NUS1 was first reported in relation to autosomal dominant progressive myoclonus epilepsy in 2017 (PMID: 29100083) when Hamdan et al. described three patients with myoclonic seizures, disorders of intellectual development and tremor, or ataxia. This gene encodes the Nogo-B receptor (NgBR), a subunit of cis-prenyltransferase (cis-PTase), and is involved in the synthesis of dolichol, which is necessary for protein glycosylation [It interacts with dehydrodolichyl diphosphate synthase complex subunit (DHDDS) and promotes cis-prenyltransferase (cis-PTase) activity] (PMID: 19723497, PMID: 21572394). Notably, in 2014 (PMID: 25066056) autosomal recessive inheritance of NUS1 p.R290H variant was linked to the congenital disorder of glycosylation type1Iaa presenting with congenital scoliosis, severe neurological impairment, refractory epilepsy, hearing deficit, and visual impairment with discrete bilateral macular lesions. The studies reported in this curation detected patients with heterozygous loss of function variants in NUS1, presenting with variable clinical presentations including different seizure types, varying degrees of developmental delay, and the presence of myoclonus or other motor phenotypes.
Several non-sense, frameshift, and splice site variants, as well as copy number variations (CNVs) affecting all or part of NUS1, are reported in more than 25 probands across 15 publications (PMIDs: 29100083, 3165617, 32485575, 33111323, 32959737, 3453230, 33731878, 33798445, 35949226, 37249665, 38291835, 37470039, 38520610, 39772664, 39934081). Most reported variants are de novo with the exception of the familial c.22_23insA (PMID:32485575), which is segregated in 5 individuals.
In summary, there is definitive evidence to support the relationship between NUS1 and autosomal dominant progressive myoclonus epilepsy. 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 Epilepsy GCEP on the meeting date 05/20/2025 (SOP Version 11).
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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