Nijmegen Breakage Syndrome via the NBN Gene

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disease that causes microcephaly, short stature, immunodeficiency, and predisposition to cancer. Approximately half of individuals with NBS develop non-Hodgkin lymphoma or leukemia. Other cancers observed include medulloblastomas, gliomas, and rhabdomyosarcomas. Individuals with NBS are 50 times more likely to develop cancer than people without this condition. Intellectual development is normal in 40% of patients, borderline-to-mild retardation is found in 50% of patients, and 10% of patients are moderately retarded (Kondratenko et al. Adv Exp Med Biol 601:61-7, 2007). Women with NBS often have premature ovarian insufficiency and are infertile. It is estimated that the incidence of NBS is 1 in 100,000, with a higher prevalence in specific European ancestries (i.e. Slavic populations) (Concannon and Gatti. GeneReviews. 2011).

Nijmegen breakage syndrome is caused by variants in the NBN gene. The protein product of NBN, Nibrin, normally associates with the MRE11A and RAD50 proteins to form the MRN complex. The MRN complex, upon DNA damage, is involved in DNA repair and cell cycle arrest via the ATM kinase; pathogenic variants in NBN lead to faulty DNA repair and improper cell cycle control. NBS is inherited in an autosomal recessive manner, although carriers of NBN variants may be at a higher risk of malignancies (Ciara et al. Acta Neuropathol 119(3):325-34, 2010; Steffen et al. Int J Cancer 111(1):67-71, 2004). Most variants reported to date in NBN result in truncation variants of Nibrin. The c.657_661del5 variant is the most common variant found in Eastern Europeans with NBS, accounting for more than 90% of all mutant alleles in NBN. Other variants are private and occur in one or a small number of families (Concannon and Gatti. GeneReviews. 2011).

Analytical sensitivity should be high because the majority of variants reported are readily detectable by gene sequencing. Most of the variants reported are based on individuals who are homozygous for the single most common Eastern European variant, c.657_661del5, which can be readily detected using sequencing. In the United States, approximately 70% of individuals with NBS tested to date are homozygous for the common allele (c.657_661del5), 15% are heterozygous for c.657_661del5 and a second unique variant, and 15% are homozygous for a unique variant (Concannon and Gatti. GeneReviews. 2011). Individuals homozygous for the NBN c.1089C>A variant have features of Fanconi anemia (Gennery et al. Clin Immunol 113(2):214-9, 2004).

This test provides full coverage of all coding exons of the NBN gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.