Submission Details

The NYX gene was first reported in relation to X-linked cases of congenital stationary night blindness by two groups in the year 2000 (PMID: 11062471, PMID: 11062472). Affected male patients have since been identified in a number of other publications (PMID: 14609846, PMID: 18617546), with causal monoallelic variants in NYX specifically diagnostic for congenital stationary night blindness type 1A. This disease entity is referred to in this curation as NYX-related congenital stationary night blindness, and represents one of two X-linked forms of congenital stationary night blindness distinguished by a single monogenic cause. The disease is sometimes referred to as complete (as opposed to incomplete) X-linked congenital stationary night blindness based on the relative severity of its electroretinogram findings. The disease appears to be fully penetrant, with patients often presenting in infancy or early childhood with ocular features of night blindness, myopia, and reduced (but non-progressive) visual acuity, as well as nystagmus in some cases. Severely reduced or absent scotopic b-wave (electronegative ERG) is a characteristic finding on ERG, while the absence of oscillatory-potential wavelets and the presence of other rod ERG abnormalities are often reported as well. Because of the broad spectrum of potential phenotypes, these cases with causal variants in NYX have been curated under the inclusive disease name NYX-related retinopathy (MONDO:0800407).

Ten suspected pathogenic variants were scored as part of this curation (three nonsense, two frameshift, two missense, two small in-frame deletions, and one disrupting splicing), which have been collectively reported in ten probands in four publications (PMID: 11062471, PMID: 11062472, PMID: 18617546, PMID: 14609846). All probands were males who were hemizygous for their respective variants, and none were reported to have consanguineous parents. Heterozygous females are generally unaffected, following X-linked recessive inheritance. One family was scored for segregation evidence (PMID: 11062471). Additional available pieces of segregation evidence (PMID: 11062472, PMID: 16670814) and case-level evidence (PMID: 11062471, PMID: 11062472, PMID: 16670814, PMID: 12397430) were not scored as part of this curation as the maximum scoring for these evidence types had already been reached. The mechanism of pathogenicity appears to be monoallelic loss-of-function, characterized in some cases by frameshift or nonsense variants predicted to disrupt the C-terminal glycosylphosphatidylinositol (GPI) anchor of the protein product. This loss has been shown to trigger NYX retention and accumulation in the endoplasmic reticulum and Golgi rather than proper localization to the cell surface (PMID: 14507859).

This gene-disease association is also supported by experimental evidence that NYX exhibits its highest expression levels in retina tissue (PMID: 30239781), including in the inner segment of photoreceptors, inner and outer nuclear layers, and ganglion cell layer (PMID: 11062471). Staining evidence from zebrafish retinas shows nyx expression specifically in the outer plexiform and inner plexiform layers, strongly co-localizing with post-synaptic but not pre-synaptic markers (PMID: 17004930). Zebrafish with nyx knockdown exhibit absence of scotopic b-wave and normal a-wave in ERG recordings as well as reduced visual contrast sensitivity (PMID: 17004930). A naturally occurring mouse model with absence of scotopic b-wave and normal a-wave in ERG recordings as well as reduced visual acuity and X-linked inheritance has been found to harbor a frameshift mutation in Nyx disrupting the majority of the protein product (PMID:1250699). Tissue-specific Nyx transgene expression in the dendritic tips of retinal depolarizing bipolar cells in this mouse model strongly rescues both the ERG phenotype and the light-evoked responses of retinal ganglion cells (PMID: 17881478). Although the exact function of Nyx has not been conclusively demonstrated, these results collectively argue that it plays a critical role in the retinal bipolar cells that synapse with rod photoreceptor cells and transmit signals to ganglion cells.

In summary, NYX is definitively associated with NYX-related retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification has been approved by the ClinGen Retina GCEP on March 3rd, 2022 (SOP Version 9).