NYX – X-linked Complete Congenital Stationary Night Blindness

Congenital stationary night blindness (CSNB) is a group of non-progressive retinal disorders characterized by impaired rod-mediated vision (nyctalopia) and a ‘negative-type’ electroretinogram. The complete form of CSNB (cCSNB) specifically disrupts the ON-bipolar cell pathway and is most commonly caused by hemizygous variants in the NYX gene (NYX), encoding the glycosylphosphatidylinositol-anchored proteoglycan nyctalopin, in an X-linked recessive pattern.

The seminal study by Zeitz et al. identified hemizygous NYX variants in 22 unrelated families, including truncating and in-frame deletions, establishing X-linked recessive inheritance (PMID:11062471). Subsequent reports have described over 150 male probands from more than 30 pedigrees harboring loss-of-function and missense NYX alleles, notably the recurrent c.1034G>A (p.Trp345Ter) variant across multiple populations (PMID:34165036, PMID:34781300).

Segregation analysis confirms hemizygous transmission of NYX alleles in at least 31 affected male relatives, and cases of maternal germline mosaicism highlight recurrence risks in families without detectable maternal heterozygosity (PMID:34165036).

The NYX variant spectrum comprises nonsense (e.g., c.1034G>A (p.Trp345Ter)), frameshift, and splice-site mutations, consistent with a loss-of-function mechanism. Founder alleles and private variants have been reported in European, South Asian, East Asian, and Middle Eastern cohorts.

Nyctalopin is localized to the dendritic tips of ON-bipolar cells, and its absence disrupts synaptic connectivity within the inner retina. Electrophysiological studies in affected humans demonstrate a selective ON-pathway defect, correlating with the complete CSNB phenotype.

Clinically, X-linked cCSNB due to NYX presents with early-onset nyctalopia, high myopia, nystagmus, strabismus, and otherwise normal fundi. Identification of NYX variants informs accurate diagnosis, genetic counseling, risk assessment, and inclusion in targeted gene panels. Hemizygous NYX loss-of-function variants are a definitive cause of X-linked complete CSNB and should be prioritized in genetic testing for male patients with suggestive ERG findings.

References

• Nature Genetics • 2000 • Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness. PMID:11062471
• Ophthalmic Genetics • 2021 • NYX-related Congenital Stationary Night Blindness in Two Siblings due to Probable Maternal Germline Mosaicism. PMID:34165036
• Ophthalmic Research • 2022 • Genetic Analysis of Consanguineous Pakistani Families with Congenital Stationary Night Blindness. PMID:34781300
• Genes • 2021 • Clinical and Genetic Characteristics of Korean Congenital Stationary Night Blindness Patients. PMID:34064005
• Investigative Ophthalmology & Visual Science • 2009 • Genotyping microarray for CSNB-associated genes. PMID:19578023

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