The Wnt signaling pathway is an influential pathway involved in intercellular signal transduction during embryonic retinal vascular development. The NDP gene is X-linked recessive inheritance. It is located on human chromosome Xp11.4 and encodes the Norrin protein, which consists of 133 amino acids. It belongs to the cystine growth factor family and can bind to FZD4-LRP5 as a ligand of the Wnt pathway. It activates the Norrin/ β-catenin signaling pathway in the Wnt pathway. When the NDP gene in the pathway is mutated, its ability to act as a ligand of the Wnt receptor complex is destroyed, which can reduce the activity of the Wnt signaling pathway to varying degrees, leading to abnormal retinal angiogenesis, FEVR, Norrie disease, Coats disease and other diseases[6].
In the study, Chongqing had a detection rate of 1.11 percent for the NDP mutation after screening according to the criteria. The detection rates in some domestic literature were about 4.65%[7], 10.77%[8], 15.63%[9], and in some foreign literature were 5%[10], 11.1% [11], which were lower than those in relevant literature at home and abroad. The following reasons were considered: 1. The FEVR cases in this study were detected by universal screening for neonatal eye disease after birth, from which patients with mild phenotypes could be detected; Most of the cases collected in other literature are patients who have already presented with the corresponding clinical manifestations. according to the existing literature, the clinical phenotype of NDP mutation is more serious, so the proportion of patients with NDP mutation in the population will increase correspondingly, resulting in a higher detection rate than that of this study [3, 9, 12, 13, 14]. 2. Currently, there are more reports of FEVR related literature in Shanghai, Tianjin and other places, but there are few reports of FEVR system studies in Chongqing, which may be related to regional and ethnic differences, but this needs to be further confirmed by large sample studies. Xinjiang has a detection rate of 0 for the NDP mutation, which was not detected in this study due to the small sample size and the fact that the NDP mutation is not the most common type of gene mutation.
At present, there is no fixed pattern of genotype-phenotype relationships in the analysis of different genotypes. There is no specific relationship between genotype and severity. According to the existing literature, NDP and KIF11 have a higher severe phenomenon type [3, 9, 12, 13, 14]. However, the proband detected in this study has a mild phenotype, that is, three peripheral retinal vascular zones in one side. We consider the following reasons: 1. In 2007, Wu WC et al [15]. conducted a study on a series of children with vitreoretinal diseases with NDP mutations, and found that mutations that can disturb the structure of cystine would affect the formation of the quaternary structure of proteins, leading to more severe vitreoretinal diseases [16]. Patients with no cystine mutation showed only varying levels of proliferation in the peripheral retinal vasculature and subretinal areas. The problem in this case, however, had a partial glycine mutation replaced by an arginine mutation without a cystine mutation, so that the fundus, which is a vascular zone at nine o 'clock in the third zone of the peripheral retina in one eye, was mild. 2. Although the shift of protein structure caused by the mutation of FEVR pathogenic gene has been confirmed to be related to the occurrence of FEVR, it still has a non-penetrance rate of 25% in the mutation carriers [17].
The NDP gene is located on chromosome XP11.4 and contains three exons. Only exons two and three encode proteins, and exon one is associated with the regulation of gene expression. In this study, we found only one mutation NDP: c. G58A (p.G20R), located in exon two, which has been reported in clinical literature. The proband had a heterozygous mutation in the FEVR 3 region of the fundus and a phase one change. The mother of the progeny had the same mutation, consistent with the X-linked recessive inheritance feature. The limitations of this study are that fundus data were not collected from mothers and it was not possible to determine whether the mothers were asymptomatic patients or carriers of the FEVR mutation.
Xu et al[18]. observed that Wnt signaling plays an essential role in vascular development of the retina, inner ear, and cerebellum. To date, more than 100 disease-causing mutations in NDP have been identified, most of which cause Norrie's disease, with only a small number of mutations causing FEVR. Some scholars believe that XL-FEVR and Norrie's disease are different degrees of retinal hypoplasia, which may be related to the formation of spatial structure of Norrin protein [15]. The clinical characteristics of patients with Norrie's disease are as follows: 1. Most of the patients were male; 2. postnatal onset; 3. it is bilateral congenital blindness with degeneration and proliferation of the neural retina, which can be complicated by cataract, snake, corneal leucoma, eyeball atrophy, etc[19]. 4. About 50 percent have complex progressive neurological conditions such as mental retardation, developmental delays and behavioral abnormalities. About 1/3 of the patients may have sensorineural hearing loss. The clinical features of patients with FEVR are mild and do not present with any symptoms, and the peripheral vascular zone of the retina is visible during screening[20]. In severe cases, secondary neovascularization, retinal folds and exudations, and tractional retinal detachment can be observed. Therefore, in daily clinical work, attention should be paid to differential diagnosis and follow-up observation of clinical manifestations in patients with mutations in the NDP gene for better assessment of their prognosis and genetic counseling and evaluation.
In conclusion, early screening for ocular diseases is important for early detection, diagnosis, treatment and timely intervention of congenital ocular diseases, and for control and reduction of visual loss due to congenital ocular diseases. Providing prenatal genetic counseling for the prevention and treatment of congenital and inherited retinal diseases through a combination of neonatal ophthalmic screening and genetic diagnosis is of great social value.