Cone-Rod Dystrophy via the DRAM2 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. PubMed ID: 17270046).

Non syndromic CRD is genetically heterogeneous and exhibits autosomal dominant (AD), autosomal recessive (AR) and, rarely, X-linked (XL) inheritance (Hamel. 2007. PubMed ID: 17270046). To date, over 25 genes have been implicated in different forms of CRD (RetNet). Due to the genetic heterogeneity, screening of all the CRD-associated genes is recommended. Most of the CRD-associated genes are also involved in other types of retinal dystrophies such as Retinitis Pigmentosa, macular dystrophies and cone dystrophies. Many of these genes encode proteins that have major roles in disc morphogenesis and the membrane- trafficking of photoreceptors (Sung and Chuang. 2010. PubMed ID: 20855501).

Bi-allelic pathogenic variants in DRAM2 cause adult-onset cone rod dystrophy with early macular involvement and associated central visual loss in the third or fourth decade of life (El-Asrag et al. 2015. PubMed ID: 25983245). Patients with DRAM2 cone rod dystrophy are typically asymptomatic in the first two decades of life (Sergouniotis et al. 2015. PubMed ID: 26720460). DRAM2 is a lysosomal protein expressed in both photoreceptor and retinal pigment epithelial cells (El-Asrag et al. 2015. PubMed ID: 25983245). DRAM2, unlike DRAM (damage-regulated autophagy modulator)-related proteins is not induced by p53 or p73. However, it remains possible that DRAM2 may still be a modulator of autophagy, perhaps in response to other stimuli (O'Prey et al. 2009. PubMed ID: 19556885; Crighton et al. 2006. PubMed ID: 16839881). DRAM2 might be involved in the process of photoreceptor renewal and recycling to preserve visual function (El-Asrag et al. 2015. PubMed ID: 25983245). To date, ~10 pathogenic variants (missense, nonsense and small in-frame and frameshift deletions) have been documented causative (Human Gene Mutation Database).

Due to the genetic heterogeneity and limited number of reported cases, it is difficult to predict clinical sensitivity. Analytical sensitivity should be high as all reported pathogenic variants are detectable by sequencing.

To date, no copy number variants have been documented causative in this gene (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the DRAM2 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).