A novel variant of the NDP gene results in Norrie disease in a Vietnamese patient
Author affiliations
DOI:
https://doi.org/10.15625/vjbt-24007Keywords:
FEVR, NDP gene, Norrie disease, retinal disorder, Sanger sequencing, WES.Abstract
Norrie disease is an X-linked recessive inherited disorder caused by pathogenic variants in the NDP gene. Common symptoms of Norrie include abnormal ophthalmological features, such as retinal detachment, cataract, iris atrophy, and corneal opacity, which could result in peripheral vascular disorder and behavioral, learning, or hearing impairments. This study reports the case of a two-month-old male infant who presented with severe ocular manifestations, including retinal detachment, vitreoretinal proliferation, cataract, and microphthalmia. Recently, molecular diagnosis played a crucial role in clarifying the underlying genetic causes of not only retinal disorders but also Norrie disease. In this study, we employed whole-exome sequencing (WES) to detect the pathogenic mutation of the patient. WES analysis of the proband identified a novel hemizygous frameshift variant in the NDP gene, c.77delC (p.T26Ifs*15), which is associated with Norrie disease and classified as likely pathogenic according to the ACMG/AMP guidelines. Concurrently, WES revealed a known heterozygous nonsense variant in the ATP7B gene, c.314C>A (p.S105*), associated with Wilson syndrome. Segregation analysis within the family by Sanger sequencing showed that the proband inherited the NDP c.77delC variant from his asymptomatic heterozygous mother, and the ATP7B c.314C>A variant from his heterozygous father. The proband’s sister was negative for both variants. The family received genetic counselling regarding the diagnosis and implications of the identified variants for future offspring. This case emphasizes the clinical value of integrating detailed ophthalmological assessment with comprehensive genomic testing to elucidate overlapping early-onset retinal phenotypes. These findings contribute to understanding the genetic etiology of severe pediatric retinal disorders in Vietnam and underscore the utility of comprehensive genetic testing like WES in achieving the precise molecular diagnosis.
Downloads
References
Dan H., Wang D., Huang Z., Shi Q., Zheng M., Xiao Y, et al. (2022). Whole exome sequencing revealed 14 variants in NDP, FZD4, LRP5, and TSPAN12 genes for 20 families with familial exudative vitreoretinopathy. BMC Medical Genomics, 15(1), 54. https://doi.org/10.1186/S12920-022-01204-0
De Silva S. R., Arno G., Robson A. G., Fakin A., Pontikos N., Mohamed M. D, et al. (2021). The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies. Progress in Retinal and Eye Research, 82, 100898. https://doi.org/10.1016/J.PRETEYERES.2020.100898
Donnai D., Mountford R. C., and Read A. P. (1988). Norrie disease resulting from a gene deletion: clinical features and DNA studies. Journal of Medical Genetics, 25(2), 73–78. https://doi.org/10.1136/JMG.25.2.73
Gong Y., Liu Z., Zhang X., Shen S., Xu Q., Zhao H, et al. (2022). Endolymphatic hydrop phenotype in familial Norrie disease caused by large fragment deletion of NDP. Frontiers in Aging Neuroscience, 14, 771328. https://doi.org/10.3389/fnagi.2022.771328
Hayashi Y., Chiang H., Tian C., Indzhykulian A. A., and Edge A. S. B. (2021). Norrie disease protein is essential for cochlear hair cell maturation. Proceedings of the National Academy of Sciences of the United States of America, 118(39), e2106369118. https://doi.org/10.1073/pnas.2106369118
Huang X., Tian M., Li J., Cui L., Li M., and Zhang J. (2017). Next-generation sequencing reveals a novel NDP gene mutation in a Chinese family with Norrie disease. Indian Journal of Ophthalmology, 65(11), 1161. https://doi.org/10.4103/IJO.IJO_442_17
Huong N. T. M., Hoa N. P. A., Ngoc N. D., Mai N. T. P., Yen P. H., Anh H. T. V, et al. (2022). Mutation spectrum of ATP7B gene in pediatric patients with Wilson disease in Vietnam. Molecular Genetics and Metabolism Reports, 31, 100861. https://doi.org/10.1016/J.YMGMR.2022.100861
Jia L. Y., and Ma K. (2021). Novel Norrie disease gene mutations in Chinese patients with familial exudative vitreoretinopathy. BMC Ophthalmology, 21(1), 84. https://doi.org/10.1186/S12886-021-01852-3
Le V., Abdelmessih G., Dailey W. A., Pinnock C., Jobczyk V., Rashingkar R, et al. (2023). Mechanisms underlying rare inherited pediatric retinal vascular diseases: FEVR, Norrie Disease, persistent fetal vascular syndrome. Cells, 12(21), 2579. https://doi.org/10.3390/CELLS12212579
Lu J., Huang L., Sun L., Li S., Zhang Z., Jiang Z, et al. (2022). FZD4 in a large Chinese population with Familial Exudative Vitreoretinopathy: molecular characteristics and clinical manifestations. Investigative Ophthalmology & Visual Science, 63(4), 7. https://doi.org/10.1167/IOVS.63.4.7
Luvisi J. R., and Blair K. (2025). Familial Exudative Vitreoretinopathy (FEVR). StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK614159/
Ohlmann A., and Tamm E. R. (2012). Norrin: Molecular and functional properties of an angiogenic and neuroprotective growth factor. Progress in Retinal and Eye Research, 31(3), 243–257. https://doi.org/10.1016/J.PRETEYERES.2012.02.002
Pham L. A. T., Nguyen T. T., Nga Le H. B., Tran D. Q., Ho C. T., Tran T. H, et al. (2017). Genetic analysis of 55 northern Vietnamese patients with Wilson disease: seven novel mutations in ATP7B. Journal of Genetics 2017 96:6, 96(6), 933–939. https://doi.org/10.1007/S12041-017-0857-9
Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., et al. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine: official journal of the American College of Medical Genetics, 17(5), 405–424. https://doi.org/10.1038/gim.2015.30
Rivera-Vega M. R., Chiñas-Lopez S., Jimenez Vaca A. L., Arenas-Sordo M. L., Kofman-Alfaro S., Messina-Baas O, et al. (2005). Molecular analysis of the NDP gene in two families with Norrie disease. Acta Ophthalmologica Scandinavica, 83(2), 210–214. https://doi.org/10.1111/J.1600-0420.2005.00398.X
Shastry B. S., Hiraoka M., Trese D. C., and Trese M. T. (1999). Norrie disease and exudative vitreoretinopathy in families with affected female carriers. European Journal of Ophthalmology, 9(3), 238–242. https://doi.org/10.1177/112067219900900312
Sims K., Irvine A. R., and Good W. V. (1997). Norrie disease in a family with a manifesting Female Carrier. Archives of Ophthalmology, 115(4), 517–519. https://doi.org/10.1001/ARCHOPHT.1997.01100150519012
Sudha D., Ganapathy A., Mohan P, et al. (2018). Clinical and genetic analysis of Indian patients with NDP-related retinopathies. International Ophthalmology, 38, 1251-1260. https://doi.org/10.1007/s10792-017-0589-0
Trang D. T., Phu N. M., Hung D. M., Nhung V. P., Ha N. N., Thuong M. T. H, et al. (2022). Whole exome sequencing revealed novel pathogenic variants in Vietnamese patients with FEVR. Molecular Vision, 28, 480-491. https://pmc.ncbi.nlm.nih.gov/articles/PMC10115361/
Wang H., Liu Z., Zhou Y., Ma Y., and Tao D. (2022). A novel frameshift c.22_25dupGCAT mutation of the NDP gene in a Chinese infant with Norrie disease A case report. Medicine (United States), 101(1), E28523. https://doi.org/10.1097/MD.0000000000028523
Wu W. C., Drenser K., Trese M., Capone, A., and Dailey W. (2007). Retinal phenotype–genotype correlation of pediatric patients expressing mutations in the Norrie disease gene. Archives of Ophthalmology, 125(2), 225–230. https://doi.org/10.1001/ARCHOPHT.125.2.225
Ye X., Wang Y., Cahill H., Yu M., Badea T. C., Smallwood P. M, et al. (2009). Norrin, Frizzled4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization. Cell, 139(2), 285-298. https://doi.org/10.1016/J.CELL.2009.07.047
Downloads
Published
How to Cite
Issue
Section
