TY - JOUR
T1 - Rare allelic forms of PRDM9 associated with childhood leukemogenesis
AU - Hussin, Julie
AU - Sinnett, Daniel
AU - Casals, Ferran
AU - Idaghdour, Youssef
AU - Bruat, Vanessa
AU - Saillour, Virginie
AU - Healy, Jasmine
AU - Grenier, Jean Christophe
AU - De Malliard, Thibault
AU - Busche, Stephan
AU - Spinella, Jean Francxois
AU - Larivière, Mathieu
AU - Gibson, Greg
AU - Andersson, Anna
AU - Holmfeldt, Linda
AU - Ma, Jing
AU - Wei, Lei
AU - Zhang, Jinghui
AU - Andelfinger, Gregor
AU - Downing, James R.
AU - Mullighan, Charles G.
AU - Awadalla, Philip
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
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U2 - 10.1101/gr.144188.112
DO - 10.1101/gr.144188.112
M3 - Article
C2 - 23222848
AN - SCOPUS:84874615220
VL - 23
SP - 419
EP - 430
JO - Genome Research
JF - Genome Research
SN - 1088-9051
IS - 3
ER -