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Background  Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. While the multi-step model of pediatric leukemogenesis suggests interplay between constitutional and somatic genomes, the role of inherited genetic variability remains largely undescribed. Nonsyndromic familial ALL, although extremely rare, provides the ideal setting to study inherited contributions to ALL. Toward this goal, we sequenced the exomes of a childhood ALL family consisting of mother, father and two non-twinned siblings diagnosed with concordant pre-B hyperdiploid ALL and previously shown to have inherited a rare form of  PRDM9 , a histone H3 methyltransferase involved in crossing-over at recombination hotspots and Holliday junctions. We postulated that inheritance of additional rare disadvantaging variants in predisposing cancer genes could affect genomic stability and lead to increased risk of hyperdiploid ALL within this family.    Methods  Whole exomes were captured using Agilent’s SureSelect kit and sequenced on the Life Technologies SOLiD System. We applied a data reduction strategy to identify candidate variants shared by both affected siblings. Under a recessive disease model, we focused on rare non-synonymous or frame-shift variants in leukemia predisposing pathways.    Results  Though the family was nonsyndromic, we identified a combination of rare variants in Fanconi anemia (FA) genes  FANCP/SLX4  (compound heterozygote - rs137976282/rs79842542) and  FANCA  (rs61753269) and a rare homozygous variant in the Holliday junction resolvase  GEN1  (rs16981869). These variants, predicted to affect  protein function, were  previously identified in familial breast cancer cases. Based on our in-house database of 369 childhood ALL exomes, the sibs were the only patients to carry this particularly rare combination and only a single hyperdiploid patient was heterozygote at both  FANCP/SLX4  positions, while no  FANCA  variant allele carriers were identified.  FANCA  is the most commonly mutated gene in FA and is essential for resolving DNA interstrand cross-links during replication.  FANCP/SLX4  and  GEN1  are involved in the cleavage of Holliday junctions and their mutated forms, in combination with the rare allele of  PRDM9 , could alter Holliday junction resolution leading to nondisjunction of chromosomes and segregation defects.    Conclusion  Taken together, these results suggest that concomitant inheritance of rare variants in  FANCA, FANCP/SLX4  and  GEN1  on the specific genetic background of this familial case, could lead to increased genomic instability, hematopoietic dysfunction, and higher risk of childhood leukemia.

bmc cancer

Whole-exome sequencing of a rare case of familial childhood acute lymphoblastic leukemia reveals putative predisposing mutations in Fanconi anemia genes