Cone-Rod and Cone Dystrophy Panel
Cone-rod and cone dystrophy, CRD
Autosomal recessive, autosomal dominant, X-linked
Cone-rod dystrophies (CORD) are inherited retinal degenerations characterized by cone degeneration which precedes the rod degeneration. Prevalence of CORD is estimated to be 1 in 40,000 1, 2. The early manifestations of CORD include decreased visual acuity, color vision defects, and photophobia, with onset usually occurring in late childhood or early adult life, followed by progressive loss in peripheral vision and night blindness.
Functional signs and symptoms of cone-rod dystrophies include the following 2:
- Decrease in visual acuity is the earliest symptom
- Photophobia also occurs early
- Frequent dyschromatopsia
- Night blindness occurs later.
The visual field loss is characterized by a central scotoma that appears first, followed by patchy losses of peripheral vision, and finally severe loss of vision that occurs earlier than in retinitis pigmentosa 2.
The fundus is characterized by pigmentary deposits resembling bone spicules, frequently in the macular area, attenuation of the retinal vessels, and waxy pallor of the optic disc 2. Various degrees of retinal atrophy are also present.
Electroretinogram (ERG) in CORD patients is characterized by a shift of the implicit time (between a- and b-wave peaks), dramatic decrease of amplitudes of both a- and b-waves, and predominant involvement of photopic (cones) over scotopic (rods) responses 2.
In contrast to the typical symptoms of the typical retinitis pigmentosa, resulting from predominant rod involvement, i.e. night blindness and loss of peripheral vision, the clinical signs of CORD reflect the predominant involvement of cones, which leads to decreased visual acuity and loss of sensitivity in the central visual field 2. In some cases, diffuse retinopathy affects the cones and rods simultaneously, resulting in both night blindness and loss of visual acuity 2.
In the first stage, the main symptom is decreased visual acuity, which is usually discovered at school, during the first decade of life, and which is not significantly improved with spectacles. Patients often have a noticeable deviated gaze, to project images on parafoveal regions of their retina that are less damaged. In the second stage of disease, night blindness becomes more apparent and the loss of peripheral visual field progresses.
Cone dystrophy is sometimes separated into two broad groups: stationary and progressive. Stationary cone dystrophy is usually present during infancy or early childhood and symptoms generally remain the same throughout life. In progressive cone dystrophy, the associated symptoms become worse over time. The rate of progression and age of onset can be very variable. Progressive cone dystrophy usually develops in late childhood or early during adulthood.
Inherited forms of cone-rod dystrophy are due to pathogenic variants in one of several different genes which have been linked to cone dystrophy. Cone-rod dystrophy can be inherited as an autosomal dominant, autosomal recessive, X-linked recessive trait, or as mitochondrial traits.
Symptoms of cone-rod dystrophies significantly overlap with symptoms of other inherited retinal degenerations (IRDs). IRDs may affect the entire retina (e.g. retinitis pigmentosa, also known as rod-cone dystrophy, cone dystrophy, cone-rod dystrophy, choroideremia, Usher syndrome, and Bardet-Bidel syndrome), or be restricted to the macula, such as Stargardt macular dystrophy, Best disease, and Sorsby fundus dystrophy, ultimately leading to blindness.
Non syndromic CORDs are genetically heterogeneous and there are dozens of genes responsible, including the genes ABCA4, ADAM9, AIPL1, BEST1, C8ORF37, CABP4, CACNA1F, CACNA2D4, CDHR1, CERKL, CNGB3, CNNM4, CRX, GUCA1A, GUCY2D, KCNV2, PDE6C, PDE6H, PITPNM3, PROM1, PRPH2, RAX2, RDH5, RGS9, RGS9BP, RIMS1, RPGR, RPGRIP1, SEMA4A, UNC119 (see Table 1).
Pathogenic variants in the ABCA4 gene are responsible for up to 79% of cases with of Stargardt macular dystrophy 4 and more than 30% of all CORD cases in Europe 4. The disease associated with the ABCA4 gene presents as a diffuse retinopathy with predominance of macular involvement.
GUCA1A encodes guanylate cyclase-activating protein, a calcium binding protein involved in signal transduction in the photoreceptor cells. Pathogenic variants of GUCA1A have been described in a few families with autosomal dominant CORD, while all other GUCA1A mutations are responsible for cone dystrophies. Another guanylate-cyclase associated gene, GUCY2D, is also associated with CORD (>23% of affected cases in Europe 21 and 1.2% of CORD cases in China 23).
The CRX gene encodes the protein involved in control of rod and cone photoreceptor differentiation and survival. Most CRX pathogenic variants cause autosomal dominant CORD, with a prevalence estimated at 1.8%-3% 20, 23. The severity of the disease is highly variable, with some mild and some severe cases. CRX pathogenic variants also cause an autosomal dominant form of Leber congenital amaurosis (LCA).
Additional genes, also associated with different subtypes of retinitis pigmentosa, have been reported as disease-associated for cone-rod dystrophies, including the genes PRPH2, RPGR, PROM1, SEMA4, and others (see Table 1).
Cone-rod dystrophies are usually nonsyndromic, but can also occur in a number of systemic conditions, such as the Bardet-Biedl syndromes, Spinocerebellar ataxia type 7, among other rare inherited diseases.
Bardet Biedl syndrome (BBS) is an autosomal recessive disease characterized by retinal dystrophy, postaxial polydactyly, obesity, hypogenitalism, mental retardation, and renal abnormalities that which can lead to renal failure. Patients affected with BSS usually show prominent macular involvement with decreased visual acuity, photophobia and foveomacular hyperfluorescence on fluorescein angiography. The diagnosis of retinal dystrophy is often established in the first decade of life, and blindness occurs before age 20 years of age 2.
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant spinocerebellar degeneration due to expansions of polyglutamine in the ataxin protein. The retinal disease in SCA7 often begins with granular macula, progressively spreading out to the entire retina, while the macula becomes atrophic. The disease often presents as an isolated retinal dystrophy 2.
The differential diagnosis of cone-rod and cone dystrophy includes the following diseases - depending on the major presenting symptoms:
- Leber’s congenital amaurosis (LCA)
- Usher syndrome.
- Best disease
- Gyrate atrophy of the choroid and retina
- Chronic Progressive External Ophthalmoplegia
- Mitochondrial disorders
CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free Whole Genome Sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for cone-rod and cone dystrophy using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Cone-rod and cone dystrophy panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no clinically relevant variant is identified after analysis of the cone-rod and cone dystrophy panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.
The following individuals are candidates for cone-rod and cone dystrophy gene testing:
- Individuals with a family history of cone-rod and cone dystrophy and presentation of the most common symptoms
- Individuals without a positive family history, but with symptoms resembling cone-rod and cone dystrophy
- Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).
Sequencing, deletion/duplication of cone-rod and cone dystrophy related genes should be performed in all individuals suspected. If the result is inconclusive, other genes (whole genome sequencing) would also be analyzed for the clinically relevant variants based on the overlap in clinical features.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of cone-rod and cone dystrophy, identify at-risk family members, provide information on reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.