Abstract 3301: Uncovering novel radiation sensitivity syndromes through exome sequencing

INTRODUCTION: The study of genetic disorders resulting in heightened sensitivity to ionizing radiation provides important molecular insights to DNA damage checkpoint and repair mechanisms. Individuals with these disorders have an increased risk of cancer and developmental abnormalities. We identified patients with unexplained radiation sensitivity disorders through the Texas Children9s Cancer Center and Genetics Consult Service at Texas Children9s Hospital. Children were screened for the known disorders prior to enrolling in a research study with whole exome sequencing. SUBJECTS: We identified three families with documented ionizing radiation sensitivity: (1) a sibling pair, one of whom had sternal osteomyelitis and a lung transplant (age 2) and a brother with eosinophilia and pneumonia (age 1); (2) a sibling pair, one child with astrocytoma (age 2) with severe leukoencephalopathy after radiation and a sister with medulloblastoma (age 2) and atypical encapsulated neuroma (age 13); and (3) a proband with leukemia and astrocytoma (age 2). All parents were unaffected. METHODS: We performed Illumina whole exome sequencing of probands and parents (when available), calling single nucleotide variants and insertions/deletions with ATLAS and PINDEL. We removed events >1% in 1079 unaffected normal samples, >1% dbSNP, or > = 20 individuals in Exome Aggregation Consortium. We kept rare missense and truncating variants, and prioritized rare compound heterozygous, homozygous, or mutations shared by affected sibs. RESULTS: In the proband with sternal osteomyelitis and lung transplant, we identified and validated compound heterozygous missense mutations in NDNL2 (MAGEG1), a small, intronless gene. NDNL2 is involved in the SMC5-SMC6 complex, and suggested to play a role in DNA repair. The known functions of NDNL2 may explain the finding of the patient9s cells displaying altered phosphorylation upon DNA damage for NBN (absent) and SMC1 (reduced). We are currently investigating the link between mutant NDNL2 and phosphorylation of NBN and SMC1. In kindred 2 (previously shown to transmit a SMARCB1 splice site mutation), the siblings share rare compound heterozygous missense mutations in ROBO1, and a nonsense mutation in MEGF6. In kindred 3, the proband with leukemia and astrocytoma was known to carry a large Xp deletion, but we identified no obvious candidate underlying radiation sensitivity. CONCLUSION: Careful study of rare kindreds with unexplained radiation sensitivity may provide new insights to the DNA damage response. Interestingly, two families also carried a known genetic condition (SMARCB1 mutation and Xp microdeletion) that may explain cancer phenotype but does not appear to underlie radiation sensitivity. The very rare biallelic missense mutations in NDNL2 implicate it as a candidate radiation sensitivity gene to be validated by further functional testing. Both siblings in this family had severe infections resulting in death in early childhood. Citation Format: Deborah I. Ritter, Andrea K. Petersen, Katherine M. Haines, Ryan C. Zabriskie, David A. Wheeler, Sharon E. Plon. Uncovering novel radiation sensitivity syndromes through exome sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3301. doi:10.1158/1538-7445.AM2015-3301