Achromatopsia 6 or Retinal Cone Dystrophy 3 via the PDE6H 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. 2007. PubMed ID: 17270046). 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. 2004. PubMed ID: 14736794). However, in Micronesian atoll of Pingelap, achromatopsia affects ~5% of the island population (Morton et al. 1972. PubMed ID: 4537352).

PDE6H-associated retinal disorder is characterized as cone dystrophy with nyctalopia and supernormal rod responses (Piri et al. 2005. PubMed ID: 15629837).

Achromatopsia is a heterogeneous genetic disease that is inherited in an autosomal recessive manner. It is caused by defects in various genes that encode important elements of the cone phototransduction process (Chang et al. 2009. PubMed ID: 19887631; Thiadens et al. 2009. PubMed ID: 19615668). PDE6H encodes the inhibitory γ-subunit of cone-specific cyclic guanosine monophosphate (cGMP)-phosphodiesterase (PDE) (Piri. 2005. PubMed ID: 15629837). To date, less than 5 PDE6H causative variants (nonsense) have been reported (Human Gene Mutation Database).

Due to genetic heterogeneity and the limited number of reported cases, the clinical sensitivity of PDE6H for cone disorders is not precisely known. However, pathogenic variants in PDE6H appear to be a rare cause of retinal disorders. So far, large deletions/duplications have not been documented in this gene (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the PDE6H 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).