NDP-related retinopathies: clinical phenotype of female carriers

Abstract

Background/aimsNorrin cysteine knot growth factor (NDP) located on the X chromosome, was previously reported to cause Norrie disease and familial exudative vitreoretinopathy (FEVR), which are blindness-causing ocular disorders, in males. In this study, we aimed to explore the clinical characteristics of female carriers with NDP mutations.MethodsTwelve female carriers from 11 unrelated families with pathogenic NDP mutations were recruited. Clinical data were collected from the NDP carriers. Comprehensive ocular examinations, including best corrected visual acuity, slit lamp examination, fundus photography and fundus fluorescein angiography (FFA) were evaluated. Targeted gene or whole exome sequencing was performed in the probands, and Sanger sequencing was performed to confirm NDP mutations in female carriers.ResultsOf the 12 females, 1 (1/12, 8.3%) presented with decreased visual acuity and 11 (11/12, 91.7%) were asymptomatic. Based on the FFA, peripheral vascular changes were noted in 66.7% (16/24) of the eyes of 75.0% (9/12) of the carriers. A total of 33.3% (8/24) had typical FEVR phenotype, 33.3% (8/24) had mild vascular abnormalities and 33.3% (8/24) was unremarkable. In addition, predominant changes such as telangiectatic endings (66.7%), anomalous circumferential vessel (37.5%), supernumerary vascular branching (33.3%), fluorescein leakage (29.2%), avascular area (8.3%), retina fold (8.3%) and peripheral straightening of retinal vessels (33.3%) were noted.ConclusionAlthough NDP-related retinopathy is an X-linked recessive disorder, most of the female carriers of NDP exhibited clinical features of FEVR. Thus, timely examinations and lifelong monitoring should be conducted in the NDP female carriers.

5' UTR variant in NDP gene leads to incorrect splicing and Familial Exudative Vitreoretinopathy

“…Most patients with FEVR caused by the NDP gene are male, some female patients were reported. The research of Huang et al (22) revealed that 33.3% (8/24) female carriers had typical familial exudative vitreoretinopathy phenotype, 33.3% (8/24) had mild vascular abnormalities. The reason of such broad spectrum of phenotypes observed in NDP variant female carriers presumed to X-chromosome inactivation (XCI).…”

“…It was consisted with the predictions of spliceAI and RDDC software. Several variants in the start code (c.1A > G, c.2T > G, c.2T > C and c.2T > A) were reported as "disease-causing mutations (DM)" of Norrie disease (20)(21)(22). The research of Li (23) et al indicated that NDP gene c.174 + 1G > A in a Chinese family with Norrie disease lead to deletion of 246 bp at the 3′ end of exon 2. c.174 + 1G > A and c.-167_174delinsAAGG have the same impact on the coding region.…”

High Myopia Is Common in Patients With X-Linked Retinopathies

“…For example, in our previous study, female carriers of NDP mutations were found to have retinal vascular abnormalities, and nearly one-third of eyes presented with a typic familial exudative vitreoretinopathy presence in fundus fluorescein angiography. 30 Females with CACNA1F mutations have rarely been reported, although mild-to-moderate loss of vision or electrophysiologic changes have been mentioned in sporadic cases. 31 The female carrier phenotype has not been documented in association with the NYX and OPN1MW mutations 7 ; however, the potential mechanism of X-chromosome inactivation has been suggested.…”