathophysiology (Yu-Wai-Man et al. 2011). Examples are Wolfram’s syndrome, Mohr-Tranebjaerg syndrome or other neuropathies associated with neurological diseases such as spinocerebellar ataxias, Friedreich’s syndrome, Charcot Marie-Tooth type 2 and 6, Deafness-Dystonia-Optic Neuropathy syndromes etc. (Lenaers et al. 2012).

Causative variants in NR2F1 (Bosch et al. 2014) and OPA1 are inherited in an autosomal dominant (AD) manner. Causative variants in AUH (Wortmann et al. 2010), C12orf65 (Tucci et al. 2014), NDUFS1 (Martín et al. 2005), TMEM126A (Hanein et al. 2009), ACO2 (Spiegel et al. 2012) and MTPAP (Crosby et al. 2010) are inherited in an autosomal recessive (AR) manner, whereas pathogenic variants in TIMM8A (DDP) (Tranebjaerg et al. 2000) are inherited in X-linked manner. Causative variants in CISD2 (WFS2) (Amr et al. 2007), MFN2 (Rouzier et al. 2012), OPA3 (Yu-Wai-Man et al. 2011) POLG (Milone et al. 2011) and SPG7 (Klebe et al. 2012) have been shown to cause AD and AR phenotypes. Causative variants in WFS1 are implicated in autosomal recessive WS (Rendtorff et al. 2011) and autosomal dominant low frequency sensorineural hearing impairment. However, a few cases of autosomal dominant WFS1 - associated WS also had been reported (Eiberg et al. 2006; Valéro et al. 2008).

See individual gene test descriptions for information on molecular biology of gene products.

In a molecular screening of 980 cases of suspected hereditary optic neuropathy, molecular defects were identified in 440. Among these 440 patients, 295 (67%) had OPA1 pathogenic variants, 131 (30%) had mtDNA pathogenic variants, and 14 patients (3%) had OPA3 pathogenic variants (Ferre et al. 2009). In another study done with ADOA patients, 75% of the patients had OPA1 pathogenic variants, whereas 1% of patients had OPA3 pathogenic variants (Lenaers et al. 2012). Clinical sensitivity for other genes is currently unknown.

AUH, MFN2, NDUFS1, NR2F1, OPA1, POLG, SPG7, WFS1 and TIMM8A have been reported to have large pathogenic deletions or insertions (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.3% coverage of all coding exons of the genes 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 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).