Cone-Rod Dystrophy via the CABP4 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, CABP4, encodes the neuronal Ca2+-binding protein, which is expressed in the retina and in the cochlea. CABP4 is shown to be essential for calcium influx and neurotransmitter release in the synaptic terminal of the photoreceptors (Maeda et al. 2005; Haeseleer et al. 2004; Littink et al. 2008). Dysfunctional CABP4 is reported to influence the cone function more than rod function (Littink et al. 2008). The patients carrying CABP4 gene mutations did not experience night blindness. The phenotype was classified as congenital cone–rod synaptic disorder (Littink et al. 2008). Mutations in CABP4 have also been shown to cause autosomal recessive congenital stationary night blindness (arCSNB) (Zeitz et al. 2006). Thus far, ~ 5 pathogenic sequence variations have been reported in CABP4 that resulted in congenital cone–rod synaptic disorder, Leber’s congenital amaurosis (LCA)-like phenotype and arCSNB (Littink et al. 2008; Aldahmesh et al. 2010; Zeitz et al. 2006; Human Gene Mutation Database).

A mutation analysis in pedigrees of two families with arCSNB, who did not carry mutations in CACNA1F gene, detected homozygous and compound heterozygous CABP4 mutations in all three affected individuals. Seven unaffected family members were heterozygous for CABP4 mutations. These mutations were absent in over 220 control alleles (Zeitz et al. 2006). Another molecular analysis in a consanguineous family with LCA-like phenotype identified a homozygous single base-pair insertion in all four siblings, while the parents and an unaffected sibling were heterozygous for this mutation (Aldahmesh et al. 2010). Another study identified a novel homozygous nonsense mutation in CABP4 in two siblings diagnosed with a congenital cone–rod synaptic disorder phenotype. The parents were heterozygous for this mutation, and the mutation was not found in 300 alleles of ethnically matched control individuals (Littink et al. 2008).

This test provides full coverage of all coding exons of the CABP4 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).