Congenital Stationary Night Blindness and Retinal Degeneration via the SLC24A1 Gene

Congenital Stationary Night Blindness (CSNB) is a retinal condition with negative bright-flash dark-adapted electroretinogram response, and optic atrophy or dysplastic changes, or both, in the optic nerve head. Typical findings of CSNB include impaired night vision, no pigmentary retinopathy, full visual fields consistent with myopia and strabismus, which appear from early childhood and are nonprogressive (Heckenlively et al. 1983; Nakamura et al. 2001).Early stages of retinitis pigmentosa (RP) and CSNB are difficult to distinguish. RP and Leber Congenital Amaurosis (LCA) are inherited degenerative diseases of the retina. RP is characterized by night blindness, with age of onset varying from childhood to middle age, progression to constriction of the peripheral visual field and, eventually, to loss of central vision. LCA is characterized by bilateral congenital blindness. Several clinical features of LCA overlap with those of RP. These include attenuated retinal vessels, abnormal ERG findings and a variable amount of retinal pigmentation (Perrault et al. 1996; Daiger et al. 2007; Gu et al. 1999). Both LCA and RP are clinically and genetically heterogeneous.

Maintenance of calcium and sodium concentrations within the rod and cone outer segments is essential for phototransduction, and is regulated by the two similar exchanger or solute carrier proteins in the rod and cones encoded by SLC24A1 and SLC24A2, respectively. Mutations in SLC24A1 are involved with autosomal recessive (AR) CSNB or retinal degeneration (Sharon et al. 2002; Riazuddin et al. 2010). A mutation analysis in a large multigeneration family found five CSNB affected individuals who were homozygous for a SLC24A1 small deletion (c.1613_1614del, p.Phe538Cysfs*23), which segregated with the disease and was not found in 384 control chromosomes (Riazuddin et al. 2010). Mouse studies have shown that SLC24A1 is predominantly expressed in the inner segment, outer and inner nuclear layers of the retina. It is also expressed at low levels in the cornea, lens, and optic nerve (Riazuddin et al. 2010). About twenty causative mutations have been reported in this rod exchanger gene in patients with retinal degeneration (Sharon et al. 2002; Human Gene Mutation Database).

Predicting clinical sensitivity for the SLC24A1 gene is challenging due to genetic heterogeneity of optic atrophy. However, analytical sensitivity should be high because nearly all reported mutations are detectable by this method (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SLC24A1 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).