Analysis of <i>CRX</i> gene variants and clinical manifestations in a consanguineous family with Leber congenital amaurosis type 7_Chinese Journal of Ocular Fundus Diseases

Authors：

Ma Jixian , Qin Yazhou ,  Li Jingming

Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710000, China;

Corresponding author：

Li Jingming, Email: jingming_li@126.com

Keywords：

Leber congenital amaurosis type 7; CRX gene; Gene mutation

DOI：

10.3760/cma.j.cn511434-20250319-00119

Video：

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Objective To identify and observe the pathogenic gene variant and clinical phenotype in a family with Leber congenital amaurosis (LCA). Methods A retrospective clinical study. Two patients and four family members from one LCA family (type 7), diagnosed via genetic testing at the First Affiliated Hospital of Xi'an Jiaotong University in January 2024 were included. Detailed patient and family histories were collected. All patients underwent examinations including best-corrected visual acuity (BCVA), intraocular pressure, color fundus photography, fundus autofluorescence (FAF), flash visual evoked potential (F-VEP), full-field electroretinography (ff-ERG), and optical coherence tomography (OCT). Family members underwent BCVA and color fundus photography examinations. Peripheral venous blood (5 ml) was collected from the patients and the four family members for genomic DNA extraction. High-throughput sequencing was used to screen for pathogenic gene variants. Identified variants were verified by Sanger sequencing. All variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Bioinformatics software including Mutation Taster, Polyphen-2, PROVEAN, and REVEL was used to analyze the pathogenicity of the variants. Results The proband (Ⅱ-2), a 14-year-old female, was born to consanguineous parents (first cousins). Her BCVA was 0.1 in both eyes; intraocular pressure was normal; the anterior segments showed no significant abnormalities. Color fundus photography showed waxy optic discs and a "coin-shaped," "salt-and-pepper" appearance in the retina. FAF revealed large areas of hypoautofluorescence in the macular region. OCT showed shallowing or disappearance of the foveal, disorganized retinal layers, and absence of the ellipsoid zone. F-VEP showed recordable P2 waves with no significant delay in peak time but slightly reduced amplitude. ff-ERG showed significantly reduced or non-detectable amplitudes of the scotopic and photopic a- and b-waves. The proband's elder sister (Ⅱ-1) had similar BCVA and fundus findings. The proband's parents (Ⅰ-1, Ⅰ-2), younger brother (Ⅱ-3), and younger sister (Ⅱ-4) showed no significant ocular phenotypic abnormalities. Genetic testing revealed that the proband and her elder sister were homozygous for the CRX gene variant c.122G>A:p.Arg41Gln. The proband's father, mother, and younger brother were heterozygous carriers of the same CRX variant; the younger sister showed no variation at this locus. Based on the clinical presentation, ff-ERG, and genetic test results, the final diagnosis was LCA type 7. According to ACMG guidelines, the c.122G>A variant was classified as likely pathogenic. Mutation Taster and Polyphen-2 software predicted the variant to be damaging; the REVEL score was 0.929, indicating a likely pathogenic variant. Conclusions The homozygous CRX gene variant c.122G>A:p.Arg41Gln causes autosomal recessive LCA type 7 in this family. LCA is characterized by early onset and severe visual impairment.

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10.	Zhu L, Ouyang W, Zhang M, et al. Molecular genetics with clinical characteristics of Leber congenital amaurosis in the Han population of western China[J]. Ophthalmic Genet, 2021, 42(4): 392-401. DOI: 10.1080/13816810.2021.1904417.
11.	Sun C, Chen S. Gene augmentation for autosomal dominant CRX-associated retinopathies[J]. Adv Exp Med Biol, 2023, 1415: 135-141. DOI: 10.1007/978-3-031-27681-1_21.
12.	Leigh A, Swaroop A, Kruczek K, et al. Cone Rod Homeobox (CRX): literature review and new insights[J]. Ophthalmic Genet, 2025, 46(4): 338-346. DOI: 10.1080/13816810.2025.2458086.
13.	Rivolta C, Berson EL, Dryja TP. Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX[J]. Hum Mutat, 2001, 18(6): 488-498. DOI: 10.1002/humu.1226.
14.	Ibrahim MT, Alarcon-Martinez T, Lopez I, et al. A complete, homozygous CRX deletion causing nullizygosity is a new genetic mechanism for Leber congenital amaurosis[J/OL]. Sci Rep, 2018, 8(1): 5034[2018-03-22]. https://pubmed.ncbi.nlm.nih.gov/29568065/. DOI: 10.1038/s41598-018-22704-z.
15.	Xu Y, Xiao X, Li S, et al. Molecular genetics of Leber congenital amaurosis in Chinese: new data from 66 probands and mutation overview of 159 probands[J]. Exp Eye Res, 2016, 149: 93-99. DOI: 10.1016/j.exer.2016.06.019.
16.	Chapi M, Sabbaghi H, Suri F, et al. Incomplete penetrance of CRX gene for autosomal dominant form of cone-rod dystrophy[J]. Ophthalmic Genet, 2019, 40(3): 259-266. DOI: 10.1080/13816810.2019.1622023.
17.	Hahn LC, van der Veen I, Georgiou M, et al. Clinical, genetic, and histopathological characteristics of CRX-associated retinal dystrophies[J]. Ophthalmol Retina, 2025, 9(1): 78-88. DOI: 10.1016/j.oret.2024.08.003.
18.	Yahya S, Smith CEL, Poulter JA, et al. Late-onset autosomal dominant macular degeneration caused by deletion of the CRX hene[J]. Ophthalmology, 2023, 130(1): 68-76. DOI: 10.1016/j.ophtha.2022.07.023.

1. Kumaran N, Moore AT, Weleber RG, et al. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions[J]. Br J Ophthalmol, 2017, 101(9): 1147-1154. DOI: 10.1136/bjophthalmol-2016-309975.
2. Daich Varela M, Cabral de Guimaraes TA, Georgiou M, et al. Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials[J]. Br J Ophthalmol, 2022, 106(4): 445-451. DOI: 10.1136/bjophthalmol-2020-318483.
3. den Hollander AI, Roepman R, Koenekoop RK, et al. Leber congenital amaurosis: genes, proteins and disease mechanisms[J]. Prog Retin Eye Res, 2008, 27(4): 391-419. DOI: 10.1016/j.preteyeres.2008.05.003.
4. Huang CH, Yang CM, Yang CH, et al. Leber's congenital amaurosis: current concepts of genotype-phenotype correlations[J/OL]. Genes (Basel), 2021, 12(8): 1261[2021-08-19]. https://pubmed.ncbi.nlm.nih.gov/34440435/. DOI: 10.3390/genes12081261.
5. Georgiou M, Robson AG, Fujinami K, et al. Phenotyping and genotyping inherited retinal diseases: molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes[J/OL]. Prog Retin Eye Res, 2024, 100: 101244[2024-01-24]. https://pubmed.ncbi.nlm.nih.gov/38278208/. DOI: 10.1016/j.preteyeres.2024.101244.
6. Chirco KR, Chew S, Moore AT, et al. Allele-specific gene editing to rescue dominant CRX-associated LCA7 phenotypes in a retinal organoid model[J]. Stem Cell Reports, 2021, 16(11): 2690-2702. DOI: 10.1016/j.stemcr.2021.09.007.
7. Xu K, Xie Y, Sun T, et al. Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy[J]. Br J Ophthalmol, 2020, 104(7): 932-937. DOI: 10.1136/bjophthalmol-2019-314281.
8. Kumaran N, Pennesi ME, Yang P, et al. Leber congenital amaurosis/early-onset severe retinal dystrophy overview[M]//Adam MP, Feldman J, Mirzaa GM, et al. Gene reviews. Seattle (WA): University of Washington, 2023: …….
9. Zhou Y, Huang L, Xie Y, et al. Clinical and genetic studies for a cohort of patients with Leber congenital amaurosis[J]. Graefe's Arch Clin Exp Ophthalmol, 2024, 262(9): 3029-3038. DOI: 10.1007/s00417-024-06450-9.
10. Zhu L, Ouyang W, Zhang M, et al. Molecular genetics with clinical characteristics of Leber congenital amaurosis in the Han population of western China[J]. Ophthalmic Genet, 2021, 42(4): 392-401. DOI: 10.1080/13816810.2021.1904417.
11. Sun C, Chen S. Gene augmentation for autosomal dominant CRX-associated retinopathies[J]. Adv Exp Med Biol, 2023, 1415: 135-141. DOI: 10.1007/978-3-031-27681-1_21.
12. Leigh A, Swaroop A, Kruczek K, et al. Cone Rod Homeobox (CRX): literature review and new insights[J]. Ophthalmic Genet, 2025, 46(4): 338-346. DOI: 10.1080/13816810.2025.2458086.
13. Rivolta C, Berson EL, Dryja TP. Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX[J]. Hum Mutat, 2001, 18(6): 488-498. DOI: 10.1002/humu.1226.
14. Ibrahim MT, Alarcon-Martinez T, Lopez I, et al. A complete, homozygous CRX deletion causing nullizygosity is a new genetic mechanism for Leber congenital amaurosis[J/OL]. Sci Rep, 2018, 8(1): 5034[2018-03-22]. https://pubmed.ncbi.nlm.nih.gov/29568065/. DOI: 10.1038/s41598-018-22704-z.
15. Xu Y, Xiao X, Li S, et al. Molecular genetics of Leber congenital amaurosis in Chinese: new data from 66 probands and mutation overview of 159 probands[J]. Exp Eye Res, 2016, 149: 93-99. DOI: 10.1016/j.exer.2016.06.019.
16. Chapi M, Sabbaghi H, Suri F, et al. Incomplete penetrance of CRX gene for autosomal dominant form of cone-rod dystrophy[J]. Ophthalmic Genet, 2019, 40(3): 259-266. DOI: 10.1080/13816810.2019.1622023.
17. Hahn LC, van der Veen I, Georgiou M, et al. Clinical, genetic, and histopathological characteristics of CRX-associated retinal dystrophies[J]. Ophthalmol Retina, 2025, 9(1): 78-88. DOI: 10.1016/j.oret.2024.08.003.
18. Yahya S, Smith CEL, Poulter JA, et al. Late-onset autosomal dominant macular degeneration caused by deletion of the CRX hene[J]. Ophthalmology, 2023, 130(1): 68-76. DOI: 10.1016/j.ophtha.2022.07.023.

Chinese Journal of Ocular Fundus Diseases

Latest ArticlesAnalysis of CRX gene variants and clinical manifestations in a consanguineous family with Leber congenital amaurosis type 7

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