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. 2025 Jul 3;15:23745. doi: 10.1038/s41598-025-08272-z

Diagnostic whole exome sequencing in presumably autosomal recessive inherited retinal dystrophies in an Iranian population

Pam AT Heutinck 1, Adriana I Iglesias 2, Dariush D Farhud 3,4, Marianne van Tienhoven 2, Atiyeh Khoshraftar 5, Marjan Zarif-Yeganeh 5, Sima Kheradmand Kia 6, Mohsen Ghanbari 7, Magda A Smoor 1,7, Caroline CW Klaver 1,7,8,9, Lies H Hoefsloot 2, Alberta AHJ Thiadens 1,#, Virginie JM Verhoeven 1,2,✉,#
PMCID: PMC12229322  PMID: 40610573

Abstract

Advances in genetic testing have improved IRD diagnostics and counseling. To enhance these advances and contribute to an inclusive genetic landscape, this study examines genetic causes in 111 Iranian patients clinically diagnosed with non-syndromic IRD (48% males, > 90% born to consanguineous parents, median age at genetic examination of 37 years (interquartile range 30–42)). Patients were analyzed by ethnicity. Whole exome sequencing using a vision disorder gene panel, including copy number variations analysis, was performed at Erasmus MC. Variants were classified per American College of Medical Genetics and Genomics guidelines, with clinical significance assessed via public databases. Genetic causes were identified in 66 patients (59%) across 31 genes, including 14 novel variants. Five patients were diagnosed with syndromic IRD based on genetic findings. Homozygous variants, indicating autosomal recessive (AR) inheritance, were detected in 62 patients (94%). The most affected genes were CERKL (n = 8), EYS (n = 7), and RPE65 (n = 6), with CERKL most common in Turks (n = 6), RPE65 in Kurds (n = 4), and EYS in Fars (n = 3). Variants of uncertain significance were identified in 35 patients (32%). This study identified 14 novel variants and a high prevalence of AR inheritance, underscoring the necessity of tailored genetic counseling and the importance of incorporating diverse populations into genetic research.

Subject terms: Genetic testing, Medical research, Genetics research

Introduction

Inherited retinal dystrophies (IRD) are a clinically and genetically heterogeneous group of disorders that lead to retinal degeneration. These disorders are caused by pathogenic or likely pathogenic variants in IRD-related genes that result in abnormal functioning or structural alterations of the retinal photoreceptors and retinal pigment epithelium cells, leading to progressive vision loss1. Worldwide, IRD have a prevalence of 1:2000 and are a significant cause of severe vision impairment in children, adolescents, and young adults2–4. Although IRD often present in childhood, their severity and lifelong impact underscore the importance of genetic diagnosis and comprehensive disease characterization across all age groups. Retinitis pigmentosa (RP) is the most common IRD, with a prevalence of 1:4000. Symptoms of RP are night blindness, peripheral vision loss and eventual central vision deterioration5.

Understanding the genetics of IRD has led to significant advances in genetic diagnosis, thereby enabling more effective genetic counseling for patients and their families, as well as facilitating research into potential treatments. Currently, variants in more than 300 genes are known to cause IRD6. Inheritance patterns for IRD vary depending on the causal gene, and understanding these patterns is essential for estimating the risk of disease for offspring and family members during genetic counseling. Autosomal dominant (AD) inheritance can occur across all populations and is generally less influenced by geographic or cultural factors7. In contrast, autosomal recessive (AR) inheritance is more prevalent in populations with higher rates of consanguinity, endogamy, or isolated populations8. These factors significantly increase the risk of AR inheritance, as individuals are more likely to inherit the same pathogenic variant from both parents if it is passed down from a common ancestor9. Such considerations are crucial for effective genetic counseling and the development of potential therapeutic strategies.

In recent years, extensive research has been conducted into therapies for IRD. This resulted in the approval of the first gene therapy, Voretigene neparvovec (Luxturna), which can treat patients with RPE65- related IRD10. Knowing the genetic cause of IRD can also give access to potential (gene) therapeutic options for affected individuals and their families.

Various methods are available to determine the genetic cause of IRD. For example, Sanger sequencing is precise for known and suspected variants but limited in the number of genes that can be tested simultaneously. Whole exome sequencing (WES) or the increasingly used whole genome sequencing (WGS) allow for the simultaneous examination of multiple genes and is preferable when the specific variants are unknown, though it presents added complexity in data interpretation. Notably, the detection rate for IRD using WES has been reported to be substantial, ranging from 55 to 71%11. As genetic testing is not accessible for everyone worldwide, the known genetic landscape might not be representative for all populations. The distribution of the most frequent causative variants in IRD-associated genes varies across populations influenced by multiple factors8,12. In Iran, for example, the rate of consanguineous marriages is approximately 20–50%, increasing the risk of diseases with AR inheritance for offspring. Additionally, the genetic isolation of certain communities, often due to geographical or social factors, further exacerbates the incidence of recessive inheritance patterns, as these populations have a limited gene pool that increases the probability of recessive alleles being expressed13,14.

In this study, we aimed to uncover the genetic cause of presumably autosomal recessive IRD in a cohort of patients living in Iran. By identifying the distribution of causative variants specific to this population, we aimed to enhance genetic counseling for this group of patients and contribute to making the genetic landscape more inclusive for the development of therapies.

Results

A total of 111 unrelated IRD patients (males 48%, females 52%) were enrolled in this study. The median age at time of genetic testing was 37 years (interquartile range (IQR) 30–42). All participants received a diagnosis of non-syndromic RP in Iran. The median age at onset of symptoms was 11 years (IQR 4–20). More than 90% of the cohort was born to consanguineous parents, primarily attributable to first cousin marriages. Autosomal recessive inheritance patterns were evident across all patients according to the pedigrees. Patients were drawn from 3 cities in Iran (Tehran, Tabriz and Kermanshah) and 9 ethnicities were identified. Demographic data is presented in Table 1.

Table 1.

Demographic data of Iranian IRD patients (N=111).

Category Subcategory Value Unit Percentage/IQR
Patients Total 111 n 100%
Males 53 n 48%
Females 58 n 52%
Median Age Overall 37 years (IQR: 30-42)
At symptom onset 11 years (IQR: 4-20)
Different Ethnicity Groups Turk 50 n 45%
Kurd 33 n 30%
Fars 19 n 17%
Other groups 9 n 8%
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The genetic cause was identified in 66 patients (59%), with causative variants found in 31 distinct genes through WES analyses. The highest prevalence (> 5%) was observed in CERKL (12%), EYS (11%), RPE65 (9%), ABCA4 (6%), CRB1 (6%), and RP1 (6%) (Fig. 1). For the two biggest genetic groups the median age at diagnosis was 18 years (IQR 18–22) for the CERKL gene and 15 years (IQR 7–26) for the EYS gene.

Fig. 1.

Fig. 1

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Distribution of involved genes (n = 31) as result of WES analyses in our Iranian cohort. Variants in the CERKL gene were most prevalent.

In total 53 causative variants were found. The causative variants per gene are presented in Table 2. All identified variants were designated as pathogenic or likely pathogenic in accordance with the ACMG criteria. 14 causal variants (26%), found in 12 different genes, were classified as novel variants as they were not reported in literature before (Table 2). In 2 of the 66 patients, in which no causal variants were detected in the first step, subsequent copy number analysis of the genetic data unveiled a causative hemizygous deletion in the RP2 gene. In the multiplex ligation-dependent probe amplification (MLPA) analysis no signal was detected for probes targeting exons 1 through 5 of the RP2 gene.

Table 2.

Pathogenic variants (n=53) in causative genes found in inherited retinal dystrophy patients (n=66). Cohort frequency = the number of cases identified in this study presenting with this variant/combination of variants. †Novel causal variants which have not been documented in patients before (n=14). ‡Identified trough additional copy number variations analysis and confirmed with MLPA (MLPA Probemix; P366-B1 CHM-RP2-RPGR, MRC Holland). § Indicates the patients with a syndromic genetic diagnosis. ACMG = American College of Medical Genetics; AF= allele frequency; NA = not available; IRD = inherited retinal dystrophy; RP = retinitis pigmentosa; LCA = leber congenital amaurosis.

Gene Transcript number Zygosity DNA code Protein code Variant classification  ACMG codes Variant type GnomAD AF Associated IRD Cohort frequency
CERKL NM_001030311.2 Homozygous c.1452dup † p.(Pro485fs) Pathogenic PVS1, PM2_sup, PP4 Frameshift NA RP 2
Homozygous c.838G>T † p.(Glu280*) Pathogenic PVS1, PM2_sup, PM3_sup Nonsense NA RP 3
Homozygous c.847C>T  p.(Arg283*) Pathogenic PVS1, PM3, PM2_sup Nonsense 5.93E-04 RP 3
EYS NM_001292009.1 Homozygous c.32dup p.(met12fs) Pathogenic PVS1, PM3, PM2_sup Frameshift 1.55E-05 RP 2
Homozygous c.490C>T  p.(Arg164*)  Pathogenic PVS1, PM3, PM2_sup Nonsense 1.43E-05 RP 2
Homozygous c.2373_2374del p.(Ser792fs) Pathogenic PVS1, PM2_sup, PP4 Frameshift NA RP 2
Homozygous c.6544_6547del p.(Asn2182fs) Pathogenic PVS1, PM3, PM2_sup Frameshift 2.60E-06 RP 1
RPE65 NM_000329.2 Homozygous c.272G>A p.(Arg91Gln) Likely pathogenic PM3_strong, PP4_mod, PM2_sup, PS3_sup, PP3, PP1 Missense 2.91E-05 RP, LCA 2
Homozygous c.354G>A p.? Likely pathogenic PVS1, PM2_sup Splice site 6.20E-07 RP, LCA 1
Homozygous c.119G>A p.(Gly40Asp) Likely pathogenic PM1, PM5, PM2_sup, PP2, PP4 Missense 6.20E-07 RP, LCA 2
Homozygous c.731G>A p.(Gly244Asp) Likely pathogenic PM5, PM2_sup, PP2, PP3, PP4 Missense 6.20E-07 RP,LCA 1
RP1 NM_006269.1 Homozygous c.1012C>T p.(Arg338*) Pathogenic PVS1, PM2_sup, PM3_sup  Nonsense 4.34E-06 RP 1
Homozygous c.4403_4404del † p.(Phe1468*) Pathogenic PVS1, PM2_sup, PP4 Nonsense NA RP 2
Homozygous c.1498_1499del p.(Met500fs) Pathogenic PVS1,PS4_sup, PM2_sup, PM3_sup, PP4 Frameshift 1.12E-05 RP 1
CRB1 NM_001257965.1 Homozygous c.1879T>C p.(Cys627Arg) Likely pathogenic PM1, PM3, PM2_sup, PP4 Missense NA RP,LCA 2
Homozygous c.3673del † p.(Cys1225fs) Pathogenic PVS1, PM2_sup, PP4 Frameshift NA RP, LCA 1
Compound Heterozygous (presumed) c.2027C>T p.(Thr676Met) Pathogenic PM3_strong, PM1, PM5, PM2_sup, PP1, PP3  Missense NA RP,LCA 1
c.1879T>C p.(Cys627Arg) Likely pathogenic PM1, PM5, PM3_sup, PP2_sup, PP3 Missense 7.56E-05
ABCA4 NM_000350.2 Homozygous c.2927del p.(Leu976fs) Pathogenic PVS1, PS4_mod, PM2_sup Frameshift NA RP 1
Homozygous c.4352+1G>A p.? Pathogenic PVS1, PM4_mod, PM2_sup Splice site 4.96E-06 RP 1
Homozygous c.4253+5G>A p.? Likely pathogenic PM3_strong, PM2_sup, PP3 Splice site 7.44E-06 RP, Stargardt disease 1
Homozygous c.5018+2T>C p.? Pathogenic PVS1, PS4_mod, PM2 Splice site 8.05E-06 RP 1
PDE6B NM_000283.3 Homozygous c.1798G>A p.(Asp600Asn) Likely pathogenic PS3_strong, PM2_sup, PP3, PP4 Missense 4.09E-05 RP 2
Homozygous c.1305C>A † p.(Tyr435*) Pathogenic PVS1, PM2_sup Nonsense 1.86E-06 RP 1
FAM161A NM_001201543.1 Homozygous c.1553dup † p.(Ser519fs) Pathogenic PVS1, PM2_sup Frameshift NA RP 1
Homozygous c.1060C>T † p.(Arg354*) Pathogenic PVS1, PM2 sup, PP5  Nonsense 3.72E-06 RP 1
Homozygous c.685C>T p.(Arg229*) Pathogenic PVS1, PM2 sup, PP5 Nonsense 3.72E-06 RP 1
MERTK NM_006343.2 Homozygous c.1450+1G>A p.? Likely pathogenic PVS1,PM2 sup Splice site NA RP 1
Homozygous c.2219C>T p.(Ala740Val) Likely pathogenic PM2 sup, PP3, PM1, PM3, PP5 Missense 1.24E-06 RP 1
COL18A1 ENST00000400337.6 Homozygous c.2824_2831del p.(Gly942fs) Pathogenic PVS1, PM2sup  Frameshift NA Knobloch syndrome§  1
Homozygous c.3834_3847del p.(Ser1279fs) Pathogenic PVS1, PM2 sup  Frameshift NA Knobloch syndrome§  1
CNGB1 NM_001297.4 Homozygous c.2185C>T p.(Arg729*) Pathogenic PVS1, PM2 sup, PP5  Nonsense 2.11E-05 RP 1
CDHR1 NM_033100.4 Homozygous c.338del p.(Gly113fs) Pathogenic PVS1, PM2 sup, PP5  Frameshift 9.30E-06 RP, Cone-rod dystrophy 1
Homozygous c.1991del † p.(Pro664fs) Pathogenic PVS1, PM2 sup, PP5  Frameshift 3.10E-06 RP, Cone-rod dystrophy 1
BBS12 NM_001178007.1 Homozygous c.265_266del p.(Leu89fs) Pathogenic PVS1, PM2 sup, PP5  Frameshift 4.96E-06 Bardet-Biedl syndrome§  2
ALMS1 NM_015120.2 Homozygous c.2311_2312del p.(IIe771fs) Pathogenic PVS1, PM2 sup, PP5  Frameshift 4.96E-06 Alstrom syndrome§  1
ARMC9 NM_001271466.3 Homozygous c.879G>A p.(Thr293=) Likely pathogenic PVS1, PM2 sup, PP5  Splice site 1.30E-05 Joubert syndrome§  1
KCNJ13 NM_002242.4 Homozygous c.496C>T p.(Arg166*) Pathogenic PVS1, PM2 sup, PP5  Nonsense 1.30E-05 LCA 1
LCA5 NM_181714.3 Homozygous c.1099-2A>G † p.? Likely pathogenic PVS1, PM2sup  Splice site NA RP, LCA 1
MFSD8 NM_152778.2  Homozygous c.1235C>T p.(Pro412Leu) Likely pathogenic PM3, PP3, PM2sup, PP2, PS3, PP1, PP5 Missense NA Macular dystrophy with central cone involvement 1
PCARE NM_001029883.2 Homozygous c.1785_1786dup † p.(Ser596fs) Likely pathogenic PVS1, PM2sup  Frameshift 7.44E-06 RP 1
PDE6A NM_000440.2 Homozygous c.769C>T p.(Arg257*) Pathogenic PVS1, PM2 sup, PP5  Nonsense NA RP 1
PDE6G NM_002602.3 Homozygous c.56delG p.(Gly19fs) Likely pathogenic PVS1, PM2 sup  Frameshift 2.48E-05 RP 1
PROM1 NM_001145847.1 Homozygous c.1596T>A † p.(Tyr532*) Likely pathogenic PVS1, PM2 sup  Nonsense NA RP, Cone-rod dystrophy 1
RDH12 NM_152443.2 Homozygous c.379G>T p.(Gly127*) Pathogenic PVS1, PM2 sup, PP5  Nonsense NA RP, LCA 1
RLBP1 NM_000326.4 Homozygous c.203del p.(Glu68fs) Pathogenic PVS1, PM2 sup, PP5  Frameshift NA RP, Bothnia retinal dystrophy 1
RP1L1 NM_178857.5 Heterozygous c.2464C>T  p.(Arg822*) Pathogenic PVS1, PS4_mod, PM2_sup Nonsense 2.23E-05 Occult macular dystrophy 2
RPGRIP1 RIMS2 NM_020366.3 Homozygous c.2690del † p.(Ala897fs) Likely pathogenic PVS1, PM2 sup  Frameshift NA Cone-rod synaptic disorder 1
NM_001348495.1 c.728del † p.(Lys243fs) Likely pathogenic PVS1, PM2 sup  Frameshift NA LCA, Cone-rod dystrophy
USH2A NM_206933.2 Homozygous c.11549-2A>T † p.? Likely pathogenic PVS1, PM2 sup  Splice site NA RP, Usher syndrome  1
TULP1 PEX6 NM_003322.5 Homozygous c.1256G>A p.(Arg419Gln) Pathogenic PM3, PP3, PM2 sup, PM5, PM1, PP5 Missense NA RP,LCA 1
NM_000287.3 c.1802G>A p.(Arg601Gln) Pathogenic PP3, PM2 sup, PM5, PP5 Missense 9.38E-06
RP2 NM_006915.2 Hemizygous g.(?_46696636)_(46739238_?)del ‡ Pathogenic CNV overlaps with established Haploinsufficient (HI) gene.  Deletion  3.09E-03 RP 2
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The inheritance pattern of the resolved patients was autosomal recessive in 62 patients, with 61(92%) cases demonstrating homozygosity for the identified variants, while one individual (2%) likely displayed compound heterozygosity. Familial segregation analysis could not be performed to confirm the variants were in trans. The inheritance pattern was X-linked recessive for the two patients with the hemizygous deletion in the RP2 gene and autosomal dominant for the two patients with the heterogenous variant in RP1L1. For 5 patients, the genetic results led to the diagnosis of syndromic IRD (Bardet-Biedl syndrome (n = 2, BBS12 gene), Knobloch syndrome (n = 2, COL18A1 gene) and Joubert syndrome (n = 1, ARMC9 gene)) instead of non-syndromic RP (Table 2). For 3 patients (MFSD8 (n = 1) and RP1L1 (n = 2) gene), the genetic result led to the diagnosis of macular dystrophy instead of non-syndromic RP (Table 2).

In 35 patients (32%), potential causative variants were identified, as outlined in Table 3. These variants were classified as variants of uncertain significance (VUS) according to the ACMG criteria.

Table 3.

Potentially causative variants per gene in 35 inherited retinal dystrophy patients. Cohort frequency = the number of cases identified in this study presenting with this variant/combination of variants. ACMG = American College of Medical Genetics; VUS = variant of uncertain significance; AF= allele frequency; NA = not available.

Gene Transcript number Zygosity DNA code Protein code ACMG ACMG codes GnomAD AF Cohort frequency
BBS2 NM_031885.3 Homozygous c.54G>A  p.(Met18Ile)  VUS PM2 NA 3
ABCA4 NM_000350.2 Homozygous c.6282G>T  p.(Leu2094=) VUS PM2 sup NA 1
Homozygous c.5882G>A  p.(Gly1961Glu) Pathogenic (risk factor) PS3, PM2 sup, PM5, PP3, PP2, PP5 3.00E-03
Homozygous c.1937+1G>A  p.? Pathogenic PVS1, PM2 sup, PP5  6.21E-06 1
Homozygous c.5329A>G  p.(Met1777Val) VUS PM2 sup, PM5, PM1, PP3, PP2 6.20E-07
Homozygous c.5603A>T  p.(Asn1868Ile) Hypomorphic allel PP2, BS1, BS3 5.58E-02
Homozygous c.2240T>G  p.(Leu747Arg) VUS PM2 sup, PP2 NA 1
USH2A NM_206933.2 Homozygous c.12878G>A  p.(Gly4293Asp) VUS PM2_sup NA 1
Homozygous c.590C>T  p.(Pro197Leu) VUS PM2_sup, PM1_sup NA 1
Heterozygous c.15143C>T  p.(Ala5048Val) VUS PM2_sup, PP3, PM2_sup 3.28E-05 1
Heterozygous c.9551G>A  p.(Cys3184Tyr) VUS PM2_sup, NA
CRB1 NM_001257965.1 Homozygous  c.3677G>A  p(Arg1226Lys) VUS PM2_sup, PP2, PP3 NA 2
Homozygous  c.3301T>C  p.(Phe1101Leu) VUS PM2_sup, PP2, PP3 NA 1
Homozygous  c.4004T>C  p.(Leu1335Pro) VUS PM2_sup, PP2, PP3 NA 2
Homozygous c.2210G>A p.(Arg737His) VUS PM2 NA 1
MKKS NM_018848.3 Homozygous  c.1655C>A  p.(Ala552Asp) VUS PM2_sup, PP3 NA 1
ASPH NM_004318.3 Homozygous c.269A>G p.(Tyr90Cys) VUS PM2_sup, PP3 2.19E-05 1
RP1 NM_006269.1 Heterozygous c.4403_4404del p.(Phe1468*) Pathogenic PVS1, PM2_sup  NA
MERTK NM_006343.2 Homozygous c.698A>C  p.(Gln233Pro) VUS PM2 NA 1
CSPP1 NM_001363131.1 Homozygous c.3028G>A  p.(Val1010Ile) VUS PM2 3.59E-05
RDH12 NM_152443.2 Homozygous  c.836G>C  p.(Gly279Ala) VUS PM2 NA 1
RAX2 NM_001319074.1 Homozygous  c.221G>A  p.(Arg74Gln) VUS PM2 2.10E-04
SCAPER NM_001353009.1 Homozygous  c.682G>A  p.(Ala228Thr) VUS PM2 2.48E-06
TULP1 NM_003322.5 Compound Heterozygous c.901C>T  p.(Gln301*) Pathogenic PVS1, PM2 sup  4.34E-06 2
TULP1 NM_003322.5 c.499+5G>C  p.? VUS PM2 2.97E-05
SEMA4A NM_001193300.1 c.1030_1031del  p.(eu344fs) Pathogenic PVS1, PM2 sup  NA
MERTK NM_006343.2 Homozygous c.698A>C  p.(Gln233Pro) VUS PM2 NA 2
GRIP1 NM_001366722.1 Homozygous c.2662_2664del p.(Glu888del) VUS PM2, PM4 NA 1
PANK2 NM_153638.2 Heterozygous c.338dup p.(Leu115Alafs*66) Pathogenic PVS1, PM2 sup, PP5  3.26E-05
ARHGEF18 NM_001367823.1 Homozygous c.1142C>T  p.(Ala381Val) VUS PM2 2.03E-04 2
AIPL1 NM_014336.4 Homozygous c.59G>A  p.(Gly20Asp) VUS PM2 1.24E-06 2
TULP1 NM_003322.5 Homozygous c.1612A>G  p.(Lys538Glu) VUS PM2, PP3 1.24E-06 2
BBS9 NM_001348038.2 Homozygous  c.1574T>C  p.(Leu525Pro) VUS PM2, PP3 1.24E-06 1
DCT NM_001922.5 Homozygous  c.1067A>G  p.Lys356Arg VUS PM2 NA 2
CERKL NM_001030311.2 Homozygous c.560_568del p.(Tyr187_Val190delinsPhe) VUS PM4, PM2_sup NA 2
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In 10 patients (9%) the genetic cause was not identified. In 4 patients, only single heterozygous pathogenic variants were identified, while no variants were detected in 6 patients.

When comparing the three largest ethnic groups (Turk (N = 27), Kurd (N = 20) and Fars (N = 10), differences in the predominant causal genes were observed between the three cohorts (Fig. 2). Variants in the CERKL gene (N = 6, 22%) were most prevalent among individuals of Turkish descent, while variants in the RPE65 gene (N = 4, 20%) were most prevalent among individuals of Kurdish descent and variants in the EYS gene (N = 3, 30%) were most prevalent among individuals of Fars descent. Figure 3 presents the available fundus color photography of 4 patients with their corresponding genetic outcome.

Fig. 2.

Fig. 2

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Comparing the most frequent causal genes in the three largest ethnic groups. Between the three largest group variants in the CERKL gene were most prevalent in the Turks, variants in the RPE65 gene in the Kurds and variants in the EYS gene in the Fars.

Fig. 3.

Fig. 3

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Color fundus photography of 4 patients of whom a genetic cause was identified.

Discussion

This study provided a comprehensive analysis of the genetic landscape of IRD in an Iranian cohort (N = 111), revealing significant insights specific to this population. The diagnostic yield was 59%, with 94% of the identified cases demonstrating AR homozygous inheritance. This underscores the significant impact of consanguinity on the genetic architecture of IRD in this population. Notably, our study identified 14 previously unreported causal genetic variants across 12 genes, thereby expanding the current spectrum of IRD genetics and contributing to the global knowledge of IRD genetic diversity.

WES was employed using the vision disorders exome sequencing panel from the clinical genetics department at Erasmus MC, University Medical Center, which is specifically designed to capture a wide array of vision-disorder-related genes15. This approach facilitated an in-depth analysis of genetic variations within this Iranian cohort. WES identified causative genetic variants in 59% of the patients, in 31 distinct genes. The variants discovered included a mix of frameshift, nonsense, missense, and splice site mutations, with frameshift mutations being the most prevalent (36%). The most frequently mutated genes were CERKL, EYS, RPE65, RP1, CRB1 and ABCA4, collectively accounting for over half of the detected variants. Particularly, variants in ABCA4, RPE65, and CRB1 have been previously recognized as important causal genes in the Iranian population16,17. These findings highlight the importance of these genes in pathogenesis of IRD in this population. Furthermore, a comparison of the causal genes identified in this study with those in other global populations reveals that these genes are consistently among the most frequently implicated in IRD pathology18,19. Interestingly, variants in USH2A were observed to be less prevalent in our study population compared to other IRD populations20–22.

IRD follow various inheritance patterns. For non-syndromic RP, 15-25% of cases demonstrate AD inheritance, 5-20% AR inheritance and 5–15% are X-linked23. In 62 of the 66 solved cases (94%), the causal variants were homozygous with an AR inheritance pattern, reflecting the high levels of consanguinity in our Iranian cohort. Therefore, genetic analyses in this population should prioritize the filtering of homozygous variants, for which WES is particularly well suited24.

The diagnostic yield in this study is comparable to other studies utilizing WES analysis in specific IRD populations (51–57%)17,20,25. VUS were identified in 35 patients (32%). Due to limited opportunities for further family segregation analysis or additional clinical investigations, the genetic cause could not be definitively established in these cases. Consequently, the diagnostic yield in our population may, in fact, be higher.

Among the six unsolved cases, potential explanations include pathogenic variants in non-coding regions, structural variants undetected by WES, or involvement of unknown disease-associated genes.

This study also emphasized genetic variations among different ethnic groups within Iran. Variants in the CERKL gene were more frequently observed among individuals of Turkish descent, while RPE65 variants were predominant among individuals of Kurdish descent and variants in EYS were most observed in individuals from Fars. These findings highlight the varying prevalence of certain variants among different ethnic groups and emphasize the importance of personalized genetic counseling and diagnostic strategies.

Fourteen novel variants (26%) were identified, this underscores the unique genetic profile of this Iranian population. Furthermore several genetic variants identified in our study, have been recently reported for the first time in various populations. In the CERKL gene, variant c.560_568del9, has been newly documented in an Iranian family26. Similarly, the c.847 C > T variant, was recently discovered in a Pakistani family27. In the EYS gene, variant c.32dupT was first reported in 2017 in an proband from East Indian/Iranian descent, and the c.490 C > T in 2019 in a Chinese family28,29. The c.731G > A variant in the RPE65 gene, classified as a VUS, has been previously reported in a Turkish population30. Additionally, the c.1879T > C variant in the CRB1 gene was recently identified in an Iranian population31. The c.2927delT variant in the ABCA4 gene in an Iranian family, and variant c.2824_2831del8 in the COL18A1 gene in an English cohort, have been reported only once32,33. Lastly, the c.1256G > A variant in the TULP1 gene have been previously reported in one single individual from Saudi-Arabia34. Furthermore several variants are specifically reported in Middle-Eastern and Asian populations35–39. Our findings reinforce the recently reported variants and facilitate the identification of the genetic causes of IRD in these populations in the future.

The novel variants identified in this study were evaluated in gnomAD (v.4.1.0, https://gnomad.broadinstitute.org/), to determine their population frequency. Given the high rate of consanguinity in the Iranian population, some variants may show an elevated frequency within our in-house control cohort. This factor was considered in the interpretation of variant significance.

This study contributes to creating a more inclusive genetic landscape of IRD. To develop a truly representative overview of the genetic landscape of IRD, it is imperative to include all countries in genetic analyses. This inclusivity will enhance our understanding of genetic diversity, reduce health disparities, and improve the development and accessibility of gene-based therapies globally9. As the field of genetics continues to advance, a concerted effort to integrate diverse populations will ensure that the benefits of genetic research are equitably distributed. Ultimately, contributing to better health outcomes for all individuals affected by IRD. Comparing our Iranian cohort with a Dutch IRD cohort revealed both similarities and differences in the most prevalent causal genes40. While certain genes were common to both populations, others were unique to the Iranian cohort, representing the genetic diversity and population-specific factors influencing IRD prevalence and mutation patterns. In patient care, an awareness of patients’ diverse migration backgrounds is thus essential, as ancestry can significantly influence the genetic factors underlying inherited conditions. By incorporating ancestry into diagnostic considerations, we can improve diagnostic accuracy and provide more tailored patient care, highlighting the value of cultural and genetic diversity in medical practice and research.

Furthermore accurate genetic diagnosis is crucial for effective IRD management and genetic counselling for family and patients, especially when clinical symptoms overlap. In this study, six patients were initially diagnosed with non-syndromic IRD; however, genetic analyses revealed syndromic IRD, indicating the broader implications of some IRD-related variants. Unfortunately, the syndromic diagnosis in these patients could not be clinically confirmed, as prior systemic evaluations were not available. Further clinical assessment would be necessary to fully characterize the systemic manifestations of these cases. Nonetheless, these findings underscore the critical role of genetic testing in identifying syndromic cases that might otherwise go unrecognized.

Genetic diagnostics for IRD in Iran currently cover only a small portion of the affected population. This is largely due to limited local resources and infrastructure, which often necessitate that genetic testing needs to be conducted abroad. For instance, in the first national IRD registry in Iran, only about 20% of registered individuals have undergone genetic testing41. This indicates a gap in access to genetic diagnostics within the country, highlighting the need for further development of local genetic testing capabilities.

To enhance clinical advice informed by genetic outcomes, it is essential to integrate clinical measurements with genetic analyses. In this study, we faced limitations in accessing all clinical data, partly due to variations in diagnostic procedures. However, in clinical practice, the integration of ophthalmic examinations with the genetic outcome is relevant.

In conclusion this study provides a detailed analysis of IRD in an Iranian cohort, highlighting the prevalence of autosomal recessive inheritance due to high grade of consanguinity. The discovery of novel genetic variants expands the understanding of IRD genetic diversity and highlights the importance of including diverse populations in genetic studies to enhance diagnosis, treatment, and equitable access to gene-based therapies globally.

Methods

All patients participating in the study were Iranian residents, who or whose guardians gave written informed consent. This diagnostic cohort study was approved by the research ethics committee of the Islamic Azad university, Tehran, Iran (IR.IAU.QOM.REC.1397.032) and adhered to the principles of the Declaration of Helsinki.

Clinical diagnosis

Patients were enrolled by local ophthalmologists affiliated with Tehran University of Medical Sciences, Iran and were all diagnosed with non-syndromic RP in Iran. The diagnostic process involved ophthalmic assessments, including best-corrected visual acuity, slit-lamp examination, fundus examination, and, when possible, multiple imaging and visual field tests. Classification of patients was done based on ethnicity and on family history included the assessment of consanguinity, defined as a marital union between a couple related as second cousins or closer13. Peripheral blood was extracted for DNA analyses following local standard protocols and stored in Iran before shipment to the Netherlands. All patients underwent genetic testing in Iran, in which only causative mutations in the RHO gene were examined.

Genetic testing

Genetic testing was conducted in 111 patients (53 males (48%) and 58 females (52%)) via whole exome sequencing (WES) at the clinical genetic laboratory of the Erasmus MC, University Medical Centre. DNA was extracted from peripheral blood according to standard protocols. DNA was enriched using the Agilent SureSelectXT Human All Exon version 7 (Agilent Technologies, Santa Clara, CA, USA, Chemical Analysis, Life Sciences, and Diagnostics | Agilent) capture kit and paired-end sequenced on the Illumina platform. Sequencing data were demultiplexed with bcl2fastq2 Conversion Software (version 4.2.4) from Illumina (Illumina, San Diego, CA, USA, Illumina | Sequencing and array solutions to fuel genomic discoveries). Illumina DRAGEN Bio IT Platform was used for read mapping to the human reference genome (GRCh37/hg19) and sequence variant detection. The detected sequence variants were annotated and filtered with Alissa Interpret (Santa Clara, CA, USA, Genomic data analysis software, Alissa Interpret | Agilent) and classified with Alamut Visual (Alamut Visual Plus - SOPHiA GENETICS)15. Filter steps included a gene panel restricted to a set of ~ 500 genes associated with vision disorders, including IRD genes (Vision disorders panel version 11, Klinische Genetica Laboratorium - Laboratoriumspecialisme - Erasmus MC)15.

Copy number variant detection was performed using the BAM multiscale reference method using depth of coverage analysis and dynamical bins in NexusClinical (Nexus Clinical, Weston, Florida, USA, Nexus Clinical EHR Software l Cloud based EMR/EHR Solution). The detected copy number variants are annotated and filtered with the NexusClinical software and classified using UCSC Genome Browser (NCBI37/hg19) (UCSC Genome Browser Home)15. For confirmation, MLPA was used (MRC-Holland SALSA MLPA Probemix P366 CHM-RP2-RPGR).

Variants were classified in accordance with the American College of Medical Genetics and Genomics (ACMG) guideline utilizing Alamut visual, the Combined Annotation Dependent Depletion scoring website (version 1.7, CADD - Combined Annotation Dependent Depletion), and the online Franklin tool (hg19) (Franklin)42. The classifications were pathogenic variant, likely pathogenic variant, VUS, likely benign variant and benign variant.

Patients were categorized into distinct groups based on variant classification and associated literature. Patients considered to have causative variants under the following conditions: the presence of one pathogenic variant in a gene with autosomal dominant or X-linked inheritance; the presence of two heterozygous variants or homozygous pathogenic variants in a gene with autosomal recessive inheritance. Clinical significance of potentially causative variant(s) and previous publications about all variants were evaluated with the help of publicly available databases such as ClinVar (version 25, (ClinVar), Leiden Open Varianten Database (LOVD) (version 3.0, LOVD - An Open Source DNA variation database system) and the Human Gene Mutation Database (HGMD) (version 27, HGMD® home page). A variant was classified as novel if it had no prior documentation in patients within scientific literature or clinical research. All variant nomenclature was verified using Mutalyzer (version 3.0.2, http://mutalyzer.nl)43. GnomAD (version 4.1.0, https://gnomad.broadinstitute.org/) was used to determine the general population allele frequency.

Statistical analysis

We used descriptive statistics (number and percentage for categorical variables; median and IQR for continuous variables) to summarize the baseline patient characteristics. All analyses were performed using SPSS Statistics for Windows, version 21 (IBM Corp., Armonk, NY, USA, IBM SPSS Statistics). Figures 1 and 2 were created by using R statistical package version 4.6.1 for Windows (http://www.r-project.org). Figure 3 was created using Adobe Photoshop 2021 version 26.0.

Author contributions

PH made substantial contributions to the conception and design of the work, the acquisition and the analysis, the interpretation of the data and drafted the work. AG made substantial contributions the analysis, the interpretation of the data and substantively revised it. DF made substantial contributions to the acquisition of the data and substantively revised it. MT made substantial contributions the analysis, the interpretation of the data and substantively revised it. AK made substantial contributions to the acquisition of the data and substantively revised it. MY made substantial contributions to the acquisition of the data and substantively revised it. SK made substantial contributions to the conception of the work, to the acquisition of the data and substantively revised it. MG made substantial contributions to substantively revising the manuscript. MM made substantial contributions to substantively revising the manuscript. CK made substantial contributions to substantively revising the manuscript. LH made substantial contributions the analysis, the interpretation of the data and substantively revised it. AT made substantial contributions to substantively revising the manuscript. VV made substantial contributions to the interpretation of the data substantively revised it. All authors read and approved the final manuscript.

Funding

This work was supported by:

- Erasmus MC fellowship, grant number year 2021 (to V.J.M. Verhoeven).

- Stichting Steunfonds Uitzicht, grant number 2019-18 through the following foundations:

Landelijke Stichting Blinden en Slechtzienden.

Algemene Nederlandse Vereniging Ter Voorkoming van Blindheid.

- Prof.dr. Henkes Stichting (without grant number).

Data availability

The datasets generated and/or analysed during the current study are available in Clinvar accessible through the following accession numbers https://www.ncbi.nlm.nih.gov/clinvar/advanced/):VCV001333339.1, VCV001376723.4, VCV000002364.66, VCV000866202.39, VCV000197186.21, VCV000813179.27, VCV000098857.17, VCV001066312.8, VCV002432988.3, VCV001416666.4, VCV000871848.34, VCV000437947.4, VCV002202908.2, VCV000005733.57, VCV002202908.2, VCV000191353.1, VCV000236113.7, VCV000236110.10, VCV000099338.39, VCV001070411.11, VCV000000035.40, VCV000979015.1, VCV000438063.1, VCV001432098.6, VCV000437971.8, VCV000037292.10, VCV000554330.31, VCV000522606.10, VCV000030331.2, VCV000001005.22, VCV000437984.37, VCV002145538.1, VCV000002051.38, VCV000191207.10, VCV000198709.69, VCV000007888.101, VCV000099104.40, VCV000099390.51, VCV001213905.1, VCV000812446.3, VCV002159687.2, VCV000828151.36. Registration of novel variants in ClinVar will be carried out through the VKGL shared initiative (https://www.vkgl.nl/nl/diagnostiek/vkgl-datashare-database). Once this process is complete, we will provide the publicly available accession numbers.

Declarations

Ethics approval and consent to participate

This diagnostic cohort study was approved by the research ethics committee of the Islamic Azad university, Tehran, Iran (IR.IAU.QOM.REC.1397.032) and adhered to the principles of the Declaration of Helsinki.

Consent for publication

Written informed consent was obtained from the patients and/or guardians.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author contribution

Alberta A.H.J. Thiadens and Virginie J.M. Verhoeven contributed equally.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets generated and/or analysed during the current study are available in Clinvar accessible through the following accession numbers https://www.ncbi.nlm.nih.gov/clinvar/advanced/):VCV001333339.1, VCV001376723.4, VCV000002364.66, VCV000866202.39, VCV000197186.21, VCV000813179.27, VCV000098857.17, VCV001066312.8, VCV002432988.3, VCV001416666.4, VCV000871848.34, VCV000437947.4, VCV002202908.2, VCV000005733.57, VCV002202908.2, VCV000191353.1, VCV000236113.7, VCV000236110.10, VCV000099338.39, VCV001070411.11, VCV000000035.40, VCV000979015.1, VCV000438063.1, VCV001432098.6, VCV000437971.8, VCV000037292.10, VCV000554330.31, VCV000522606.10, VCV000030331.2, VCV000001005.22, VCV000437984.37, VCV002145538.1, VCV000002051.38, VCV000191207.10, VCV000198709.69, VCV000007888.101, VCV000099104.40, VCV000099390.51, VCV001213905.1, VCV000812446.3, VCV002159687.2, VCV000828151.36. Registration of novel variants in ClinVar will be carried out through the VKGL shared initiative (https://www.vkgl.nl/nl/diagnostiek/vkgl-datashare-database). Once this process is complete, we will provide the publicly available accession numbers.

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