Cone-Rod Dystrophy via the CACNA2D4 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).

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 causative genes CACNA2D4 encodes a voltage-gated L-type calcium channel auxiliary subunit and is mostly expressed in the retina (Postel et al. 2013; Wycisk 2006). Mouse model studies have shown that the mutations in CACNA2D4 result in profound loss of retinal signal transmission and an abnormal morphology of ribbon synapses in photoreceptors (Wycisk 2006). A mutation in its human orthologue, CACNA2D4, has been shown to cause autosomal recessive cone dystrophy. Thus far, only a nonsense mutation in CACNA2D4 has been reported to be causative for arCRD (Wycisk et al. 2006). A gross deletion in CACNA2D4 has been reported to result in psychiatric diseases in general and Bipolar disorder in particular (Van Den Bossche et al. 2012; Human Gene Mutation Database).

A CACNA2D4 mutation analysis in a pedigree of an index patient diagnosed with cone dystrophy detected a homozygous c.2406C>A substitution (p.Tyr802*) in the index patient and in an affected sibling, whereas unaffected father was heterozygous for this mutation. This mutation was absent in the index patient's unaffected siblings and in over 224 control chromosomes (Wycisk et al. 2006).

This test provides full coverage of all coding exons of the CACNA2D4 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).