Introduction
Norrie disease, a rare X-linked genetic disorder, is characterized by vision loss at birth or a few weeks after an eye lesion such as retinal detachment occurs which threatens vision and can lead to severe visual impairment or loss of vision. Cognitive/behavioral findings: Approximately 30-50% of males with the Norrie disease phenotype have poorly characterized behavioral disturbances or developmental delay/intellectual disability and may show psychotic-like features. At present there is no medical therapy useful for the ocular manifestations of the disease. Mutations in the NDP gene at position Xp11.3 are responsible for this syndrome.

Case Presentation
A couple with a family history of multiple male members with retinal detachment leading to vision loss within a few weeks of giving birth were referred to our reproductive assisted center for preconception counseling. They had a son who was born blind. The medical history showed that the wife's pregnancy was completely normal, the baby was born normally, full term, birth weight 3300g, newborn examination found no abnormalities. Signs began to appear when the baby was 3 months old, the baby had no eye reflexes and the family took him to the doctor, discovered retinal detachment. Mental, motor, and physical development milestones were also slower than normal. Currently, the baby has not received any treatment. His family history is remarkable because a cousin had similar symptoms including congenital blindness, retinal detachment, and mental retardation.

Diagnostic Workup
WES and aCGH were performed to find the cause of the disease. Preimplantation genetic diagnosis is performed by PCR of the deletion sequence containing the NDP gene, helping to select embryos that do not carry the mutation for embryo transfer. Prenatal diagnosis is performed by aCGH to confirm the genetic status of the fetus. Pregnancy outcome was collected and analyzed.

 

Outcome and Follow-Up
aCGH revealed an aproximately 1.2 milion base deletion on the short arm of the X chromosome, containing the NDP gene, which is the cause of Norrie disease in the patient. The variant was confirmed in members with and without the disease. The couple chose to take the preimplantation genetic testing (PGT) procedure. One unaffected embryo was transferred to the uterus, and a singleton pregnancy was achieved, respectively. Prenatal diagnosis using aCGH helps verify the genetic status of the fetus. Pregnancy proceeds normally and they delivered at full-term. Postpartum status has not yet detected any abnormal signs.

 

Discussion
Norrie disease is caused by pathogenic variants of the NDP gene. NDP consists of three exons located on chromosome Xp11.3, spanning 28kb. Exons 2 and 3 are the coding region of NDP, while exon 1 is not translated and can act as a catalyst for gene transcription. As a protein product of NDP, Norrin participates in the regulation of retinal growth and regression of hyaloid blood vessels in the eye. 

Some studies have shown that NDP loss is associated with more severe disease manifestations than other mutations. In a report on Norrie syndrome due to deletion mutation, the patient may have some eye features such as: bilateral posterior lens angiofibromas, cataracts, PFV signs and retinal detachment — causing severe visual impairment. However, our patient's condition did not detect the above abnormalities. In addition to the eye manifestations, our patient had mental retardation - a common symptom in Norrie disease. This is consistent with mutations in the NDP gene, especially deletion mutations that cause more common neurological abnormalities.

The NDP deletion mutation of about 1.2Mb in size in the NDP gene was not detected by the coding genome sequencing test, indicating that this is a limitation of the technique when it cannot detect large deletions in the gene.

By analyzing embryos derived from IVF and then implanting only unaffected embryos, this technique is favored by women undergoing IVF for other reasons. PGD is extremely accurate, with a misdiagnosis rate of less than 1%. Although rare, misdiagnosis can occur for many reasons, including embryo mosaicism, the presence of contaminated DNA, allelic loss (i.e. amplification of only one allele), and mislabeling of samples in the laboratory. Although PGD is relatively difficult, expensive, and time-consuming, it is now widely used to prevent many monogenic diseases. Prenatal genetic diagnosis is necessary to rule out the risk of ADO.

Conclusion
In summary, we have reported a patient with a deletion in the coding region of the NDP gene leading to Norrie disease and the mutation could have been missed if only sequencing was performed. The patient had a diverse spectrum of phenotypic expression, requiring further studies on the relationship between genotype and phenotype in Norrie disease. Preimplantation genetic diagnosis is an effective measure to prevent the risk of having children with Norrie eyes.