Cone-Rod Dystrophy (CORDX3) via the CACNA1F Gene

Cone-rod dystrophy (CORD/CRD) is a rare hereditary retinal disorder with a worldwide prevalence of ~1 in 40,000. CRD is 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).

Incomplete X-linked congenital stationary night blindness (CSNB2) is a recessive, non-progressive (stationary) retinal disorder characterized by night blindness moderate myopia, nystagmus, strabismus and electroretinogram abnormalities of the Schubert-Bornschein type. Female carriers usually do not show any clinical signs. (Wutz et al. 2002; Bech-Hansen et al. 1998; Boycott et al. 1993).

Aland Island eye disease (AIED), also known as Forsius-Eriksson ocular albinism, is an X-linked recessive retinal disease characterized by reduced visual acuity, mild red-green colour blindness, nystagmus, fundus hypopigmentation and foveal hypoplasia, astigmatism and progressive myopia. AIED symptoms have similarities with Ocular Albinism type 1. However, there is no misrouting of optic nerve fibers in AIED. Female carries may exhibit latent nystagmus and high myopia (Hawksworth et al. 1995; Jalkanen et al. 2007).

Non syndromic CRD is genetically heterogeneous and exhibits autosomal dominant (ad), autosomal recessive (ar) and, rarely, X-linked (xl) inheritance (Hamel 2007). So far about 25 genes have been implicated in different forms of CRD (RetNet). One of the xl-CRD (CORDX3) causative genes, CACNA1F, encodes retina-specific voltage-dependent calcium channel alpha 1F subunit (Cav1.4) and is localized to the Xp11.23 region. CACNA1F is also responsible for CSNB2 and AIED (Jalkanen 2006; Doering et al. 2007). Clinically, CORDX3 and CSNB2 have some overlapping clinical features such as the range of visual acuities, myopic refraction, and the ERG abnormalities. However, they are distinguishable from each other in some cases. For instance, CORDX3 is progressive, has onset between 3 and 33 years, has no congenital nystagmus or hyperopic refraction, and has only low grade astigmatism (Jalkanen 2006). In contrast, CSNB2 is stationary, in severe cases is seen early in life, and congenital nystagmus, hyperopic refraction, and astigmatism can be seen. AIED and CSNB2 also have some overlapping phenotypes but AIED has some additional features such as progressive myopia, dyschromatopsia, iris trans-illumination defects, and foveal hypoplasia (Vincent et al. 2011).

Retina-specific CACNA1F is shown to have a specific functional role in visual processing (Naylor et al. 2000). Mouse mutant studies have shown that Cav1.4 calcium channel is crucial for the synaptic transmission at photoreceptor ribbon synapses (Morgans 2001). There are about hundred pathogenic variations in CACNA1F, which are associated with X-linked CORDX3, CSNB2 and AIED (Human Gene Mutation Database). A founder mutation in exon 27 of CACNA1F (c.3166dupC; p.Leu1056Profs*11) was identified Sixty-six male patients from 15 families of Mennonite ancestry (Boycott et al. 2000). A CACNA1F mutation screening in a large Finnish family (seven affected males, 10 carrier females, and 33 unaffected family members) identified a splice site variant, which co-segregated with the disease phenotype and not found in 200 control chromosomes (Jalkanen 2006). While gross deletions have also been reported, the percentage of cases due to gross deletions is unknown at this time (Human Gene Mutation Database).

Approximately 55% of X-Linked Congenital Stationary Night Blindness cases are due to mutations in CACNA1F gene (CSNB2) and the rest (45%) are caused by mutations in the NYX gene (CSNB1) (Boycott et al. 1993). Exome sequencing of 47 Chinese families with CORD identified CACNA1F mutations in ~2% (1/47) of their patient population (Huang et al. 2013).

This test provides full coverage of all coding exons of the CACNA1F 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).