Rare allelic forms of PRDM9 associated with childhood leukemogenesis

Julie Hussin, Daniel Sinnett, Ferran Casals, Youssef Idaghdhour, Vanessa Bruat, Virginie Saillour, Jasmine Healy, Jean Christophe Grenier, Thibault De Malliard, Stephan Busche, Jean Francxois Spinella, Mathieu Larivière, Greg Gibson, Anna Andersson, Linda Holmfeldt, Jing Ma, Lei Wei, Jinghui Zhang, Gregor Andelfinger, James R. Downing & 2 others Charles G. Mullighan, Philip Awadalla

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish (US)
    Pages (from-to)419-430
    Number of pages12
    JournalGenome Research
    Volume23
    Issue number3
    DOIs
    StatePublished - Mar 1 2013

    Fingerprint

    B-Lymphoid Precursor Cells
    Precursor Cell Lymphoblastic Leukemia-Lymphoma
    Alleles
    Genetic Recombination
    Aneuploidy
    Mothers
    Exome
    Polyploidy
    Genomic Instability
    Male Infertility
    Genes
    Siblings
    Parents
    Observation
    Genome
    Mutation

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)

    Cite this

    Hussin, J., Sinnett, D., Casals, F., Idaghdhour, Y., Bruat, V., Saillour, V., ... Awadalla, P. (2013). Rare allelic forms of PRDM9 associated with childhood leukemogenesis. Genome Research, 23(3), 419-430. https://doi.org/10.1101/gr.144188.112

    Rare allelic forms of PRDM9 associated with childhood leukemogenesis. / Hussin, Julie; Sinnett, Daniel; Casals, Ferran; Idaghdhour, Youssef; Bruat, Vanessa; Saillour, Virginie; Healy, Jasmine; Grenier, Jean Christophe; De Malliard, Thibault; Busche, Stephan; Spinella, Jean Francxois; Larivière, Mathieu; Gibson, Greg; Andersson, Anna; Holmfeldt, Linda; Ma, Jing; Wei, Lei; Zhang, Jinghui; Andelfinger, Gregor; Downing, James R.; Mullighan, Charles G.; Awadalla, Philip.

    In: Genome Research, Vol. 23, No. 3, 01.03.2013, p. 419-430.

    Research output: Contribution to journalArticle

    Hussin, J, Sinnett, D, Casals, F, Idaghdhour, Y, Bruat, V, Saillour, V, Healy, J, Grenier, JC, De Malliard, T, Busche, S, Spinella, JF, Larivière, M, Gibson, G, Andersson, A, Holmfeldt, L, Ma, J, Wei, L, Zhang, J, Andelfinger, G, Downing, JR, Mullighan, CG & Awadalla, P 2013, 'Rare allelic forms of PRDM9 associated with childhood leukemogenesis', Genome Research, vol. 23, no. 3, pp. 419-430. https://doi.org/10.1101/gr.144188.112
    Hussin J, Sinnett D, Casals F, Idaghdhour Y, Bruat V, Saillour V et al. Rare allelic forms of PRDM9 associated with childhood leukemogenesis. Genome Research. 2013 Mar 1;23(3):419-430. https://doi.org/10.1101/gr.144188.112
    Hussin, Julie ; Sinnett, Daniel ; Casals, Ferran ; Idaghdhour, Youssef ; Bruat, Vanessa ; Saillour, Virginie ; Healy, Jasmine ; Grenier, Jean Christophe ; De Malliard, Thibault ; Busche, Stephan ; Spinella, Jean Francxois ; Larivière, Mathieu ; Gibson, Greg ; Andersson, Anna ; Holmfeldt, Linda ; Ma, Jing ; Wei, Lei ; Zhang, Jinghui ; Andelfinger, Gregor ; Downing, James R. ; Mullighan, Charles G. ; Awadalla, Philip. / Rare allelic forms of PRDM9 associated with childhood leukemogenesis. In: Genome Research. 2013 ; Vol. 23, No. 3. pp. 419-430.
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    AU - Bruat, Vanessa

    AU - Saillour, Virginie

    AU - Healy, Jasmine

    AU - Grenier, Jean Christophe

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    AU - Busche, Stephan

    AU - Spinella, Jean Francxois

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