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Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder caused by biallelic mutations in the NBN gene, which encodes the DNA double-strand break repair protein nibrin. Patients present with congenital microcephaly, growth retardation, immunodeficiency and cancer predisposition. Over 200 unrelated individuals with NBS harbor loss-of-function NBN alleles, most commonly the founder 5 bp deletion c.657_661del (p.Lys219fs), confirming an autosomal recessive inheritance (PMID:9590180).
Segregation studies in consanguineous and non-consanguineous families demonstrate perfect cosegregation of homozygous or compound heterozygous NBN variants with disease, with at least 19 affected relatives documented across multiple pedigrees. Chromosomal instability assays in patient lymphocytes reveal spontaneous and irradiation-induced translocations, reinforcing the pathogenicity of identified variants (PMID:8554361).
Case series have described a spectrum of NBN variants: the Slavic founder mutation c.657_661del (p.Lys219fs) predominates, but additional truncating (e.g., c.353del (p.Ser118fs)), splice (c.1914+1G>T), and missense (c.643C>T (p.Arg215Trp)) alleles have been reported in diverse populations (PMID:10852373). Compound heterozygosity with hypomorphic alleles (e.g., c.643C>T (p.Arg215Trp)) can exacerbate neurological features, underscoring allelic heterogeneity and founder effects.
Functional assays reveal that nibrin associates with the MRE11–RAD50 complex at sites of DNA damage and is phosphorylated by ATM at Ser343, a modification required for efficient DNA-damage signaling and repair; ATM-deficient cells fail to phosphorylate nibrin and exhibit impaired G2/M checkpoints (PMID:10802669). Alternative translation initiation of the common c.657_661del allele yields a partially functional NBS1p70 fragment that retains MRE11 binding, explaining the hypomorphic nature of this allele (PMID:11279524).
Mouse models with conditional Nbn knockout recapitulate key NBS features: complete loss of nibrin is embryonic lethal, whereas tissue-specific deletion in lymphoid or neural precursors leads to immunodeficiency, microcephaly, and defective DNA repair, supporting a haploinsufficiency mechanism and the essential role of nibrin in genome maintenance (PMID:12422221).
No significant conflicting evidence has been reported that refutes the NBN–NBS association; heterozygous carriers show variable cancer risk in adulthood but do not manifest classical NBS. Studies assessing the role of NBN heterozygosity in lymphoma development in childhood found no major effect, indicating that biallelic loss is required for the syndrome (PMID:10848790).
Integration of genetic and experimental data establishes a definitive association between NBN and Nijmegen breakage syndrome. Biallelic inactivation of NBN causes defective double-strand break repair, leading to a consistent phenotype of microcephaly, immunodeficiency, and cancer predisposition. Diagnostic screening for the founder c.657_661del (p.Lys219fs) and other pathogenic variants enables early identification and informed management, including radiation-sparing therapies.
Gene–Disease AssociationDefinitiveOver 200 unrelated probands with biallelic loss-of-function NBN alleles; multi-family segregation; concordant functional data Genetic EvidenceStrongNumerous homozygous and compound heterozygous cases across diverse populations; founder mutation plus additional truncating and missense variants Functional EvidenceModerateATM phosphorylation assays, in vitro DNA repair studies, and tissue-specific Nbn knockout models replicate human phenotype |