ORIGINAL ARTICLE Identification of a rare germline NBN gene mutation by whole exome sequencing in a lung-cancer survivor from a large family with various types of cancer Makia J. Marafie 1 • Mohammed Dashti 1 • Fahd Al-Mulla 2 Ó Springer Science+Business Media Dordrecht 2016 Abstract Nijmegen breakage syndrome is an autosomal recessive disorder caused by biallelic mutation in NBN gene. It is characterized by microcephaly, growth retarda- tion, immuno-deficiency and cancer predisposition. The monoallelic carriers of NBN gene are also reported to be at increased risk of developing various types of malignancy. We have investigated an individual with lung cancer from an extended family segregating different types of heredi- tary cancer over several generations, including lung, breast, ovarian, colon, prostate and renal cancers. By using next generation whole exome sequencing approach, we identi- fied a rare heterozygous frameshift mutation in NBN gene; c.93_94delTG (Ala32HisfsTer4), which is predicted to be pathogenic together with 3 other variants; 2 being in the BRCA1 gene, c.1648A [ C (p.Asn550His) and c.536A [ G (p.Tyr179Cys), and one in RAD50 gene, c.3539G [ A (p.Arg1180Gln). Some of the variants were also found in six out of eight clinically normal relatives, but in different combinations. To our knowledge, this is the first report of NBN gene mutation in an individual with lung cancer in the Arab world. Reporting such findings may aid in variants’ risk classification and clinical decision in the future. Keywords Arab Á BRCA1 Á Lung cancer Á Next generation sequencing Á NBN Á Whole-exome sequencing Introduction Maintenance of genome stability depends on many DNA repairing proteins, of which NBN gene product plays an important role. Biallelic mutation of this gene leads to Nij- megen breakage syndrome (NBS). NBS is an autosomal recessive disorder characterized by microcephaly, growth retardation, immunodeficiency, predisposition to malig- nancy, and hypersensitivity to X-irradiation. Monoallelic relatives of NBS patients are also reported to be at increased risk of developing various cancer types. The NBN gene is located on chromosome 8q21 [1, 2] and encodes a protein named Nibrin (or p95), that is part of the MRE11/RAD50/ NBN (MRN) nuclease complex, which is an integral com- ponent of the BRCA1-associated genome surveillance com- plex, involving many proteins such as MSH2–MSH6, and MLH1, ATM, NBS1, MRE11, and BLM [2, 3]. This complex is responsible for double-strand DNA damage repair. The NBN common founder mutation 657del5 had been identified mostly in patients of Central or Eastern European origin (Poland, Russia, the Czech Republic and Germany), with more than 90% found to be in a homozygous state [4]. Heterozygous carriers of NBN 657del5 founder mutation are reported to be at increased risk of developing various types of cancer such as breast, prostate, urinary system, lymphosar- coma and other cancers [5]. Interestingly, an association between NBN exon variant rs1805794G [ C (p.Glu185Gln) polymorphism and lung cancer risk has been demonstrated in the Chinese populations [6]. In this article we describe the result of whole exome sequencing of a DNA sample from a patient presented with lung cancer, from an extended Arab family with several individuals manifesting different cancer types over several generations. We then checked for the existence of the detected variants in her available unaffected relatives. & Makia J. Marafie mj_marafie@yahoo.com 1 Kuwait Medical Genetics Centre, Maternity Hospital, Sabah Medical Area, P.O. Box 5833, 13059 Safat, Kuwait 2 Department of Pathology, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait 123 Familial Cancer DOI 10.1007/s10689-016-9954-9