A recent study in Genes expands the list of known genetic mutations tied to inherited retinal diseases (IRDs), aiming to improve diagnostic accuracy.
Give me some background first.
IRDs refer to a group of disorders that affect the photoreceptor cells and/or the retinal pigment epithelium—impacting roughly 1 in 3,000 individuals worldwide—and can lead to vision loss and retinal degeneration.
- To note: Different IRDs often present with similar combinations of symptoms, making them difficult to diagnose with accuracy.
As such: With currently 326 genes out of 20,000 in the human genome known to be associated with the development of IRDs, it is believed that further study of the genetic basis of IRDs may help pinpoint an accurate diagnosis with greater confidence, leading to tailored treatment plans and better outcomes.
Now, talk about the study.
Researchers at the University of Oklahoma set out to broaden the current list of genetic variants implicated in IRDs.
The goal: To identify reasons for negative genetic test results in IRD patients as well as to characterize the phenotype of several of these mutations.
Who was included in the study?
In total, 103 individuals were seen by an ophthalmologist at Dean McGee Eye Institute (DMEI) at the University of Oklahoma Health Sciences Center (OUHSC).
And the evaluations?
Vision was assessed using a Snellen eye chart, while images of the back of the eye (fundus) were retrieved using the Optos camera.
- A retinal specialist diagnosed each participant with an IRD—the majority of patients were diagnosed with retinitis pigmentosa (RP), which affects the photoreceptors, followed by:
- Cone and cone-rod dystrophy (CD/CRD)
- Macular dystrophy
- Pattern dystrophy
- Best disease
- Stargardt disease
- Third branch disorders (familial exudative vitreoretinopathy and X-linked retinoschisis)
Note: Patients were excluded if their retinal complications were due to an autoimmune disorder, infection, or age-related degeneration.
And the investigation itself?
After obtaining informed, written consent, swabs were taken from the inner cheek (the buccal mucosa) for genetic testing.
- Genetic sequencing was done by Blueprint Genetics Laboratory; the gene panel consisted of known IRD mutations, as well as the mitochondrial genome.
Variants identified in each individual’s genetic screening were classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS).
- Other information obtained from each participant included race, age of onset, and family history.
Next up: the findings.
Pathogenic variants were found in 29 genes in 70 of the 103 participants.
The most commonly identified gene was ATP-binding cassette subfamily A, member 4 (ABCA4)—notably: mutations in this gene lead to Stargardt disease—followed by:
- Pattern dystrophy (PRPH2)
- Usher syndrome type 2A (USH2A)
- Bestrophinopathy (BEST1).
Interestingly: Some patients with Bardet–Biedl syndrome (BBS) showcased variants in BBS1, BBS4, and BBS10.
Talk about gene frequency and age of onset.
Of the 70 patients for whom genetic testing was positive, 20 novel variants were identified in 19 patients, consisting of missenses, duplications, insertion–deletion, copy number variants, nonsense, and frameshift mutations.
- To note: “Novel” was defined as not present in the existing literature or in large population databases, such as the Genome Aggregation Database.
Phenotypically: The patients displayed typical symptoms of BEST1, PRPH2, and BBS (BBS1, BBS4, BBS10). Patients with RP showed varying degrees of bone spicule and optic disc pigmentation, as well as vessel attenuation.
The novel variants of genes ALMS1, GNAT1, RAX2, and RDH5 were linked to rare conditions with little published literature about them.
ALMS1: A homozygous ALMS1 duplication VUS…
- May assist in early detection of Alstrom syndrome
GNAT1: A novel homozygous pathogenic variant…
- Found in a patient with autosomal recessive RP
- May result in slow degeneration of rod photoreceptors
RAX2: A heterozygous pathogenic variant and a novel heterozygous VUS…
- Found in patients with autosomal recessive RP
- The heterozygous pathogenic variant: leads to faulty photoreceptor gene regulation during retinal development
RDH5: A heterozygous pathogenic frameshift variant and a novel heterozygous missense variant…
- Found in a patient with fundus albipunctatus
- May result in a shortage of 11-cis retinal and an accumulation of toxic 11-cis retinol, which leads to a characteristic flecked appearance of the retina
Tell me more.
Although every participant had an IRD diagnosis, 32% had a genetic testing that was negative.
Further: Researchers sought to determine factors influencing these results and found that the majority of these patients had no family history.
- These patients were also found to be significantly older (34 ± 19 years) than those patients for whom IRD-associated genetic mutations had been found (9 ± 16 years).
Limitations?
The authors noted a few …
- The genetic testing technology used in this study may not have detected more elusive genetic variants—such as deep intronic mutations, large deletions or duplications, or epigenetic changes—which may also play a role in IRDs. Some genetic variants found may not have been labeled as pathogenic, as they have not yet been found in existing genetic databases
- Underrepresentation of non-Whites in genetic databases made for a higher likelihood that non-White participants had a false negative in their genetic testing, as their genetic variants may not have matched up with the database
- As IRDs may present with symptoms that overlap with other conditions, it is possible that patients with negative genetic testing may have had an IRD-mimicking condition
Expert opinion?
Of the 20 novel variants found in this study, six were reclassified from VUS to likely pathogenic.
Although genetics may play a crucial role in IRD diagnostics in the future, the American College of Medical Genetics and Genomics (ACMG) advises caution in clinical decision-making based on VUS, instead emphasizing the role of personal and family history.
Take home.
Overall, IRDs appear to have a robust spectrum of causative mutations.
The authors advised that further genetic testing is needed to confirm pathogenic variants to enable their use for early detection, treatment planning, counseling, and family planning.