Achromatopsia via the CNGB3 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 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. Variants in four genes, including CNGB3 (Sundin et al. Nat Genet 25:289-293, 2000), have been identified in patients with achromatopsia. At least 37 different CNGB3 causative variants have been reported. Most variants are expected to result in truncated proteins and include nonsense and splice site variants and small insertions, deletions, and indels. Only three missense variants have been reported to date. No large deletions, duplications, or complex rearrangements have been reported. A founder missense variant, c.1304C>T, causes achromatopsia in the Pingelap population (Sundin, 2000). In addition to achromatopsia (OMIM 262300), CNGB3 variants were identified in patients with juvenile onset macular degeneration (OMIM 248200; Nishiguchi et al. Hum Mutat 25:248-258, 2005) and patients with progressive cone dystrophy (Michaelides et al. Invest Ophthalmol Vis Sci 45:1975-1982, 2004).

The CNGB3 gene encodes the beta subunit of the cyclic nucleotide-gated cation channel in cone photoreceptor cells.

This test will detect variants in up to 50% of patients with clinical diagnosis of achromatopsia (Kohl et al. Eur J Hum Genet13:302-308, 2005).

This test provides full coverage of all coding exons of the CNGB3 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.