NMNAT1 was first reported in relation to NMNAT1-related retinopathy in 2012 in a patient described as having autosomal recessive Leber congenital amaurosis (PMID: 22842230, 22842231, 22842227). Leber congenital amaurosis (LCA) is a severe form of inherited photoreceptor-neuron degeneration resulting in congenital blindness. To take into account the range of phenotypes and genetic heterogeneity in retinal disorders, the ClinGen Retina GCEP has labeled the disease entity associated with biallelic variants in NMNAT1 as "NMNAT1-related retinopathy". At least 14 variants (missense and nonsense) that have been reported in 15 probands in publications (PMID: 22842230, 22842231, 22842227, 32150116). Variants in NMNAT1 was found to be segregated in at least one large family (PMID: 22842230).More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by in-vitro studies (e.g. animal models, expression studies, in vitro functional assays, etc.) (PMIDs: 22842230, 22842227). When measuring NAD levels in red blood cells, affected individuals with homozygous NMNAT1 variant had significantly lower levels of NAD compared to unaffected carrier (PMID: 22842230). Other in-vitro studies showed that, when cells are transfected with constructs encoding wild-type or mutant NMNAT1, those with NMNAT1 variants had lower enzymatic activities, compared to wildtype (PMID: 22842230, 22842227). Of note, one study demonstrated that patients with two homozygous variants in NMNAT in a large consanguineous family presented with global developmental delay, hypotonia with joint hypermobility and autism, in addition to LCA (PMID: 22842227). A limited number of patients have been recorded as having spondyloepiphyseal dysplasia syndrome (SHILCA), including sensorineural hearing loss, intellectual disability in addition to LCA, however additional studies are needed to definitively describe this disease association (PMID: 33668384, 32533184). In summary, NMNAT1 is definitively associated with autosomal recessive NMNAT1-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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