Clinical features, gene analysis and prenatal diagnosis with <i>NDP</i> gene mutation in a family_Chinese Journal of Ocular Fundus Diseases

Authors：

Du wanli ¹ , Wu Caiyun ¹ , Lian Lulu ¹ , Zhang Chuan ^2,3 , Wang Yupei ^2,3 , Hao Shengju ^2,3 , Hui Ling ^2,3 ,  Zhang Qinghua ^2,3

1. Department of Ophthalmology, Gansu Provincial Maternity and Child-care Hospital (Gansu Province Central Hospital), Lanzhou 730050, China;
2. Medical Genetics Center, Gansu Provincial Maternity and Child-care Hospital (Gansu Province Central Hospital), Lanzhou 730050, China;
3. Gansu Provincial Clinical Research Center for Birth Defects and Rare Diseases, Lanzhou 730050, China;

Corresponding author：

Zhang Qinghua, Email: 0929zhangqh@163.com

Keywords：

NDP gene mutation; Prenatal diagnosis

DOI：

10.3760/cma.j.cn511434-20221008-00527

Video：

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Objective To observe and determine the gene mutation site and clinical phenotype of a NDP gene mutant family, and provide a basis for the prenatal diagnosis of offspring. Methods A pedigree investigation study. Two patients and 6 family members of a third-generation Han family with NDP gene mutation who were admitted to the Maternal and Child Health Hospital of Gansu Province from July 2019 to December 2021 were included in the study. The patients and their parents underwent the examination of pupil light reflex, strip light imaging, visual acuity evaluation, fundus color photography, and wide-field fluorescein fundus angiography (FFA). Peripheral blood of all the subjects was collected, the pathogenic genes were screened by whole exome sequencing, and NDP genes were detected by amplification of multiple ligated probes. DNA prenatal diagnosis was performed by amniocentesis at 19th weeks of the mother's third gestation.Results Proband (Ⅲ1), male, 4 years old, full term natural delivery. At about 40 days after birth, B-mode ultrasonography indicated total retinal detachment in both eyes. Normal hearing and intelligence. Fundus examination was not performed. First sibling of proband (Ⅲ2, big younger brother), ophthalmologic examination 30 days after birth, retinal detachment in both eyes. Proband's mother (Ⅱ2) had unvascularized peripheral temporal retina in both eyes. Wide-angle FFA examination showed no vascularization of the peripheral temporal retina in both eyes, and slight leakage of peripheral vascular fluorescein. The proband's second sibling (Ⅲ3, little younger brother) was screened for neonatal eye disease 1 day after birth. No abnormalities were observed outside both eyes. Cornea and lens transparent. No abnormalities were observed in the optic disc and macula in both eyes. No vascular curvature was observed in the peripheral retina. The results of gene detection showed that there was hemizygote deletion in exon 2 of NDP gene of the proband (Ⅲ1) and its big younger brother (Ⅲ2). His mother (Ⅱ2) had heterozygosity deletion in exon 2 of NDP gene. The phenotype and genetic test results of the proband's father (Ⅱ1), uncle (Ⅱ3), maternal grandfather (Ⅰ1) and maternal grandmother (Ⅰ2) were not abnormal. Conclusions The hemizygote deletion in exon 2 of NDP gene is a pathogenic variation in the native family. The clinical phenotypes of different genders are different. Prenatal diagnosis is an effective way to block hereditary diseases in families.

Citation： Du wanli, Wu Caiyun, Lian Lulu, Zhang Chuan, Wang Yupei, Hao Shengju, Hui Ling, Zhang Qinghua. Clinical features, gene analysis and prenatal diagnosis with NDP gene mutation in a family. Chinese Journal of Ocular Fundus Diseases, 2023, 39(7): 549-553. doi: 10.3760/cma.j.cn511434-20221008-00527 Copy

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10.	Walsh MK, Drenser KA, Capone A, et alNorrie disease vs familial exudative vitreoretinopathy[J]. Arch Ophthalmol20111296805820. DOI: 10.1001/archophthalmol.2011.131.
11.	Huang L, Sun L, Li X, et al. NDP-related retinopathies: clinical phenotype of female carriers[J/OL]. Br J Ophthalmol, 2022, 2022: bjophthalmol-2021-320084[2022-03-31]. https://bjo.bmj.com/content/early/2022/03/30/bjophthalmol-2021-320084.long. DOI: 10.1136/bjophthalmol-2021-320084. [published online ahead of print].
12.	Chen ZY, Battinelli E, Hendriks R, et alNorrie disease gene: characterization of deletions and possible function[J]. Genomics1993162533535. DOI: 10.1006/geno.1993.1224.
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15.	Halpin C, Sims KTwenty years of audiology in a patient with Norrie disease[J]. Int J Pediatr Otorhinolaryngol2008721117051710. DOI: 10.1016/j.ijporl.2008.08.007.
16.	Liu J, Zhu J, Yang J, et al. Prenatal diagnosis of familial exudative vitreoretinopathy and Norrie disease[J/OL]. Mol Genet Genomic Med, 2019, 7(1): e00503[2018-11-25]. https://europepmc.org/article/MED/30474316. DOI: 10.1002/mgg3.503.
17.	Nikopoulos K, Venselaar H, Collin RW, et alOverview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP[J]. Hum Mutat2010316656666. DOI: 10.1002/humu.21250.

1. Wu WC, Drenser K, Trese M, et alRetinal phenotype–genotype correlation of pediatric patients expressing mutations in the Norrie disease gene[J]. Arch Ophthalmol20071252225230. DOI: 10.1001/archopht.125.2.225.
2. Bao Y, Yang J, Chen L, et alA novel mutation in the NDP gene is associated with familial exudative vitreoretinopathy in a southern Chinese family[J]. Genet Test Mol Biomarkers20192312850856. DOI: 10.1089/gtmb.2019.0099.
3. Retterer K, Juusola J, Cho MT, et alClinical application of whole-exome sequencing across clinical indications[J]. Genet Med2016187696704. DOI: 10.1038/gim.2015.148.
4. Huang L, Zhang L, Li X, et alOcular manifestations of Chinese patients with copy number variants in the NDP gene[J]. Mol Vis20222829.
5. Shen G, Ke J, Wang Z, et alStructural basis of the Norrin-Frizzled 4 interaction[J]. Cell Res201525910781081. DOI: 10.1038/cr.2015.92.
6. Chang TH, Hsieh FL, Zebisch M, et al. Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan[J/OL]. Elife, 2015, 4: e06554[2015-07-04]. https://europepmc.org/article/MED/26158506. DOI: 10.7554/eLife.06554.
7. Smith SE, Mullen TE, Graham D, et alNorrie disease: extraocular clinical manifestations in 56 patients[J]. Am J Med Genet A2012158819091917. DOI: 10.1002/ajmg.a.35469.
8. Michaelides M, Luthert P, Moore A, et alNorrie disease and peripheral venous insufficiency[J]. Br J Ophthalmol200488111475. DOI: 10.1136/bjo.2004.042556.
9. 张琦, 赵培泉. 家族性渗出性玻璃体视网膜病变的荧光素眼底血管造影特征及其诊断价值[J]. 中华眼底病杂志, 2011, 27(3): 263-266. DOI: 10.3760/cma.j.issn.1005-1015.2011.03.015..Zhang Q, Zhao PQ. The characteristics and diagnostic value of fluorescein fundus angiography in familial exudative vitreoretinopathy[J]. Chin J Fundus Dis, 2011, 27 (3): 263-266. DOI: 10.3760/cma.j.issn.1005-1015.2011.03.015.
10. Walsh MK, Drenser KA, Capone A, et alNorrie disease vs familial exudative vitreoretinopathy[J]. Arch Ophthalmol20111296805820. DOI: 10.1001/archophthalmol.2011.131.
11. Huang L, Sun L, Li X, et al. NDP-related retinopathies: clinical phenotype of female carriers[J/OL]. Br J Ophthalmol, 2022, 2022: bjophthalmol-2021-320084[2022-03-31]. https://bjo.bmj.com/content/early/2022/03/30/bjophthalmol-2021-320084.long. DOI: 10.1136/bjophthalmol-2021-320084. [published online ahead of print].
12. Chen ZY, Battinelli E, Hendriks R, et alNorrie disease gene: characterization of deletions and possible function[J]. Genomics1993162533535. DOI: 10.1006/geno.1993.1224.
13. Clevers HWnt signaling: Ig-norrin the dogma[J]. Curr Biol20041411R436437. DOI: 10.1016/j.cub.2004.05.039.
14. Schuback DE, Chen ZY, Craig IW, et alMutations in the Norrie disease gene[J]. Hum Mutat199554285292. DOI: 10.1002/humu.1380050403.
15. Halpin C, Sims KTwenty years of audiology in a patient with Norrie disease[J]. Int J Pediatr Otorhinolaryngol2008721117051710. DOI: 10.1016/j.ijporl.2008.08.007.
16. Liu J, Zhu J, Yang J, et al. Prenatal diagnosis of familial exudative vitreoretinopathy and Norrie disease[J/OL]. Mol Genet Genomic Med, 2019, 7(1): e00503[2018-11-25]. https://europepmc.org/article/MED/30474316. DOI: 10.1002/mgg3.503.
17. Nikopoulos K, Venselaar H, Collin RW, et alOverview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP[J]. Hum Mutat2010316656666. DOI: 10.1002/humu.21250.

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