Published in Retina

Genetic Testing for Inherited Retinal Diseases

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Discover how ophthalmologists can use genetic testing to evaluate patients for inherited retinal diseases.
Genetic Testing for Inherited Retinal Diseases
The first inherited retinal disease (IRD) was identified in 1988 after a mutation in the OAT gene, responsible for ornithine aminotransferase, was discovered.1
Now, as our understanding of genetics and our ability to study them expands, the true impact of IRDs is coming into frame.
It is estimated that the incidence of IRDs is nearly 1 in 2,000 individuals, and they now take the crown as the leading cause of vision loss in ages 15 to 45.1

Overview of common IRDs

The most common IRD, retinitis pigmentosa, is estimated to affect 1 in 4,000 individuals, while less common IRDs, such as Leber congenital amaurosis and Stargardt disease, affect about 1 in 50,000 and 1 in 10,000 individuals, respectively.2,3,4
This article will aim to inform and shed light upon IRDs, including the current guidelines for testing, clinical trials, and genetic counseling.

What qualifies as an inherited retinal disease?

An inherited retinal disease is an umbrella term that can be defined as a diverse range of genetic diseases that lead to photoreceptor and visual loss.
IRDs are generally split into four categories which include:5
Additionally, IRDs can be categorized as progressive or stationary depending on the onset and timing of the loss of function. Furthermore, rod-cone dystrophies (also known as retinitis pigmentosa) are often discussed through the lens of three subgroups. These subgroups include non-syndromic, in which the disease is limited to the eye; syndromic, in which other systems such as hearing are involved; and systemic, in which a wide range of tissues and organs are affected.6

Inherited retinal diseases and their associated genes

The inheritance pattern of IRDs is predominately Mendelian, including autosomal dominant, autosomal recessive, and X-linked. Mitochondrial inheritance is also a factor, particularly in the IRDs associated with other systemic manifestations.
There are nearly 260 genes known to cause IRDs, and mutations in several genes result in similar phenotypes. For example, mutations in nearly 84 different genes are associated with retinitis pigmentosa.1,7 The table below further highlights the heterogenicity of some of the genes involved in IRDs.
Table 1 outlines various inherited retinal diseases and the number of non-syndromic genes associated with them.
Inherited Retinal DiseaseNumber of Non-syndromic Genes Associated
Retinitis pigmentosa84
Leber congenital amaurosis 24
Cone-rod dystrophy33
Congenital stationary night blindness 15
Macular dystrophy 20
Exudative vitreoretinopathy 9
Table 1: Courtesy of Cremers et al.
Not illustrated within the above table is just how much overlap exists between diseases. For example, retinitis pigmentosa is associated with eight genes that are also associated with Leber congenital amaurosis. Congenital stationary night blindness and cone-rod dystrophies are associated with two of the same genes. In total, 39 of the above genes display some redundancy between diseases.1
As our ability (and the availability) to perform genomic sequencing advances, the scientific community has been able to increase its understanding of the genes and loci involved with each IRD. The below table summarizes just how much we have now identified.8
Table 2 lists the number of identified genes and loci per inherited retinal disease category.
Disease CategoryTotal No. of Genes and LociNo. of Identified Genes
Bardet-Biedl syndrome, autosomal recessive1818
Chorioretinal atrophy or degeneration, autosomal dominant11
Cone or cone-rod dystrophy, autosomal dominant95
Cone or cone-rod dystrophy, autosomal recessive1918
Cone or cone-rod dystrophy, X-linked10
Congenital stationary night blindness, autosomal dominant11
Congenital stationary night blindness, autosomal recessive1010
Congenital stationary night blindness, X-linked22
Leber congenital amaurosis, autosomal dominant11
Leber congenital amaurosis, autosomal recessive1313
Macular degeneration, autosomal dominant1410
Macular degeneration, autosomal recessive44
Ocular-retinal developmental disease, autosomal dominant11
Optic atrophy, autosomal dominant85
Optic atrophy, autosomal recessive43
Optic atrophy, X-linked10
Retinitis pigmentosa, autosomal dominant2423
Retinitis pigmentosa, autosomal recessive4644
Retinitis pigmentosa, X-linked52
Syndromic/systemic diseases with retinopathy, autosomal dominant98
Syndromic/systemic diseases with retinopathy, autosomal recessive5653
Syndromic/systemic diseases with retinopathy, X-linked32
Usher syndrome, autosomal recessive1815
Other retinopathy, autosomal dominant1511
Other retinopathy, autosomal recessive1917
Other retinopathy, mitochondrial77
Other retinopathy, X-linked87
Table 2: Courtesy of RetNet.

Workup and testing of suspected IRDs

The workup regarding suspected IRDs begins in the office. American Academy of Ophthalmology (AAO) guidelines about clinical evaluation are extensive and vary depending on which category of IRD is suspected or confirmed. Of note, for all four categories of IRDs, it is recommended a thorough family history of vision problems be taken, and a pedigree be created.
Patients should receive imaging, including color fundus photos, optical coherence tomography (OCT), fundus autofluorescence, visual fields, and full-field electroretinogram (ERG) when appropriate.5 The role of genetic testing for IRDs has expanded as technology has continued to advance.
Specifically, the advent of next-generation sequencing, which allows multiple genes to be tested at a time (compared to single-gene testing), has made genetic testing for IRDs more practical than in the past. It is now estimated that 56 to 76% of patients can have a causative gene of their IRD identified with genetic testing.5 With that in mind, it is appropriate to test most patients whom a provider suspects an IRD.

Genetic testing for inherited retinal diseases

Testing susceptible family members is something that can be done but not without considering the psychosocial risks of testing an asymptomatic individual for a disease that may have no disease-modifying agents currently available. Additionally, a negative test does not necessarily rule out disease because, as we illustrated above, many diseases have multiple different genetic variants, some of which may not be included on a specific panel of tests.5
The first step in testing an appropriate patient is most often a retinal dystrophy panel, which tests for a wide variety of genomic variations using a single DNA sample from a patient. There are several options for physicians seeking a retinal dystrophy panel. One example is The Foundation Fighting Blindness My Retina Tracker, which offers no-cost testing for patients. This panel tests for 351 genes associated with IRDs and has 33 eligible diagnoses.2
Previously, genetic testing for IRDs was not routinely done, with the major driving force behind that trend being a lack of available treatments. Without any available disease-modifying treatments, there was less motivation to discover the gene or genes mutated in an individual patient’s disease. Then, in 2017, the FDA approved gene therapy for Leber congenital amaurosis due to an RPE65 gene mutation, changing the landscape and rendering tests like retinal dystrophy panels useful for some patients.

IRD treatments currently in the pipeline

Currently, there are numerous clinical trials and pipeline treatments for IRDs, creating an environment in which it may benefit patients and their physicians to understand the specifics behind their inherited retinal disease. The retina itself is an ideal target for numerous types of gene therapy. The eye is easily accessible via intravitreal and subretinal injections.
Additionally, it is immune privileged, allowing it to tolerate foreign antigens, and retinal cells better do not replicate after birth, creating a situation in which a single dose could result in the lifetime expression of an altered gene.3 The table below summarizes some current clinical trial pipelines that have reached phase 3.2
Table 3 features a summary of select clinical trials for inherited retinal diseases.
Inherited Retinal DiseaseMechanism (Gene of Interest)Company/InstitutionPhase
X-linked retinitis pigmentosaGene therapy (RPGR)MeiraGTx/Janssen3
Leber's congenital amaurosisRNA/Other (CEP290, AON)ProQR2/3
Usher syndrome 2ARNA/Other (AON)ProQR2/3
dry age-related macular degenerationSmall molecule-C5 InhibitorIveric Bio3
Retinitis pigmentosaSmall molecule-NAC-anti-oxidantJohns Hopkins3
Stargardt diseaseSmall molecule-anti-RBP4Belite Bio3
Table 3: Courtesy of the Fighting Blindness Foundation.

The role of genetic counseling for IRDs

With the understanding that the ability to both identify and attempt to treat via enrollment in clinical trials is a possibility for patients with IRDs, it is extremely important that patients receive genetic counseling in addition to actual gene testing. Genetic counseling should be offered to patients after testing and can be performed by a clinical geneticist or an in-person or telephone-based genetic counselor.5
Patients should be educated on the entirety of the genetic testing process, including the availability of clinical trials and what their results mean in terms of risks for IRDs in future generations. As more individuals get tested, the data pool and understanding of the genetic variants behind IRDs expand. This increase in available data, coupled with advancing genetic technologies and clinical trials, is opening the possibility that more and more IRDs may be treatable.
Now more than ever, it is important that physicians stay aware of and educated on emerging genetic technologies and treatments to best serve their patients.
  1. Cremers FPM, Boon CJF, Bujakowska K, Zeitz C. Special Issue Introduction: Inherited Retinal Disease: Novel Candidate Genes, Genotype-Phenotype Correlations, and Inheritance Models. Genes. 2018;9(4):215.
  2. Fighting Blindness Foundation. “Open Access Genetic Testing Program.”
  3. Chiu W, Lin TY, Chang YC, et al. “An Update on Gene Therapy for Inherited Retinal Dystrophy: Experience in Leber Congenital Amaurosis Clinical Trials.” MDPI. Multidisciplinary Digital Publishing Institute. Published April 26, 2021.
  4. Allikmets R. Leber congenital amaurosis: a genetic paradigm. Ophthalmic genetics. 2004;25(2):67–79.
  5. Duncan JL, Branham K, Birch DG, et al. “Guidelines on Clinical Assessment of Patients with Inherited Retinal Degenerations - 2022.” American Academy of Ophthalmology. Published October 6, 2022.
  6. Sahel JA, Marazova K, Audo I. Clinical characteristics and current therapies for inherited retinal degenerations. Cold Spring Harbor perspectives in medicine. 2014;5(2), a017111.
  7. Prevent Blindness. “Inherited Retinal Diseases.” Published May 13, 2022.
  8. Daiger SP. “Summaries of Genes and Loci Causing Retinal Diseases.” RetNet: Summaries.
  9. O'Neal TB, Luther EE. “Retinitis Pigmentosa.” National Center for Biotechnology Information. US National Library of Medicine.
  10. Strauss RW, Muñoz B, Ho A, et al. Incidence of Atrophic Lesions in Stargardt Disease in the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: Report No. 5. JAMA Ophthalmol. 2017;135(7):687–695. doi:10.1001/jamaophthalmol.2017.1121.
Michael Parise
About Michael Parise

Michael Parise is in his final year of medical school at Touro College of Osteopathic Medicine in New York City where he has fostered his interests in education as a peer tutor. He has developed a passion for ophthalmology and will be applying to ophthalmology residency programs this upcoming year!

Michael grew up just north of New York City, spending most his time enjoying the outdoors. He went on to graduate from the University of Maryland with a degree in Biology before working various healthcare-related jobs ranging from scribe to medical device rep.

Michael Parise
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