Autosomal Dominant Cone Dystrophy 3 (COD3) and Cone-Rod Dystrophy 14 (CRD14) via the GUCA1A Gene

Hereditary cone dystrophies (COD) are clinically and genetically heterogeneous disorders that result in the dysfunction of the cone photoreceptors. Major clinical features include bilateral visual loss, abnormal color vision, central scotomata, variable degrees of nystagmus and photophobia. CODs manifest as progressive or stationary disorders. The stationary subtype CODs occur within the first months of life with pendular nystagmus and photophobia with normal rod function and are better described as cone dysfunction syndromes, whereas progressive CODs usually occur in childhood or early adulthood and patients often develop rod photoreceptor dysfunction in later life. The stationary subtype CODs are uncommon with an incidence of about 1 in 30,000 (Michaelides et al., 2004; Simunovic and Moore, 1998).

Cone rod dystrophies (CORDs/CRDs) are also rare with a worldwide prevalence of ~1 in 40,000. CORDs are characterized by dysfunction or degeneration of cone photoreceptors with relative preservation of rod function in the initial stages. The most common symptoms are photophobia and epiphora in bright light, decreased visual acuity, and dyschromatopsia. Fundus changes may vary from mild pigment granularity to a distinct atrophic lesion in the central macula. As the disease progresses, degeneration of rod photoreceptors also occurs and leads to progressive night blindness and peripheral visual field loss (Hamel, 2007).

COD and CRD are diagnosed mainly on the basis of photopic and scotopic electroretinogram responses, fundoscopy and optical coherence tomography (Jiang and Baehr, 2010).

Both COD and CRD exhibit autosomal dominant (ad), autosomal recessive (ar) or X-linked (XL) inheritance. (RetNet). Thus far, the best characterized genes associated with ad COD and CRD are GUCY2D, encoding photoreceptor guanylate cyclase 1 (retGC-1 or GC1), and GUCA1A, encoding the Ca2+-binding protein (GCAP1), which are expressed in the outer segments of the photoreceptors (Jiang and Baehr, 2010). GC1 and GCAP1 play major roles in visual phototransduction, which is a biochemical process responsible for light conversion into electrical signals in the rod and cone cells. In this process, GC1 helps in restoring photoreceptor sensitivity by synthesizing cyclic guanosine monophosphate (cGMP), which is regulated by guanylate cyclase activator proteins (GCAPs: 1 and 2). GCAPs are sensitive to changes in the cytoplasmic Ca2+ concentrations. It has been reported that GCAP2 is activated at lower Ca2+ concentrations than GCAP1 (Hwang et al., 2003). However, GCAP1 and GCAP2 regulate the Ca2+ signaling of GC1 in different ways. At lower cytoplasmic Ca2+ concentrations, GCAP1 interacts with GC1 and stimulates it, and consequently, the cGMP level is restored (Jiang et al., 2005). Even in the absence of GCAP2, GCAP1alone can restore rod and cone responses, whereas GCAP2 can only partially compensate (Kitiratschky et al., 2009). Thus, GCAP1 plays a major role in regaining the dark-adapted state after excitation of the photoreceptor (Mendez et al., 2001; Pennesi et al., 2003). Disruption of Ca2+ homeostasis, due either to genetic or environmental factors leads to apoptosis of the photoreceptor cells (Baehr and Palczewski., 2007; Garcia-Hoyos et al., 2011). So far, about ten causative mutations (mostly missense) in GUCA1A have been associated with adCOD and adCRD (The Human Gene Mutation Database).

A mutation analysis in an American five-generation pedigree with 30 living family members identified heterozygous GUCA1A mutations in all affected family members (11/30; ~36%), which segregated with the disease phenotype and was not found in 200 normal controls (Jiang et al., 2005). Another mutation screening in a three-generation Spanish family with ad retinal dystrophy detected a GUCA1A mutation in all affected individuals (5/9; ~55%), which also co-segregated with the disease phenotype and was not found in 200 ethnically matched control individuals (Kamenarova et al., 2013). In another study with 24 unrelated patients (19 patients had adCOD and five patients had adCRD) GUCA1A mutations were identified in four patients (4/24; ~16%) (Kitiratschky et al., 2009). The GUCA1A gene was analyzed in 216 patients with various hereditary retinal disorders in which cones were dysfunctional and five causative mutations in a total of six patients were identified (6/216; ~3%) (Nishiguchi et al., 2004).

So far, no gross deletions or duplications have been reported in GUCA1A (The Human Gene Mutation Database).

This test provides full coverage of all coding exons of the GUCA1A 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).