title: Rare allelic forms of PRDM9 associated with childhood leukemogenesis.
abstract: One of the most rapidly evolving genes in humans, PRDM9, is a key determinant of the distribution of meiotic recombination events. Mutations in this meiotic-specific gene have previously been associated with male infertility in humans and recent studies suggest that PRDM9 may be involved in pathological genomic rearrangements. In studying genomes from families with children affected by B-cell precursor acute lymphoblastic leukemia (B-ALL), we characterized meiotic recombination patterns within a family with two siblings having hyperdiploid childhood B-ALL and observed unusual localization of maternal recombination events. The mother of the family carries a rare PRDM9 allele, potentially explaining the unusual patterns found. From exomes sequenced in 44 additional parents of children affected with B-ALL, we discovered a substantial and significant excess of rare allelic forms of PRDM9. The rare PRDM9 alleles are transmitted to the affected children in half the cases; nonetheless there remains a significant excess of rare alleles among patients relative to controls. We successfully replicated this latter observation in an independent cohort of 50 children with B-ALL, where we found an excess of rare PRDM9 alleles in aneuploid and infant B-ALL patients. PRDM9 variability in humans is thought to influence genomic instability, and these data support a potential role for PRDM9 variation in risk of acquiring aneuploidies or genomic rearrangements associated with childhood leukemogenesis.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Montreal, Montreal H3C 3J7, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Hussin
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnett
authors.forename: Ferran
authors.initials: F
authors.lastname: Casals
authors.forename: Youssef
authors.initials: Y
authors.lastname: Idaghdour
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bruat
authors.forename: Virginie
authors.initials: V
authors.lastname: Saillour
authors.forename: Jasmine
authors.initials: J
authors.lastname: Healy
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Grenier
authors.forename: Thibault
authors.initials: T
authors.lastname: de Malliard
authors.forename: Stephan
authors.initials: S
authors.lastname: Busche
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Spinella
authors.forename: Mathieu
authors.initials: M
authors.lastname: Larivière
authors.forename: Greg
authors.initials: G
authors.lastname: Gibson
authors.forename: Anna
authors.initials: A
authors.lastname: Andersson
authors.forename: Linda
authors.initials: L
authors.lastname: Holmfeldt
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.forename: Gregor
authors.initials: G
authors.lastname: Andelfinger
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Philip
authors.initials: P
authors.lastname: Awadalla
mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003434:Crossing Over, Genetic; D059472:Exome; D005260:Female; D005787:Gene Frequency; D015321:Gene Rearrangement; D042822:Genomic Instability; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D015456:Leukemia, Biphenotypic, Acute / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008540:Meiosis; D046228:Microarray Analysis; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic
chemical_list: D011495:Histone-Lysine N-Methyltransferase; C544431:PRDM9 protein, human