Cone-Rod Dystrophy (CRD11) via the RAX2 (Qrx) 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).

Cone-rod dystrophy 11 is an autosomal dominant condition caused by mutations in a novel retinal homeobox 2 gene, RAX2 /QRX (Q50-type) located on chromosome 19p13.3 (Wang 2004). 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).

Members of the Rx/Rax (retinal homeobox) gene family are shown to be essential for vertebrate eye development. Abnormal expression has been shown to have profound effects on eye development (Pan et al. 2010; Mathers et al. 1997; Bailey et al. 2004). Mouse studies have shown that the embryos carrying dominant null alles of this gene did not form optic cups and therefore did not develop eyes (Mathers et al. 1997). RAX protein is co-expressed along with HES1 (basic helix-loop-helix protein), and NOTCH1 (transmembrane receptor protein) in retinal progenitor cells and promote the formation of Müller glia and bipolar cells (Furukawa et al. 2000). Also, RAX is a transcriptional regulator protein which regulates many photoreceptor-specific genes by binding to their regulatory regions (Kimura et al. 2000). RAX2/QRX protein, which is the closest homologue of RAX (93% identical in the homeodomain) may also play a role in regulation of Rhodopsin and possibly other photoreceptor-specific gene expression. QRX stimulates CRX (cone rod Homeobox) activity and with the help of CRX it also activates NRL (Neural Retina Leucine Zipper), which are also involved with retinal disorders (Wang 2004; Chen et al. 1997). So far, very few pathogenic variations in RAX2 that are associated with autosomal dominant cone-rod dystrophy have been reported (Human Gene Mutation Database).

A RAX2 mutational screening in a cohort of 322 cone-rod dystrophy (CRD), 107 Leber congenital amaurosis (LCA), 92 age-related macular degeneration (ARMD), 14 autosomal recessive retinitis pigmentosa (ARRP) and 14 autosomal dominant retinitis pigmentosa (ADRP) identified two different heterozygous sequence variations in CRD and AMD patients. These mutations were not found in the pool of 94 control individuals (Wang 2004). Analytical sensitivity is expected to be high because all sequence variations that have been reported are detectable by sequencing.

This test provides full coverage of all coding exons of the RAX2 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).