ClinVar

In patients of Slavic origin with Nijmegen breakage syndrome (NBS; 251260), Varon et al. (1998) identified a common deletion of 5 nucleotides in exon 6 of the NBS1 gene (657del5), resulting in a frameshift and a truncated protein. A total of 46 patients homozygous for this mutation were identified. The mutation was found exclusively on a specific 'Slavic' haplotype of linked polymorphic markers.

Matsuura et al. (1998) found the same 5-bp deletion in the NBS1 gene in 13 NBS patients of Slavic or German origin. Twelve patients were homozygous for the deletion and 1 was heterozygous. The deletion introduced a premature termination signal at codon 218, which was predicted to result in a severely truncated polypeptide. Matsuura et al. (1998) concluded that they had identified the gene involved in NBS because complementation was effected by a YAC that contained the gene and because no (or extremely reduced) expression of the gene was found in a patient without the deletion but with the NBS phenotype. The presence of a founder mutation in 13 of 14 cases, with no demonstration of the deletion in 50 normal individuals of the same ethnic origin or in 7 normal chromosomes from NBS parents, supported this conclusion.

The truncating 657del5 had been identified in 90% of NBS patients. NBS shares a number of features with ataxia-telangiectasia (208900), the most notable being high sensitivity to ionizing radiation and predisposition to cancer. Patients who are heterozygous for the ATM mutation are predisposed to breast cancer. Since the NBS phenotype at the cellular level is very similar to that of ataxia-telangiectasia, Carlomagno et al. (1999) screened 477 German breast cancer patients, aged under 51 years, and 866 matched controls for the common NBS mutation. They identified 1 carrier among the cases and 1 among the controls, indicating that the population frequency of this NBS mutation is 1 in 866 persons (95% CI = 1 in 34,376 to 1 in 156) and the estimated prevalence of NBS is thus 1 in 3 million persons. The proportion of breast cancer attributable to this mutation is less than 1%.

Kleier et al. (2000) reported a 5-year-old Bosnian boy with severe microcephaly. Because of multiple structural aberrations involving chromosomes 7 and 14 typical for ataxia-telangiectasia, that disorder was diagnosed. However, the diagnosis of NBS was suggested by the boy's remarkable microcephaly, his facial appearance, and the absence of ataxia and telangiectasia. DNA analysis demonstrated homozygosity for the major mutation in the NBS1 gene, 657del5.

Maser et al. (2001) tested the hypothesis that the NBS1 657del5 mutation is a hypomorphic defect. They showed that NBS cells harboring the 657del5 mutation contained a predicted 26-kD N-terminal protein, NBS1(p26), and a 70-kD NBS1 protein, NBS1(p70), lacking the native N terminus. The 26-kD protein is not physically associated with the MRE11 complex (600814), whereas the 70-kD species is physically associated with it. NBS1(p70) is produced by internal translation initiation within the NBS mRNA using an open reading frame generated by the 657del5 frameshift. Maser et al. (2001) proposed that the common NBS1 allele encodes a partially functional protein that diminishes the severity of the NBS phenotype.

Tekin et al. (2002) reported a consanguineous Turkish family whose first son died of anal atresia and whose second son, the proband, presented with severe pre- and postnatal growth retardation as well as striking microcephaly, immunodeficiency, congenital heart disease, chromosome instability, and rhabdomyosarcoma in the anal region. The patient was homozygous for the 657del5 mutation in the NBS1 gene, which is responsible for NBS in most Slavic populations. The family was the first diagnosed with NBS in the Turkish population and was one of the most severely affected examples of the syndrome.

Drabek et al. (2002) presented PCR with sequence specific primers as a method for detection of the 657del5 mutation. They confirmed a high carrier frequency in the Czech population (1 in 106 persons; 95% CI = 1 in 331 to 1 in 46).

In Russian children, Resnick et al. (2003) screened for the 657del5 NBS1 mutation in 548 controls and 68 patients with lymphoid malignancies. No carrier of the mutation was found in the control group. The mutation was found in heterozygous form in 2 of the 68 patients from the group of lymphoid malignancies, 1 with acute lymphoblastic leukemia (see 159555) and 1 with non-Hodgkin lymphoma (605027). Several relatives of the patient with non-Hodgkin lymphoma who carried the same mutation had cancer (acute lymphoblastic leukemia, breast cancer, gastrointestinal cancers), suggesting that heterozygosity may predispose to malignant disorders.

In monozygotic twin brothers with a severe form of NBS without chromosomal instability, Seemanova et al. (2006) identified compound heterozygosity for the 657del5 mutation and a 643C-T transition in exon 6 of the NBS1 gene, resulting in an arg215-to-trp (R215W) substitution (602667.0009). Both infants showed reduced expression of full-length nibrin, and radiation response processes were strongly reduced in their cells. Their mother and father were heterozygous for the 657del5 mutation and the R215W mutation, respectively, as were their respective grandfathers.

In a 3-month-old boy with NBS, Varon et al. (2007) identified homozygosity for the 657del5 mutation; the patient's mother carried the mutation, whereas his father was homozygous for the wildtype allele. Analysis of 27 microsatellite markers covering all of chromosome 8 revealed that the patient had a homozygous haplotype for all of the markers, whereas the mother carried the same haplotype in heterozygous state. The authors stated that this was the first patient with NBS due to maternal isodisomy of chromosome 8.

Porhanova et al. (2008) reported a 52-year-old Russian woman with ovarian cancer (see 604370) who was found to be compound heterozygous for a mutation in the BRCA1 gene (113705.0018) and the common Slavic 657del5 mutation in the NBN gene. Investigation of the ovarian cancer tissue showed somatic loss of heterozygosity for NBN, but retention of heterozygosity for BRCA1. The patient did not have a particularly severe cancer-prone phenotype, and her parents did not have cancer, although 3 sibs developed cancer as adults. Porhanova et al. (2008) commented that haploinsufficiency of the BRCA1 gene may contribute to cancer progression without somatic changes.