Genetics of inherited retinal dystrophies – Global insights and the importance of Omani research

Inherited retinal dystrophies (IRDs) comprise a spectrum of genetic disorders characterized by the progressive degeneration of photoreceptors and other retinal cells, resulting in visual impairment and, often, blindness.[1,2] While uncommon, IRDs are likely underdiagnosed because of limited awareness of their range of symptoms and signs, limited access to electrodiagnostics, and inadequate molecular diagnostic capabilities. Milder forms, in particular, may go unnoticed, which can lead to delays or missed diagnoses.

According to recent major reviews, over 307 genes have been linked to IRDs, with many of them linked to multiple genes.[1,3,4] The genetic heterogeneity of IRDs is profound. Molecular genetic testing laboratories worldwide use computational algorithms and classification guidelines to categorize genetic variants as benign, likely benign, variants of uncertain significance, likely pathogenic, or pathogenic.[4,5] This ensures accuracy in diagnosis and patient management.

Accurate interpretation of genetic variants associated with IRDs is crucial for accurate diagnosis, prognosis, and genetic counseling, especially for at-risk family members. Furthermore, identifying the underlying genetic cause is essential for determining eligibility for emerging gene-based or targeted therapies, which hold immense promise for various IRD subtypes.[2,6]

The Global Landscape of Inherited Retinal Dystrophy Genetics

The prevalence and genetic profiles of IRDs vary across different populations, influenced by factors such as genetic diversity, consanguinity rates, and diagnostic accessibility. Certain genes exhibit higher prevalence in specific ethnic or geographic groups.[2,3,4,5,6,7]

Regional Insights into Inherited Retinal Dystrophy Epidemiology [Table 1]

Table 1.

Inherited retinal dystrophy by country and region

Country/region	Study – key features	Most common clinical form(s)	Most common gene(s)
Italy[2]	n=2790 Single-center-based Diagnostic rate - 2036/2790 (72.9%)	Stargardt disease	ABCA4 (26.3%), USH2A (11.2%), RPGR (5.0%)
Germany[3]	n=2158; 1785 families (9-years) Single-center-based Nine gene panel designs (128–379 genes) were used	RP, Achromatopsia, Alström (after reclassification)	ABCA4, RPGR, RP2, ALMS1, PRPH 2, USH2A
Japan[4]	n=1204 RP cohort Diagnostic rate - 29.6% 6 genes=65.4%	RP	EYS, USH2A, RP1L1, RHO, RP1, RPGR
Taiwan[6]	IRD families n=312 NGS targeting 212 IRD-related genes Pathogenic variants in 57.1%	Mixed IRD spectrum	ABCA4 (most common), other variants reported
Brazil[5]	n=1246	Nonsyndromic RP (35%), Stargardt (21%), LCA (9%)	ABCA4, USH2A, CEP290, RPGREYS, RPE65
Egypt[1]	n=971 IRD cases Single-center-based Diagnoses relied on clinical examination for 70.2% of cases	Isolated RP (78.9%), Stargardt (6.3%), cone-rod dystrophy 2.0%), ARB (1.9%)	Not specified
Israel[8]	n=9396 Nationwide prevalence ≈0.1% (1:1043) Most diagnoses relied solely on clinical features	RP is the most common, followed by cone-rod dystrophy, Stargardt, Usher syndrome, Congenital Stationary Night Blindness	Not specified
Saudi Arabia[9]	CSNB cohort Literature review	CSNB (complete and incomplete), Fundus albipunctatus	TRPM1, CABP4, RIMS2, GNB3, GUCY2D, ABCA4, RDH5, RPE65
Arab World[10]	1621 individuals 16 Arab countries Systematic review	Rod-cone dystrophy (nonsyndromic), Usher syndrome (syndromic)	TULP1, ABCA4, RP1, CRB1, MYO7A, RPE65, KCNV2, IMPG2
Global meta-analysis[7]	22 studies; 21,530 probands Systematic review	Regional variation (Europe, Americas, Western Pacific)	ABCA4 (12.9%), USH2A (6.8%), RPGR (2.7%), EYS (2.1%), RHO (1.9%)

Table 1 presents the distribution of IRD across various countries and regions. It highlights the key features of the referenced studies along with the most prevalent form of the IRD and the commonly observed genetic mutations in each area. RP: Retinitis pigmentosa, IRD: Inherited retinal dystrophies, NGS: Next generation sequencing, LCA: Leber congenital amaurosis, ARB: Autosomal recessive bestrophinopathy, CSNB: Congenital stationary night blindness

Europe

Studies across Europe reveal diverse genetic landscapes. In Italy, among a large cohort of 2790 patients, molecular diagnoses were made in 2036 (73%) cases. ABCA4 mutations, primarily causing Stargardt disease, were most prevalent (26.3%), followed by USH2A (11.2%), which causes Usher syndrome type 2, and RPGR (5.01%), which causes X-linked retinitis pigmentosa (RP) and cone dystrophy.[2] Similarly, in Germany, analysis of 2158 patients identified 1161 distinct genetic variants across 112 genes. The diagnostic rates varied widely depending on the clinical entity (35%–95%), highlighting the ongoing challenges in diagnosing certain IRD subtypes, such as macular dystrophy. Reclassification was necessary in specific instances. For example, patients initially diagnosed with RP were reassigned to the X-linked RP category after pathogenic variants in RPGR or RP2 were identified. Several very young patients diagnosed with achromatopsia were revised to Alstrom syndrome upon detecting pathogenic variants in ALMS1.[3]

Asia

In Japan, among 1204 RP patients, pathogenic variants were identified in 29.6% of cases, with six genes (EYS, USH2A, RP1 L1, RHO, RP1, and RPGR) accounting for 65.4% of these cases.[4] The spectrum of RP mutations in Japanese patients differs significantly from that found in non-Asian populations, particularly for genes such as EYS and USH2A. In Taiwan, a study of 312 families with IRDs identified disease-causing variants in 57.1%. ABCA4 variants were the most frequent (15.2%).[6] One variant, c.1804C>T, was found to have a high prevalence in Taiwan compared to other East Asian cohorts.

Americas

Among 1246 patients in Brazil, nonsyndromic RP was the most common form, accounting for 35%, followed by Stargardt disease at 21% and Leber congenital amaurosis (LCA) at 9%.[5] The most common disease-causing genes were ABCA4, causing Stargardt disease, forms of cone-rod dystrophy, and EORD; USH2A causing Usher syndrome and nonsyndromic RP; CEP290 causing LCA; RPGR causing X-linked RP; EYS causing autosomal recessive RP; RPE65 causing LCA.[5]

Global Meta-Analysis

A comprehensive 2023 meta-analysis of 22 studies (21,530 probands), published between 2013 and 2022, from 19 countries across Europe (11 studies), the Western Pacific (6 studies), the Americas (4 studies), and the East Mediterranean (1 study) identified ABCA4 (12.9%), USH2A (6.8%), RPGR (2.7%), EYS (2.1%), and RHO (1.9%) as the five most frequently reported IRD genes. Regional patterns varied, highlighting the importance of population-specific studies to identify prevalent mutations and guide targeted genetic testing strategies. In Europe: ABCA4, USH2A, RPGR, RHO, and PRPH 2; in the Americas: ABCA4, USH2A, RPGR, EYS, and CRB1, and in the Western Pacific: EYS, CYP4V2, USH2A, ABCA4, and RPGR.[7] The median genetically solved rate was 61% (range 32%–86%), indicating that a significant proportion of included cases remained genetically undiagnosed.

Research into indigenous populations has further revealed distinct gene-disease associations, such as rod-cone dystrophy in the Diné (Navajo Nation) and Bardet–Biedl syndrome in the Bedouin populations of the Middle East.[11]

Inherited Retinal Dystrophies in Arab Populations

Data concerning IRDs in Arab countries are relatively limited. However, studies consistently point to a high prevalence of autosomal recessive IRDs. This trend is largely attributable to the high rates of consanguinity prevalent in many Arab communities.

Saudi Arabia

A literature review in Saudi Arabia on patients with congenital stationary night blindness (CSNB) identified 24 patients. Mutations in TRPM1 for complete CSNB with myopia, and CABP4 for incomplete CSNB with hyperopia were reported as predominant mutations alongside novel mutations in RIMS2, GNB3, GUCY2D, and ABCA4. Cases of fundus albipunctatus were associated with mutations in RDH5 and RPE65.[9]

Egypt

A recent hospital-based analysis of 478,222 patients revealed a prevalence of 971 (0.2%) IRD cases, with isolated RP accounting for 78.9% cases, and Stargardt disease and cone-rod dystrophy comprising 6.3% and 2.0%, respectively. Usher syndrome, the most common syndromic IRD, had a prevalence of 2.4%. However, most diagnoses (70.2%) were made using only a clinical examination. Limited genetic testing means many cases may have been undiagnosed or misclassified.[1]

Israel

A 2024 nationwide study of 9396 individuals with IRDs reported a prevalence of 0.1%, with RP being the most common form (0.04%), followed by cone-rod dystrophy, Stargardt disease, Usher syndrome, and CSNB.[8] This study also included individuals regardless of genetic diagnosis availability, and some diagnoses relied solely on clinical features.

Pan-Arab analysis

A review of 198 studies across 16 Arab countries, including Saudi Arabia (47%), Tunisia (14%), and the United Arab Emirates (9%), identified rod-cone dystrophy as the most prevalent nonsyndromic form and Usher syndrome as the leading syndromic form of IRD. Commonly implicated genes included TULP1, ABCA4, RP1, CRB1, MYO7A, RPE65, KCNV2, and IMPG2, with notable regional differences in mutation patterns. For instance, TULP1, RP1, and ALMS1 were prominent in Saudi Arabia, whereas ABCA4, IMPG2, and CNG3 were significant in the United Arab Emirates, ABCA4, RPE65, and GPR98 in Tunisia, and RP1 and PDE6B in Kuwait.[10] In Arab populations, consanguinity is a significant factor contributing to the high frequency of certain IRD genes, particularly those with founder mutations.

These genetic studies are crucial steps toward improving diagnostic and treatment options across these diverse populations.

The Case for Genetic Studies in Oman

Oman shares important demographic traits with other Arab countries, especially a high consanguinity rate, which is likely to result in a higher occurrence of autosomal recessive IRDs within its population. Studies from Oman are limited, contributing only 0.8% to the broader Pan-Arab analysis of IRD genetics.[10] This highlights a pressing need for targeted genetic research within the Sultanate.

Dedicated genetic research in Oman is crucial for:

1. Epidemiological insight: Understanding the prevalence, distribution, and clinical and genetic spectrum of IRDs

2. Healthcare planning and resource allocation: Robust epidemiological data will guide the development of specialized centers for the diagnosis and management of IRDs. This will enable the development of targeted public health strategies and optimize resource allocation to achieve better health outcomes for affected individuals and families

3. Accurate genetic counselling: With precise knowledge of common genetic mutations, healthcare providers can offer accurate risk assessments and personalized genetic counselling to Omani families, empowering them with essential information for family planning and disease management

4. Therapeutic access: A thorough understanding of Oman’s specific genetic landscape for IRDs can enable Omani patients to participate in ongoing clinical trials and future gene-specific therapies, providing hope and tangible solutions for those affected.

Conclusion

IRDs are a major cause of visual impairment worldwide, but their prevalence and genetic profiles vary greatly across populations. While significant progress has been made in understanding their genetic complexities in many parts of the world, a gap remains regarding data from Arab countries, especially Oman. Given Oman’s unique demographic profile, characterized by high consanguinity rates and a likely predisposition to autosomal recessive IRDs, comprehensive genetic studies in Oman are not just beneficial; they are imperative. Such research will lay the groundwork for improved diagnostic, counseling, and therapeutic services tailored to the needs of the Omani population, ultimately improving patient outcomes.