Inherited retinal disorders (IRDs) are genetically heterogeneous vision disorders, including conditions such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), and congenital achromatopsia. This study aimed to identify the underlying genetic causes of IRDs in six consanguineous Iranian families. We performed whole-exome sequencing (WES) on probands from six families with IRDs. Putative pathogenic variants were validated and analyzed for segregation in family members using Sanger sequencing. We identified six homozygous, likely causative variants in five distinct IRD- associated genes. A novel frameshift variant, c.408delG (p.Val136fs), in CNGB3 led to a definitive diagnosis of achromatopsia in one family, revising the initial clinical impression. A novel missense variant, c.G1216A (p.Glu406Lys), was identified in IFT140 in a patient with RP. Previously reported pathogenic variants were found in TULP1 (c.1199G>A; p.Arg400Gln) and MERTK (c.392G>A; p.Trp131Ter) in two families with RP. In two other families with LCA, we identified known pathogenic variants in RPE65 (c.1088C>G; p.Pro363Arg and c.858+1delG). All variants segregated with the disease in an autosomal recessive pattern. Our findings expand the mutational spectrum of IRDs and highlight the crucial role of WES in providing precise molecular diagnoses, which can refine clinical classifications and inform genetic counseling. The identification of two novel variants underscores the importance of studying underrepresented populations, such as that of Iran, to fully characterize the genetic architecture of these disorders.
SchneiderNSundaresanYGopalakrishnanP, et al. Inherited retinal diseases: linking genes, disease-causing variants, and relevant therapeutic modalities. Prog Retin Eye Res2022; 89: 101029.
2.
ManleyAMeshkatBIJablonskiMM, et al. Cellular and molecular mechanisms of pathogenesis underlying inherited retinal dystrophies. Biomolecules2023; 13: 271.
3.
PeterVGKaminskaKSantosC, et al. The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis. PNAS Nexus2023; 2: pgad043.
4.
MurroVBanfiSTestaF, et al. A multidisciplinary approach to inherited retinal dystrophies from diagnosis to initial care: a narrative review with inputs from clinical practice. Orphanet J Rare Dis2023; 18: 223.
NarayanDSWoodJPChidlowG, et al. A review of the mechanisms of cone degeneration in retinitis pigmentosa. Acta Ophthalmol201694: 748–754.
7.
AliMURahmanMSUCaoJ, et al. Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario. 3 Biotech2017; 7: 1–20.
8.
Fernandez-San JosePCortonMBlanco-KellyF, et al. Targeted next-generation sequencing improves the diagnosis of autosomal dominant retinitis pigmentosa in Spanish patients. Invest Ophthalmol Vis Sci2015; 56: 2173–2182.
9.
DeilamaniaFK.Novel mutations in patients with retinitis pigmentosa detected by whole exome sequencing. J Hum Genet Genomics2022; 6.
10.
DiasMFJooKKempJA, et al. Molecular genetics and emerging therapies for retinitis pigmentosa: basic research and clinical perspectives. Prog Retin Eye Res2018; 63: 107–131.
11.
BirtelJGliemMMangoldE, et al. Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa. PLoS One2018; 13: e0207958.
12.
YangLCuiHYinX, et al. Dependable and efficient clinical molecular diagnosis of Chinese RP patient with targeted exon sequencing. PLoS One2015; 10: e0140684.
13.
HuangLZhangQHuangX, et al. Mutation screening in genes known to be responsible for retinitis pigmentosa in 98 small Han Chinese families. Sci Rep2017; 7: 1948.
14.
Skorczyk-WernerASowińska-SeidlerAWawrockaA, et al. Molecular background of Leber congenital amaurosis in a Polish cohort of patients—novel variants discovered by NGS. J Appl Genet2023; 64: 89–104.
15.
SatherRIIIIhingerJSimmonsM, et al. The clinical findings, pathogenic variants, and gene therapy qualifications found in a Leber congenital amaurosis phenotypic spectrum patient cohort. Int J Mol Sci2024; 25: 1253.
16.
ChenLWangNLaiM, et al. Clinical and genetic investigations in Chinese families with retinitis pigmentosa. Exp Biol Med (Maywood)2022; 247: 1030–1038.
17.
XinWXiaoXLiS, et al. Late-onset CORD in a patient with RDH12 mutations identified by whole exome sequencing. Ophthalmic Genet2016; 37: 345–348.
18.
BeigiFMehrjardiMYVManaviatMR, et al. Study of patterns of inheritance in affected patients with retinitis pigmentosa in Iranian populations. Int J Med Lab2020.
19.
RezaieTKarimi-NejadM-HMeshkatM-R, et al. Genetic screening of Leber congenital amaurosis in a large consanguineous Iranian family. Ophthalmic Genet2007; 28224–228.
20.
LiSYangMLiuW, et al. Targeted next-generation sequencing reveals novel RP1 mutations in autosomal recessive retinitis pigmentosa. Genet Test Mol Biomarkers2018; 22: 109–114.
21.
GhiasvandNMShirzadENaghaviM, et al. High incidence of autosomal recessive nonsyndromal congenital retinal nonattachment (NCRNA) in an Iranian founding population. Am J Med Genet1998; 78: 226–232.
22.
KariminejadABarzgarMBozorgmehrB, et al. Novel mutations and a severe neurological phenotype in Sjögren-Larsson syndrome patients from Iran. Eur J Med Genet2018; 61: 139–144.
23.
ParsamaneshNMoossaviMTavakkoliT, et al. Positive correlation between vitamin D receptor gene TaqI variant and gastric cancer predisposition in a sample of Iranian population. J Cell Physiol2019; 234: 15044–15047.
24.
LiHDurbinR.Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics2009; 25: 1754–1760.
25.
McKennaAHannaMBanksE, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res2010; 20: 1297–1303.
26.
Miraldi UtzVCoussaRGAntakiF, et al. Gene therapy for RPE65-related retinal disease. Ophthalmic Genet2018; 39: 671–677.
27.
LiuSBiJGHuY, et al. Targeted next generation sequencing identified novel loss-of-function mutations in MERTK gene in Chinese patients with retinitis pigmentosa. Mol Genet Genomic Med2019; 7: e00577.
28.
ZhongZRongFDaiY, et al. Seven novel variants expand the spectrum of RPE65-related Leber congenital amaurosis in the Chinese population. Mol Vis2019; 25: 204.
29.
SunYLiWLiJK, et al. Genetic and clinical findings of panel-based targeted exome sequencing in a northeast Chinese cohort with retinitis pigmentosa. Mol Genet Genomic Med2020; 8: e1184.
30.
MaDJLeeHSKimK, et al. Whole-exome sequencing in 168 Korean patients with inherited retinal degeneration. BMC Med Genomics2021; 14: 1–12.
31.
RehmanAUSepahiNBedoniN, et al. Whole exome sequencing in 17 consanguineous Iranian pedigrees expands the mutational spectrum of inherited retinal dystrophies. Sci Rep2021; 11: 19332.
32.
SinghHPJalaliSNarayananR, et al. Genetic analysis of Indian families with autosomal recessive retinitis pigmentosa by homozygosity screening. Invest Ophthalmol Vis Sci2009; 50: 4065–4071.
33.
BainbridgeJWSmithAJBarkerSS, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med2008; 358: 2231–2239.
34.
WangXWangHSunV, et al. Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing. J Med Genet2013; 50: 674–688.
35.
HaneinSPerraultIGerberS, et al. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype–phenotype correlations as a strategy for molecular diagnosis. Hum Mutat2004; 23: 306–317.
36.
EisenbergerTNeuhausCKhanAO, et al. Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies. PLoS One2013; 8: e78496.
37.
JacobsonSGCideciyanAVHuangWC, et al. TULP1 mutations causing early-onset retinal degeneration: preserved but insensitive macular cones. Invest Ophthalmol Vis Sci2014; 55: 5354–5364.
38.
ChenXShengXLiuY, et al. Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees. J Transl Med2018; 16: 1–12.
39.
SalmaninejadABedoniNRaveshZ, et al. Whole exome sequencing and homozygosity mapping reveals genetic defects in consanguineous Iranian families with inherited retinal dystrophies. Sci Rep2020; 10: 19413.
