Findings from a recent study published in the American Journal of Ophthalmology assessed changes in the prevalence and incidence of inherited retinal diseases (IRDs) in the United States.
Give me some background.
IRDs are a diverse group of genetic conditions characterized by photoreceptor degeneration and subsequent vision loss.
- Note: Over 300 genes have been implicated in their pathogenesis—increasing the diagnostic challenges for this disease class.
However: Advances in genetic sequencing—particularly next-generation sequencing (NGS)—have revolutionized the diagnosis of these conditions and led to more cost efficient methods to identify common pathogenic variants in hundreds of potential genes simultaneously.
- In addition: Advancements in genetic engineering approaches, coupled with NGS, have led to a surge in therapeutic innovations, such as gene therapy.
Keep going…
The first retinal gene therapy in the United States was Spark Therapeutics’ Luxturna (voretigene neparvovec-rzyl), approved by the FDA in 2017 for the treatment of Leber congenital amaurosis (LCA) caused by RPE65 mutations.
- Note: While no additional gene therapies have been approved since then, there are currently 30+ IRD gene therapy trials underway.
As these therapies progress and come to market, it is essential to understand the epidemiology of IRDs in the United States to estimate how many patients may be impacted—as for many of these conditions, the U.S.-based prevalence data are sparse, outdated, or nonexistent.
- For example: The most recent prevalence figure for retinitis pigmentosa in the U.S. comes from a study conducted in Maine over 40 years ago.
With rapid advances in diagnostic technology, data from even a few years ago may not reflect the current landscape, particularly since clinical trials require a confirmed genetic diagnosis for eligibility.
Now talk about this study.
In this cross-sectional study, investigators utilized the U.S. Collaborative Network within the TriNetX platform to analyze electronic health record (EHR) data of patients with IRDs from 2016 to 2023.
- The U.S. Collaborative Network hosts EHR data of over 117 million U.S. patients and 68 healthcare organizations—representing over ⅓ of the total U.S. population.
The study included patients with International Classification of Diseases, Tenth Revision (ICD-10) codes for the following IRDs:
- Pigmentary retinal dystrophy (retinitis pigmentosa; H35.63)
- Choroideremia (H31.21)
- Achromatopsia (H53.51)
- Congenital night blindness (H53.63)
- Hereditary retinal dystrophy (H35.5)
And the findings?
In 2023, the overall prevalence of all included IRDs was 106 per 100,000 persons—a 1.84-fold (95% confidence interval [CI]: 1.81-1.87) increase from 2016.
Annual incidence also increased significantly, from 12.5 per 100,000 in 2016 to 15.5 per 100,000 in 2023 (incidence ratio [IR]: 1.24, 95% CI: 1.19-1.28).
Males exhibited a significantly higher risk of certain IRDs, including:
- Choroideremia (male to female prevalence odds ratio [POR]: 5.17, 95% CI: 4.07-6.59)
- Congenital night blindness (male to female POR: 2.58, 95% CI: 2.11-3.15)
- Achromatopsia (male to female POR: 1.65, 95% CI: 1.43-1.91)
Anything else?
White patients were disproportionately affected compared to Black and Hispanic populations for nearly all IRDs.
- Interestingly: A 2020 global study found that the genetic prevalence of autosomal recessive IRDs was nearly identical between European and African populations.
Additionally: Age distribution varied by condition, but the prevalence of all hereditary retinal dystrophies combined increased with rising age.
Expert opinion?
The study authors hypothesized that the increased incidence and prevalence of IRDs may be a result of “a greater diagnostic ability and motivation, rather than a true increase in the occurrence of these conditions.”
Moreover: They noted that a majority of genomic studies have included only individuals of European ancestry, likely resulting in undiscovered genes that cause IRDs in those of African ancestry.
- Meaning: “This, in conjunction with other known barriers to accessing ophthalmic care for minorities in the U.S., likely contribute to the disparities reported in this study, and an underestimation of the prevalence of these conditions in minority populations.”
Limitations?
These included:
- Reliance on ICD encounter diagnosis codes introduces uncertainty as coding is not always carried out accurately in a clinical setting
- Without clinical and genetic testing information, the research team was unable to confirm the accuracy of the encounter diagnosis code
- Only some IRDs have their own unique ICD-10 code, limiting the number of conditions that could be evaluated
- TriNetX lacks socioeconomic information, further limiting further analysis of the reported racial and ethnic disparities
- Certain patient populations may also be underrepresented, such as rural patients who have more difficulty accessing the specialized providers needed to diagnose an IRD
Tie it all together.
These findings demonstrate an increasing incidence and prevalence of IRDs in the U.S.
Disparities in the prevalence of these conditions by race highlight a potential gap in the understanding of genetic disease in diverse populations.