Submission Details

NRL was first reported in relation to NRL-related dominant retinopathy in 1999 (Bessant et al., PMID: 10192380). In 2004, loss of function variants were linked to a recessive form of retinopathy (Nishiguchi et al., PMID: 15591106 ). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found a difference in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities, Retinitis pigmentosa 27 (OMIM:613750) as NRL-related dominant retinopathy and NRL-related recessive retinopathy (also called clumped pigmentary retinal degeneration or enhanced S-cone syndrome). The split curation for NRL-related recessive retinopathy has been curated separately. Nine missense variants that have been reported in 14 probands in 10 publications (PMIDs: 10192380, 11039579, 11385710, 11879142, 15994872, 21981118, 27081294, 28106895, 31736247, 35653045) are included in this curation, including segregation analysis in three families. The mechanism of pathogenicity appears to be gain of function in which the altered NRL protein over activates the rhodopsin promoter. This gene-disease relationship is also supported by expression studies and* in vitro* functional assays (PMIDs: 1147710816505381, 17335001, 8552602). These studies show that NRL is specifically expressed in rod photoreceptors and is capable of activating the rhodopsin promoter. The pathogenic variants alter phosphorylation of NRL and result in increased activation of the rhodopsin promoter. In summary, there is definitive evidence supporting the relationship between NRL and NRL-related dominant retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Retina GCEP on the meeting date March, 6, 2025] (SOP Version 11)].