Submission Details

The NBN gene encodes nibrin protein, a member of the MRE11/RAD50/NBN (MRN) double-strand break repair complex that is involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. NBN variants have been associated with Nijmegen breakage syndrome (NBS), aplastic anemia, multiple cancers described below and breast cancer in individuals with heterozygous mutations. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, this curation focuses solely on autosomal recessive NBS (MONDO: 0009623) due to the differences in inheritance pattern and phenotypic variability. The association with breast cancer for heterozygous mutation carriers was noted to be limited by ClinGen (PMIDs: 10802669, 11889050, 23765759, 25613900). NBN was first reported in relation to autosomal recessive NBS in 1998 (Varon et al., PMID: 9590180). NBS is characterized by progressive microcephaly, intrauterine growth retardation and short stature, recurrent sinopulmonary infections due to immune deficiency, and an increased risk for cancer. Approximately 40% of NBS patients develop malignancies before age 20 years. Malignancies are primarily lymphomas (45% of lymphomas are of B cell origin and 55% are T cell lymphomas). In addition, solid tumors, including medulloblastomas, glioma, and rhabdomyosarcoma have been observed in NBS patients in their childhood (PMID: 20301355). Note that the curation for immune deficiency phenotypes in NBS was contributed by The Severe Combined Immune Deficiency (SCID) and Combined Immune Deficiency (CID) Gene Curation Expert Panel (please refer to the evidence summary addendum). 9 variants (nonsense and frameshift) that have been reported in more than 50 probands with NBS in 3 publications (PMIDs: 9590180, 12447395, 25677497) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. These variants are predicted to produce truncated protein (PMIDs: 9590180, 12447395) and immunoblotting demonstrates no nibrin protein expression in patient cells (PMIDs: 25677497). Thus, the mechanism of pathogenicity appears to be loss of function (LOF). Note that RAD50, another component of the MRE11-RAD50-NBN (MRN) complex, causes a Nijmegen breakage syndrome-like disorder. ATM and MRE11 are associated with an ataxia-telangiectasia(-like) disorder which shares a number of features in common with NBS. This gene-disease association is also supported by experimental evidence (11.5 points). Multiple NBN deficient mouse models have been established to show consistent phenotypes with NBS patients, including increased sensitivity to ionizing radiation, loss of the G2/M checkpoint, increased chromosome damage and susceptible to tumor development. (PMIDs: 11967151, 14612522, 15333589, 20921278). In summary, NBN is definitively associated with autosomal recessive NBS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Evidence summary addendum: The Severe Combined Immune Deficiency (SCID) and Combined Immune Deficiency (CID) Gene Curation Expert Panel reviewed the association of immunodeficiency with Nijmegen Syndrome (NBS). Immune deficiency in NBS is characterized by variably decreased immunoglobulin levels, T cell lymphopenia and decreased T cell function associated with recurrent bacterial and viral infections (PMIDs:14632755, PMID:12390322). Immunodeficiency is found in patients with the common 657del5 variant and can also be found in other nonsense variants associated with NBS (PMID: 15451479; PMID:25677497). Some NBS patients can be identified through newborn screening analyzing T-cell excision circles (TRECs), and most NBS patients demonstrate low TRECs number throughout life (PMIDs: 28791007, 25677497). Functional evidence further supports the gene-disease relationship for NBN and immunodeficiency, including mouse models demonstrating NBN’s role in T cell receptor recombination (PMID: 20921278), rescue of the immune phenotype with successful BMT (PMID: 19684627) and expression studies (PMIDs: 25677497,15451479). The SCID-CID GCEP curated an additional two variants with further description of immunological findings. This addendum was approved by the SCID-CID Gene Curation Expert Panel on the meeting date March 17, 2022.