title: 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.
abstract: Nijmegen breakage syndrome is an autosomal recessive disorder caused by biallelic mutation in NBN gene. It is characterized by microcephaly, growth retardation, 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 hereditary cancer over several generations, including lung, breast, ovarian, colon, prostate and renal cancers. By using next generation whole exome sequencing approach, we identified 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.
authors.affiliation: Kuwait Medical Genetics Centre, Maternity Hospital, Sabah Medical Area, P.O. Box 5833, 13059, Safat, Kuwait. mj_marafie@yahoo.com.
authors.forename: Makia J
authors.identifier: 0000-0003-0853-2039
authors.initials: MJ
authors.lastname: Marafie
authors.affiliation: Kuwait Medical Genetics Centre, Maternity Hospital, Sabah Medical Area, P.O. Box 5833, 13059, Safat, Kuwait.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Dashti
authors.affiliation: Department of Pathology, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110, Safat, Kuwait.
authors.forename: Fahd
authors.initials: F
authors.lastname: Al-Mulla
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D018912:Arabs / Q000235:genetics; D000073116:Cancer Survivors; D018797:Cell Cycle Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D000073359:Exome Sequencing
chemical_list: D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins
keywords: Arab; BRCA1; Lung cancer; NBN; Next generation sequencing; Whole-exome sequencing