Cone-Rod Dystrophy Panel

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). Causative variants in the genes ABCA4, ADAM9, AIPL1, CFAP410, C8orf37, CABP4, CACNA2D4, CDHR1, CERKL, CNGB3, CNNM4, DRAM2, KCNV2, PDE6C, POC1B, RAB28, RPGRIP1, RGS9, RGS9BP and TTLL5 are inherited in an AR manner. Causative variants in the genes CRX, GUCA1A, GUCY2D, PITPNM3, RAX2, RIMS1, SEMA4A, UNC119 show AD inheritance. Pathogenic variants in BEST1, PDE6H, PROM1 and PRPH2 are inherited in both autosomal dominant and recessive manner. CACNA1F and RPGR are the only genes associated with XL-CRD in male patients. Females are often but not always asymptomatic, possibly due to random X inactivation. RPGR is a major gene responsible for ~70% of the XL- Retinitis pigmentosa (RP) cases. Currently, its contribution to the XL-CRD is unknown (Hamel. 2007. PubMed ID: 17270046). RPGR gene open reading frame 15 (ORF15) sequence analysis is not included in this panel. 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 RP, 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).

See individual gene test descriptions for further information on molecular biology of gene products and mutation spectra.

A mutation spectrum analysis by Sanger sequencing of eight autosomal dominant (AD) Cone-Rod Dystrophy (CRD) associated genes identified pathogenic variations in ~50% of all AD CD (cone dystrophy) and AD CRD cases (Kohl et al. 2012. PubMed ID: 22183351). Causative variants were identified in GUCY2D (23%), PRPH2 (11%), GUCA1A (8%), CRX (4%), and PROM1 (2%). No pathogenic variants were detected in AIPL1, UNC119 and PITPNM3, suggesting they may have a minor role in AD CD and AD CRD . A study based on literature searches (RetNet) reports that the autosomal recessive Cone-Rod Dystrophy (AR CRD) genes ABCA4, RPGRIP1, ADAM9 and CERKL are responsible for nearly 40% of AR CRD cases, ABCA4 being the major causative gene (den Hollander et al. 2010. PubMed ID: 20811160). Whole exome sequencing in 47 Chinese Families with CRD identified 14 potential pathogenic variations in 10 families (21.3%). These causative sequence variations were found in 6 of the 25 CRD-associated genes: CNGB3 (6.4%), PDE6C (4.3%), RPGR (4.3%), ABCA4 (2.0%), RPGRIP1 (2.0%), and CACNA1F (2.0%). The authors report that this is the first systemic exome-sequencing analysis of all 25 CRD-associated genes (Huang et al. 2013. PubMed ID: 23776498). All these genes together account for only about half of the ad/ar CRD cases, which indicates that there are still many genes that need to be identified (Hamel. 2007. PubMed ID: 17270046).

Gross deletions/duplications have been reported in BEST1, PRPH2, CRX, CNGB3, ABCA4, GUCY2D, CACNA2D4, CNNM4, KCNV2, RGS9BP, RPGR, and CACNA1F (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.2% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing. Exon 1 of CERKL, exon 15 in RPGR, exon 1 of RPGRIP1, and a region in RIMS1 exon 1 are not covered for technical reasons.

If one single suspected pathogenic variant is found in ABCA4, CERKL, or RPGRIP1, we will complete coverage of these genes using Sanger sequencing, which includes documented deep intronic variants in ABCA4.

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).