Gyrate Atrophy of Choroid and Retina via the OAT Gene

Gyrate atrophy (GA) is an autosomal recessive eye disorder characterized by progressive chorioretinal degeneration that leads to loss of vision. Other symptoms include hyperornithinemia, progressive centripetal loss of vision, minor central and peripheral nervous system abnormalities, and type II muscle fiber atrophy with accumulation of tubular aggregates (Mitchell et al. 1988; Peltola et al. 2002). However, the clinical phenotype is largely confined to the eye (Ramesh et al. 1991).

Pathogenic variants in OAT have been reported to be causative for autosomal-recessive Gyrate atrophy (GA). The OAT gene on chromosome 10 encodes Ornithine delta-aminotransferase, which is a nuclear-encoded mitochondrial matrix enzyme (OATase). This enzyme catalyzes the reversible interconversion of ornithine and alpha-ketoglutarate to glutamate semialdehyde and glutamate. Functional studies have shown that the majority of the causative variants inactivate enzyme activity. These studies also suggested allelic heterogeneity causing both pyridoxine responsive and non-responsive forms of GA, reflecting the clinical and biochemical heterogeneity in this disease (Ramesh et al. 1991; Brody et al. 1992). OAT gene sequences are also found on the X chromosome (Xp11.2) that map to the same region as L1.28 (Xp11.0-p11.3), a marker closely linked to X-linked recessive retinitis pigmentosa. However, the functional OAT gene is on chromosome 10 (Barrett et al. 1987). So far, about 70 causative variants (Missense/nonsense, splicing and small and large deletions and insertions) have been reported in OAT-associated disorders (Human Gene Mutation Database).

Mashima et al. identified causative variants (missense, nonsense, small deletions and splice-site variants) in 95.5% (21/22) mutant OAT alleles from 11 patients, which indicates that large copy number variants are a rare cause of the disease (Mashima et al. 1994).

This test provides full coverage of all coding exons of the OAT 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).