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Nijmegen Breakage Syndrome

Synonyms: Berlin Breakage Syndrome, Ataxia-Telangiectasia Variant 1

, PhD and , MD.

Author Information
, PhD
Center for Public Health Genomics
University of Virginia
Charlottesville, Virginia
, MD
Department of Pathology
David Geffen School of Medicine at UCLA
Los Angeles, California

Initial Posting: ; Last Update: March 1, 2011.

Summary

Disease characteristics. Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, intrauterine growth retardation and short stature, recurrent sinopulmonary infections, an increased risk for cancer, and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time and most children tested after age seven years have mild to moderate intellectual disability. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. About 35% of those reported have developed malignancies between ages one and 34 years, with the risk being highest for B-cell lymphomas. Other tumors include T-cell lymphoma and solid tumors, such as medulloblastoma, glioma, and rhabdomyosarcoma. Note, however, that much of what is reported about NBS is based on individuals who are homozygous for the single most common Eastern European mutation, 657_661del5.

Diagnosis/testing. Diagnosis is based on molecular genetic testing of NBS1, the only gene known to be associated with Nijmegen breakage syndrome. Disease-causing mutations are identified in almost 100% of affected individuals. If the diagnosis is not established by molecular genetic testing, immunoblotting to determine if the nibrin protein is absent and colony survival assay to determine radiosensitivity can be used for diagnosis.

Management. Treatment of manifestations: Use of IVIg should be considered in individuals with severe humoral immunodeficiency and frequent infections.

Surveillance: Periodic follow-up to monitor mental and physical growth and infection frequency. Monitoring for premature ovarian insufficiency should be considered in females.

Agents/circumstances to avoid: Because the cells from individuals with NBS are radiosensitive in vitro, doses of radiation used in radiotherapy need to be reduced.

Genetic counseling. NBS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing are possible if both disease-causing alleles of an affected family member have been identified.

Diagnosis

Clinical Diagnosis

The diagnosis of Nijmegen breakage syndrome (NBS) is suspected in individuals with the following findings:

  • Microcephaly is present in about 75% of affected individuals at birth, and in the remainder during the first months of life.
  • Growth retardation is either present at birth or manifests before age two years. Thereafter, growth rate is appropriate, but individuals remain small for age.
  • Characteristic facial features — a sloping forehead, receding mandible, prominent nasal root and nose, large ears, and upward slant of the palpebral fissures — become apparent at about age three years.
  • Recurrent sinopulmonary infections include pneumonia, bronchitis, otitis media, sinusitis, and mastoiditis.
  • Malignancies, most commonly B-cell lymphoma, which develops in most individuals before age 15 years, occur in approximately 50% of individuals with NBS.
  • Decline in intellectual ability results in intellectual disability in the borderline-to-moderate range by age ten years in most affected children

Testing

Immunoblotting is used to determine if the nibrin protein is present or absent.

Note: This test requires that a lymphoblastoid cell line be established.

Radiation sensitivity. Cells from individuals with NBS have a decrease of colony-forming ability following exposure to ionizing radiation and radiomimetics in vitro. S

Note: This test requires that a lymphoblastoid cell line be established.

Immunodeficiency involving the humoral and cellular system:

  • Agammaglobulinemia has been found in 35% and IgA deficiency in 20% of affected individuals.
  • Deficiencies in IgG2 and IgG4 are frequent even when the IgG serum concentration is normal.
  • The most commonly reported defects in cellular immunity are reduced percentages of total CD3+ T cells and CD4+ cells.
  • An increased frequency of T cells with a memory phenotype (CD45RO+) and a concomitant decrease in naive T cells (CD45RA+) has been reported [Michalkiewicz et al 2003].

Chromosomal instability. Inversions and translocations involving chromosomes 7 and 14 are observed in PHA-stimulated lymphocytes in 10%-50% of metaphases. The breakpoints most commonly involved are 7p13, 7q35, 14q11, and 14q32, which are the loci for immunoglobulin and T cell-receptor genes.

Molecular Genetic Testing

Gene. NBN is the only gene in which mutations are known to cause Nijmegen breakage syndrome.

Other loci. Approximately 50% of individuals referred for diagnostic testing for NBS share significant clinical overlap and have pronounced radiosensitivity, but lack mutations in NBN [Author, unpublished observation]. A number of reports suggest that mutations in other genes such as LIG4 and RAD50 can lead to disorders with similar clinical presentations. However, mutations in these genes are very rare and do not account for the incidence of NBS-like clinical presentation in persons lacking NBN mutations. Presently, distinction can only be made by excluding mutations in NBN.

Clinical testing

    • All affected individuals from Poland, the Czech Republic, and the Ukraine tested to date are homozygous for the common mutation c.657_661del5. In a study of eight unrelated individuals with NBS from the Russian population, Resnick et al [2002] found that all but one of the 16 alleles were 657_657del5.
    • In the US, about 70% of individuals tested to date are homozygous for the common allele, 15% are heterozygous for c.657_661del5 and a second unique mutation, and 15% are homozygous for a unique mutation.

      Note: (1) Unique mutations are identified by sequence analysis. (2) In the US patient population, almost all affected individuals who have the p.657_661del5 mutation are of known Eastern European ancestry.
  • Sequence analysis can detect the common allele and other mutations including small intragenic deletions/insertions and missense, nonsense, and splice site mutations. Of individuals with NBS tested to date in the US, 15% are heterozygous for the common allele (c.657_661del5) and a second unique mutation, and 15% are homozygous for a unique mutation.

    Note: Unique mutations are identified by sequence analysis.

Table 1. Summary of Molecular Genetic Testing Used in Nijmegen Breakage Syndrome

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method and Population 1, 2
Slavic 3North American 4
NBNTargeted mutation analysisc.657_661del5Homozygous (c.657_661del5/ c.657_661del5): 100%Homozygous (c.657_661del5/ c.657_661del5): 70%
Sequence analysisSequence variants 5Not applicableSee footnote 6

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Given the rarity of NBS it is likely that most of the mutations show some kind of founder effect, making

reliable estimates of incidence difficult to establish.

3. Slavic = Poland, Czech Republic, Ukraine

4. Based on the small number of individuals observed

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

6. Of individuals tested to date in the US, 15% are heterozygous for the common allele (c.657_661del5) and a second unique mutation; 15% are homozygous for a unique mutation.

Testing Strategy

To confirm/establish the diagnosis in a proband. Diagnostic testing for NBS can be performed on a single sample of heparinized blood:

If the common allele is not present:

  • Perform immunoblotting to determine if the nibrin protein is present or absent
  • Perform colony survival assay to determine radiosensitivity

If all three tests (targeted mutation analysis, immunoblotting, colony survival assay) are normal, a diagnosis of NBS is extremely unlikely.

  • Full gene sequencing is performed only after prior testing has revealed that:
    • The c.657_661del5 mutation is not present,
    • The nibrin protein is absent or truncated, and
    • The cells are radiosensitive.
  • If nibrin is present, but the cells are radiosensitive, evaluation for other disorders of DNA repair or immunodeficiency is warranted. (See Differential Diagnosis.)

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are at some increased risk of developing malignancy related to Nijmegen breakage syndrome.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Growth. Children with Nijmegen breakage syndrome (NBS) generally have lower than normal birth weight and are small for gestational age. If not present from birth, microcephaly develops during the first months of life and progresses to severe microcephaly. Growth failure during the first two years of life results in height that is usually less than the third centile by age two years. The linear growth rate tends to be normal after age two years, but individuals remain small for age.

Facial features. As microcephaly progresses, the facial features tend to become distinct, with sloping forehead, upslanting palpebral fissures, prominent midface, long nose, and small jaw. The ears may be large.

Psychomotor development. Developmental milestones are attained at the usual time during the first year. Borderline delays in development and psychomotor hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time and most children tested after age seven years have mild-to-moderate intellectual disability. The children are described as having a cheerful, shy personality with good interpersonal skills.

Infections. Respiratory infections are the most common. Recurrent pneumonia and bronchitis may result in pulmonary failure and early death. Chronic diarrhea and urinary tract infections may also occur.

Malignancy. According to Wegner et al [1999], 25 of the 70 individuals (35%) reported to date have developed malignancies between ages one and 34 years. Twenty-two of the 25 were lymphomas, of which 19 occurred before age 15 years. Nine out of 19 were B-cell lymphomas; 1/19 was a T-cell lymphoma [Michallet et al 2003]. Several children developed solid tumors, including medulloblastomas, glioma, and rhabdomyosarcoma [Hiel et al 2001, Bakhshi et al 2003, Distel et al 2003, Meyer et al 2004].

Fertility. Wegner et al [1999] report a high incidence of premature ovarian insufficiency in both prepubertal girls with NBS and adolescent and post-adolescent women with NBS, as evidenced by elevated serum concentration of gonadotropins in both groups and primary amenorrhea and lack of secondary sexual development in the latter. Chrzanowska et al [2010] provide further support for these findings in a larger study of females with NBS, all homozygous for the common c.657_661del5 mutation.

No detailed studies of fertility in males with NBS have been published. However, Warcoin et al [2009] did describe an atypical male with oligo-terato-asthenozoospermia who had biallelic truncating mutations in NBN but none of the clinical features of NBS. Whether gonadal failure is part of the NBS phenotype in males is not yet clear.

Other findings

  • Irregular skin pigmentation, manifested as hyperpigmented or hypopigmented irregular spots, is seen in most individuals.
  • Congenital malformations, usually observed in single cases, include hydrocephalus, preaxial polydactyly, occipital cyst, choanal atresia, cleft lip and palate, tracheal hypoplasia, horseshoe kidney, hydronephrosis, hypospadias, anal stenosis/atresia, and congenital hip dysplasia.

Genotype-Phenotype Correlations

There are two reports of families in which biallelic truncating mutations in NBN occur in healthy adult individuals:

  • Varon et al [2006] described a 53-year-old woman who was homozygous for the NBN truncating allele c.742insGG, but had no clinical features of NBS other than primary amenorrhea. However, analysis of transcripts from the patient’s cells indicated a highly prevalent alternatively spliced form of NBN lacking exons 6 and 7 (where the mutation is located). This transcript produces a 73-kd form of NBN with an internal deletion.
  • Warcoin et al [2009] described a family in which two healthy adult sibs had biallelic truncating mutations in NBN (c.330T>G and c.1125G>A). Both were normal on clinical examination and did not have any evidence of short stature, reduced head circumference, or facial dysmorphology; however, both were referred for fertility defects and were subsequently found to have the cellular phenotypes typical of NBS including chromosomal instability, hypersensitivity to ionizing radiation, and impaired checkpoint responses.

While the clinical findings in these individuals would not suggest a diagnosis of NBS, the testing strategy would have identified these individuals based on the presence of two truncating mutations and radiation hypersensitivity.

Heterozygotes. Heterozygotes are asymptomatic. Epidemiologic studies are underway to investigate a possible increased susceptibility to malignancy in heterozygotes. These studies are ideally performed in Eastern European populations where the incidence of the c.657_661del5 mutation is high, allowing direct screening for this single variant in individuals with cancer. Preliminary studies have provided suggestive evidence of an increased frequency of c.657_661del5 carriers in several different cancers including breast cancer, prostate cancer, medulloblastoma, and melanoma [Cybulski et al 2004, Steffen et al 2004, Ciara et al 2010]. There is also anecdotal evidence of increased frequencies of cancer in relatives of individuals with NBS.

Nomenclature

The Nijmegen breakage syndrome was described by Weemaes et al [1981].

Three Czech families with Seemanova syndrome [Seemanová et al 1985] were later identified as having NBS.

Genetic complementation studies are no longer of clinical importance. The report of Jaspers et al [1988] noted a strong similarity between NBS cells and ataxia-telangiectasia (A-T) cells; however, they also described the NBS cells as genetically distinct from A-T, grouping individuals with either Nijmegen breakage syndrome or Czech breakage syndrome into A-T variant group V1 and Germans with 'Berlin breakage syndrome' [Wegner et al 1999] into A-T variant group V2 [Jaspers et al 1988]. Subsequently, NBN mutations were found in all individuals studied from the A-T variant groups V1 and V2, indicating that these individuals had NBS, not ataxia-telangiectasia.

Prevalence

No reliable estimates of world-wide prevalence exist, but it is likely to approximate 1:100,000 live births.

NBS is most common in Eastern European/Slavic populations. Studies in Poland, the Czech Republic, and the Ukraine have suggested that the carrier frequency of the common allele approaches 1:155 in these populations. The highest reported prevalence is in Sorbians, a Slavic population isolate from Southeastern Germany, in whom the carrier frequency is estimated at 1:34 [Maurer et al 2010].

Differential Diagnosis

Recurrent infections, poor growth, and immunodeficiency can be observed in other inherited immunodeficiencies. Some inherited immunodeficiencies (e.g., X-linked agammaglobulinemia [Bruton's agammaglobulinemia] and X-linked severe combined immunodeficiency) also demonstrate radiosensitivity (in colony survival assays).

Individuals homozygous for the NBN c.1089C>A mutation have features of Fanconi anemia [Gennery et al 2004].

Occasionally individuals with the ATM mutation A-TFresno have symptoms of both Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia (A-T) [Curry et al 1989, Gilad et al 1998].

Microcephaly, midface prominence, and intellectual disability suggest syndromes such as Seckel syndrome [O'Driscoll et al 2003] and Rubinstein-Taybi syndrome; however, cells from these individuals are not typically radiosensitive by colony survival assay [O’Driscoll et al 2003]. Seeman et al [2004] suggest that NBN mutations account for a significant number of children with primary microcephaly in the Czech Republic. See also Primary Autosomal Recessive Microcephaly.

Individuals with ligase IV syndrome [O'Driscoll et al 2001] may present with features of NBS, including microcephaly, short stature, midface prominence, immunodeficiency, and radiosensitivity. However, the immunodeficiency (pancytopenia) in individuals with ligase IV syndrome is typically more severe than in individuals with NBS and may present in infancy as severe combined immunodeficiency [Enders et al 2006]. Ligase IV syndrome, caused by mutations in LIG4, is not associated with an increase in chromosomal instability or t(7;14). The two disorders can be differentiated by molecular genetic testing of LIG4 and NBN.

Waltes et al [2009] described a single individual with biallelic mutations in RAD50 resulting in production of reduced levels of an unstable RAD50 protein. This person had microcephaly, intellectual disability, short stature and facial dysmorphology typical of NBS, but had normal immunoglobulin levels and did not have recurrent sinopulmonary infections. As only one individual with RAD50 mutations has been described, it is unclear how consistent the clinical features of RAD50 deficiency will be; hence, the overlap with NBS.

The early growth failure in NBS may suggest other disorders of growth, such as thyroid hormone or growth hormone deficiency, or primary disorders of bone growth (i.e., a skeletal dysplasia).

Because lymphoma may be the presenting finding in NBS, the diagnosis of NBS should be considered before radiotherapy is initiated in individuals with lymphoma who are younger than age three years [Bakhshi et al 2003, Distel et al 2003, Meyer et al 2004].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluation Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Nijmegen breakage syndrome (NBS), the following evaluations are recommended:

  • Baseline evaluation of immune and endocrinologic status, degree of mental impairment, and head circumference
  • History of radiation exposure
  • Familial history of cancer

Treatment of Manifestations

In individuals with severe humoral immunodeficiency and frequent infections, IVIg should be considered. The spectrum of recurrent infections in NBS is not opportunistic; therefore, the antibiotic selected should be appropriate for the microorganism being treated.

Because of chromosomal instability, vitamin E and folic acid supplementation in doses appropriate for body weight is recommended.

Children with developmental delay should be referred to special services for treatment options.

Surveillance

Affected individuals

  • Periodic follow-up to monitor mental and physical growth and frequency of infections
  • For females with NBS, periodic monitoring for premature ovarian insufficiency [Chrzanowska et al 2010]
  • Monitoring for weight loss, which may signal the presence of a malignancy

Carriers (heterozygotes)

  • Parents. As obligate carriers, parents should be monitored for malignancy.
  • At-risk sibs. Evidence of cancer risk in young carriers is insufficient to warrant testing in childhood.

Agents/Circumstances to Avoid

Because the cells from individuals with NBS are as radiosensitive in vitro as those from individuals with ataxia-telangiectasia (another chromosomal instability syndrome), conventional doses of radiation used in radiotherapy could be lethal in individuals with NBS. Family members should be made aware of this risk so that they can discuss appropriate treatment options should a malignancy be diagnosed.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

NBS is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry a single copy of a disease-causing NBN mutation.
  • Heterozygotes are asymptomatic; however, anecdotal reports suggest an increased risk for malignancy in individuals who are heterozygous for the common Slavic mutation c.657_661del5 [Ciara et al 2010].

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic; however, anecdotal reports suggest an increased risk of malignancy in carriers for the common Slavic mutation, c.657_661del5.

Offspring of a proband. No affected individuals have been reported to reproduce.

Other family members of a proband. Sibs of the proband's parents are at 50% risk of also being carriers.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    UFK, Hugstetter Strasse 55
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: registry@esid.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Nijmegen Breakage Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Nijmegen Breakage Syndrome (View All in OMIM)

251260NIJMEGEN BREAKAGE SYNDROME
602667NIBRIN; NBN

Normal allelic variants. NBN is encoded in 16 exons and spans approximately 51 kb of DNA. The entire gene and flanking genomic regions have been sequenced. The gene encodes two transcripts of 4.4 and 2.4 kb that are expressed in all tissues examined and differ only in their site of polyadenylation. Both transcripts contain a single open reading frame coding for a protein of 754 amino acids with a predicted molecular weight of 85 kd. A number of normal and rare allelic variants in NBN have been described. Table 2 lists examples for which unaffected homozygous individuals have been identified, verifying that they are not disease-causing alleles. Alleles at these sites are all in very strong linkage disequilibrium in the general population. Additional variants such as c.283G>A (p.Asp95Asn), c.628G>T (p.Val210Phe), c.643C>T (p.Arg215Trp), and c.797C>T (p.Pro266Leu) have been reported in various cancer cases and controls. Their role in NBS, if any, is unclear as they are too rare to have been observed in homozygotes or in conjunction with a confirmed NBN mutation.

Table 2. Selected NBN Normal Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.102G>ANo changeNM_002485​.4
NP_002476​.2
c.553G>Cp.Glu185Gln
c.1197T>CNo change
c.2016A>GNo change

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Pathologic allelic variants. Most disease-causing NBN alleles identified to date are predicted to result in truncation of the nibrin protein (see Table 3). The c.657_661del5 mutation predominates in affected persons from Eastern Europe, accounting for more than 90% of all mutant alleles in NBN. Each of the other mutations listed in Table 3 occurs in one or a small number of families. NBN mRNA is always detectable in cell lines from individuals with NBS, but full-length nibrin protein is not detectable by Western blotting. Although some, and possibly all, NBN alleles produce one or more partial proteins, their abundance is generally low and varies in different cell types, making them a poor diagnostic marker.

One mutation, c.1089C>A is particularly noteworthy. It was originally described in a person diagnosed with atypical Fanconi anemia. Subsequent testing revealed homozygosity for an NBN mutation. Several additional families with this mutation have been identified and all display overlapping clinical features with Fanconi anemia syndrome [Gennery et al 2004, New et al 2005]. These findings highlight the lack of disease specificity in assays that test for sensitivity to DNA crosslinking agents.

While the overwhelming majority of persons with NBS have biallelic truncating alleles at NBN, Seemanová et al [2006] have described a unique set of monozygotic twins who are compound heterozygotes for the common c.657_661del5 mutation and a missense mutation, c.643C>T resulting in p.Arg215Trp. These twins had a more severe clinical course than typical for NBS, particularly with respect to neurologic features, but lacked the cellular chromosomal instability and radiation sensitivity characteristic of the disorder.

Table 3. Selected NBN Pathologic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change Reference Sequence OriginNumber of Families in Which Mutation is Observed
c.330T>Gp.Tyr110*NM_002485​.4
NP_002476​.2
1
c.643C>Tp.Arg215TrpSlavic1
c.657_661del5
(657del5)
p.Lys219Asnfs*15 SlavicN/A
c.681delTp.Phe228Leufs*3 Russian1
c.698_701del4p.Lys233Serfs*4English2
c.741_742dup
(742insGG)
p.Glu248Glyfs*5Italian1
c.835_838del4p.Gln279Profs*1 Italian1
c.842insTp.Leu281Phefs*3 Mexican1
c.900del25p.Gly301Lysfs*5Moroccan1
c.976C>Tp.Gln326*Dutch1
c.1089C>Ap.Tyr363*Pakistani 23
c.1125G>Ap.Trp375*1
c.1142delCp.Pro381Glnfs*22Canadian2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Individual originally diagnosed as having Fanconi anemia with atypical clinical features

Normal gene product. The NBN protein product is nibrin (also referred to as p95). Nibrin is a protein of 85 kd in mass that is ubiquitously expressed. There are no global sequence similarities between nibrin and any other known proteins. However, nibrin contains two recognizable protein domains, a forkhead-associated domain and a breast cancer carboxy-terminal domain, which are found in other proteins involved in cellular responses to DNA damage. In normal fibroblasts, nibrin is associated with two other proteins involved in DNA repair, hMre11 and hRad50. Upon exposure to ionizing radiation, this complex of proteins, including nibrin, forms nuclear foci at sites where DNA repair has taken place. Nibrin targets the NBN/Mre11/Rad50 complex to sites of double-strand breaks and interacts with ATM kinase to coordinate cell cycle arrest with DNA repair [Carney et al 1998, Matsuura et al 2004, Falck et al 2005].

Abnormal gene product. Most known NBN mutations are predicted to result in truncation of the nibrin protein. All known NBS mutations occur in exons 6-10; this is thought to reflect a requirement for production of a C-terminal protein fragment of nibrin that occurs by translational reinitiation mechanism [Maser et al 2001]. The requirement that protein termination and reinitiation occur in the same reading frame potentially limits the mutations that can give rise to NBS. Knockout mice homozygous for null alleles of NBN are embryonic lethal, suggesting that the partial protein produced from NBN alleles in humans is necessary for survival.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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Suggested Reading

  1. Dutrannoy V, Demuth I, Baumann U, Schindler D, Konrat K, Neitzel H, Gillessen-Kaesbach G, Radszewski J, Rothe S, Schellenberger MT, Nürnberg G, Nürnberg P, Teik KW, Nallusamy R, Reis A, Sperling K, Digweed M, Varon R. Clinical variability and novel mutations in the NHEJ1 gene in patients with a Nijmegen breakage syndrome-like phenotype. Hum Mutat. 2010;31:1059–68. [PubMed: 20597108]
  2. Eich M, Roos WP, Gianov GL, Digweed M, Kalina B. Nijmegen breakage syndrome protein (NBN) causes resistance to methylating anticancer drugs such as temozolomide. Mol Pharmacol. 2010;78:943–51. [PubMed: 20729302]
  3. Lins S, Krugger L, Chrzanowska KH, Seemanova E, Digweed M. Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome. Gene. 2009;447:12–17. [PubMed: 19635536]

Chapter Notes

Acknowledgments

PC is supported by grant CA57569 from the NIH. RAG is supported by grant 87ER60548 from the DOE, grant NS35322 from NIH and a grant from the AT Medical Research Foundation.

Revision History

  • 1 March 2011 (me) Comprehensive update posted live
  • 14 June 2005 (me) Comprehensive update posted to live Web site
  • 14 March 2003 (me) Comprehensive update posted to live Web site
  • 17 May 1999 (me) Review posted to live Web site
  • 5 January 1999 (pc) Original submission
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