Purpose: To explore the genetic defects in two Chinese families with X-linked Norrie disease (ND). Methods: We analyzed two Chinese families with ND at molecular level through clinical exome sequencing and the variations were identified by Sanger sequencing. Results: Two genetic variations were found in the NDP gene by clinical exome sequencing, a partial deletion of 801 bp contained the whole exon 2 and a missense variant (164G>A) within codon 55 that resulted in the interchange of cysteine by phenylalanine. Clinical findings were more severe in the patients who presented the missense variant. Conclusion: We report two genetic variations in the NDP gene in Chinese that extend the mutational and phenotypic spectra of NDP gene, and also demonstrate the feasibility of clinical exome sequencing in application of molecular diagnosis.

A Norrie disease protein gene (NDP) variant, c.174 + 1G > A, was found in a Chinese family through next-generation sequencing and verified with Sanger sequencing. A case of Norrie disease was reported in the first child, and the symptoms were consistent with the results of gene sequencing. The child\'s mother, who was pregnant at the time, was found to be a carrier of the identified pathogenic variant. To determine if the fetus carried the same disease-causing variant, prenatal examination and prenatal diagnosis were conducted. The fetus had biocular vitreous abnormalities and complete retinal abnormalities. Genetic testing showed that the fetus had maternally inherited the NDP gene variant found in the proband. It was concurrently confirmed that the NDP gene variant led to the deletion of 246 bp at the 3\' end of exon 2, resulting in the deletion of the initiation codon and the occurrence of disease. Our study suggests that the diagnosis of rare diseases through next-generation sequencing, combined with prenatal ultrasound and prenatal diagnosis, can help families with known familial genetic diseases. Furthermore, the findings of this study broaden the known genetic spectrum of Norrie disease.

Norrie disease (ND; OMIM 310600), a rare X-linked recessive genetic disorder, is characterized by congenital blindness and occasionally, sensorineural hearing loss, and developmental delay. The congenital blindness of ND patients is almost untreatable; thus, hearing is particularly important for them. However, the mechanism of hearing loss of ND patients is unclear, and no good treatment is available except wearing hearing-aid. Therefore, revealing the mechanism of hearing loss in ND patients and exploring effective treatment methods are greatly important. In addition, as a serious monogenic genetic disease, convenient gene identification method is important for ND patients and their family members, as well as prenatal diagnosis and preimplantation genetic diagnosis to block intergenerational transmission of pathogenic genes. In this study, a Norrie family with two male patients was reported. This pedigree was ND caused by large fragment deletion of NDP (norrin cystine knot growth factor NDP) gene. In addition to typical severe ophthalmologic and audiologic defects, the patients showed new pathological features of endolymphatic hydrops (EH), and they also showed acoustic nerves abnormal as described in a very recent report. PCR methods were developed to analyze and diagnose the variation of the family members. This study expands the understanding of the clinical manifestation and pathogenesis of ND and provides a new idea for the treatment of patients in this family and a convenient method for the genetic screen for this ND family.

Norrie disease is a rare X-linked recessive disorder in affected males. The typical features are congenital blindness, progressive hearing impairment, and, in some cases, some degree of mental retardation, microphthalmia, microcornea, growth failure, and seizures. Norrie disease is caused by mutations in the Norrie disease pseudoglioma gene (NDP), which encodes the Norrin protein that plays a crucial role in vascular development, neural cell differentiation, and proliferation in the retina and cerebellum. The aim of the present study was to identify the genetic cause of the disease and the phenotypic characteristics of the patients in an affected Chinese family.
A Chinese family with Norrie disease was studied, and clinical phenotypes of the proband were observed. With informed consent from the patients\' family, blood samples from family members were collected, genomic DNA was extracted, and Sanger sequencing was performed to identify the disease-causing mutation.
sults: The c.287 G > T mutation of NDP was identified by Sanger sequencing and resulted in p.Cys96Phe. The pathogenicity prediction was performed by MutationTaster, Polyphen-2, SIFT, and PROVEAN, all of which suggested that the mutation is disease-causing and may be responsible for the phenotypes of Norrie disease.
The c.287 G > T of NDP is a novel mutation responsible for Norrie disease in a Chinese family.

Both familial exudative vitreoretinopathy (FEVR) and Norrie disease (ND) are hereditary retinal disorders which can cause severe visual impairment and blindness at a young age. The present study aimed to report the use of antenatal genetic testing and ultrasound in the diagnosis and counseling of FEVR and ND.
Amniocentesis and ultrasonography were performed in high-risk mothers, with children having FEVR or ND, to predict severe ocular abnormalities.
Case 1: A homozygous NDP mutation (c.376T>C, NM_000266) was detected in the proband and his mother. Molecular prenatal analysis of the fetal DNA revealed no mutations. No ocular abnormalities were detected on ultrasonography. The pregnancy progressed uneventfully to a normal outcome. Case 2: A novel heterozygous FZD4 mutation (c.1010dupA, NM_012193) was detected in the proband and his mother. The same mutation was detected in the fetus, but ultrasonography showed no ocular abnormalities. A healthy baby boy with stage 1 FEVR was born after an uneventful pregnancy. Case 3: Deletions of exons 2 and 3 in the NDP were found in the proband and his mother. The same deletion mutation was detected in the female fetus, but the ultrasound scan was normal. The pregnancy progressed uneventfully to a normal outcome.
To our knowledge, antenatal genetic analyses were used in conjunction with ultrasound for the first time, to diagnose FEVR and ND, and predict the postnatal prognoses in at-risk babies.

We report a case of Norrie disease, diagnosed by prenatal ultrasound, confirmed by Sanger sequencing of the DNP gene from the aborted fetal cord blood and histologically. Prenatal ultrasound revealed no abnormality in either eye at 22+1 and 31+4 gestational weeks, but at 36+5 gestational weeks both eyes had massive vitreous cavity opacities with complete retinal detachment. Norrie disease was initially suspected because of an older male sibling with the disease. To our knowledge, prenatal ultrasound diagnosis of Norrie disease has been previously described only one case in 1993 in a 34-week-old fetus. The normal eye development until after 31 + 4 gestational weeks provides insight into the first manifestation and then the rapid progression of the eye disease.

OBJECTIVE: To investigate the genetic findings and phenotypic characteristics of a Chinese family with Norrie disease (ND).
METHODS: Molecular genetic analysis and clinical examinations were performed on a Chinese family with ND. Mutations in the Norrie disease pseudoglioma (NDP) gene were detected by direct sequencing. Haplotypes were constructed and compared with the phenotypes in the family. Evolutionary comparisons and mutant open reading frame (ORF) prediction were also undertaken.
RESULTS: Two family members with ocular manifestations were diagnosed with ND. No signs of sensorineural hearing loss were observed in either patient, while one of them showed signs of mild mental retardation. A novel heterozygous mutation in the NDP gene, c.-1_2delAAT, was detected in both patients. The mutation and the mutation bearing haplotype co-segregated with the ND phenotype in males and was transmitted from their mothers and/or grandmothers (II:2). The male without ND did not harbor the mutation. The mutation occurred at the highly conserved nucleotides. ORF finder predicted that the mutation would lead to the production of a truncated protein that lacks the first 11 N-terminal amino acids.
CONCLUSIONS: A novel mutation, c.-1_2delAAT in the NDP gene, was identified in a Chinese family with ND. This mutation caused ND without obvious sensorineural hearing loss. Mental disorder was found in one but not the other patients. The clinical heterogeneity in the family indicated that other genetic variants and epigenetic factors may also play a role in the disease presentation.