Achromatopsia via the PDE6C Gene

Achromatopsia is a congenital cone rod dystrophy (CRD) that can be distinguished from other CRDs on the basis of primary cone involvement, stationary course, and normal fundus (Hamel Orphanet J Rare Dis 2:7, 2007).  Two clinical types of achromatopsia, complete and incomplete, are recognized.  In patients with complete achromatopsia, symptoms usually begin in infancy and include nystagmus, low visual acuity, photophobia, severe color vision defects, and selective absence of functioning cone photoreceptor cells in electroretinogram (ERG) findings.  Patients with incomplete achromatopsia retain residual functioning cone cells.  In addition, they have mild visual acuity and mild color vision defects.  The prevalence of complete achromatopsia is 1 per 30,000 people worldwide (Michaelides et al. Br J Ophthalmol 88 291–297, 2004).  However, in the Micronesian atoll of Pingelap, achromatopsia affects ~ 5 % of the island population (Morton et al. Am J Hum Genet 24:277-289, 1972).

Achromatopsia is a heterogeneous genetic disease inherited in an autosomal recessive manner. It is caused by defects in various genes that encode important elements of the cone phototransduction process. Variants in four genes, including PDE6C (Chang et al. Proc Natl Acad Sci USA 106:19581-19586, 2009; Thiadens et al. Am J Hum Genet 85:240-247, 2009), have been identified in patients with achromatopsia. To date, ~15 different PDE6C causative variants have been reported. Variants include missense, nonsense, splicing, and small insertions or deletions. No large deletions, duplications, or complex rearrangements have been reported. In addition to achromatopsia, PDE6C variants were identified in patients with autosomal recessive, early-onset progressive cone dystrophy (arCD), suggesting that ACHM and arCD are clinically and genetically overlapping disorders (Thiadens et al. 2009). The PDE6C gene encodes the alpha subunit of phosphodiesterase in cone photoreceptor cells.

About 2% of achromatopsia patients with known causative variants have variants in PDE6C (Thiadens et al. Am J Hum Genet 85:240-247, 2009).

This test provides full coverage of all coding exons of the PDE6C 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).