The NRROS gene is located on chromosome 3 at 3q29 and encodes the negative regulator of reactive oxygen species (NRROS) protein, a leucine-rich repeat domain containing transmembrane protein that localizes to the endoplasmic reticulum and plasma membrane. The protein is preferentially expressed in the myeloid cells, microglia and periventricular macrophages of the brain and plays a role in the activation of the TGF-beta-1 signaling pathway and other proteins associated with innate immunity. The NRROS gene was first reported in relation to autosomal recessive early onset seizures with neurodegeneration and brain calcification in 2020 (Smith et al., PMID: 32100099). The clinical course is characterized by normal development to moderate global developmental delay during the first months of life, followed by the onset of seizures and then rapid, severe, progressive developmental regression and neurodegeneration. The seizures are typically refractory and include febrile seizures, infantile spasms, focal seizures, and myoclonic seizures, and occur at frequencies of multiple seizures daily or hourly. Most patients develop hypotonia early in life and can develop peripheral limb hypertonia later. Additional features include issues with recurrent aspiration and feeding difficulties requiring enteral feeding. Findings from brain MRI are variable but include reduction in white matter volume, delayed myelination, thin corpus callosum and cerebral atrophy. Patients for whom CT scans are available all showed punctate calcifications of cerebral matter. A total of 9 variants, including 2 missense and 7 truncating variants, have been reported in 7 probands from 4 publications and are included in this curation (PMIDs: 32100099, 32197075, 35099671, 35716448). The mechanism of pathogenicity is reported to be biallelic loss of function. This gene-disease relationship is also supported by expression studies and mouse models which recapitulate the clinical phenotype (PMIDs: 32100099, 29909984, 32197075). In summary, NRROS is definitively associated with autosomal recessive early onset seizures with neurodegeneration and brain calcification. 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 Syndromic Disorders GCEP on the meeting date 15th September 2023 (SOP Version 9.0).
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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