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Rare allelic forms of PRDM9 associated with childhood leukemogenesis

Hussin, Julie; Sinnett, Daniel; Casals, Ferran; Idaghdour, Youssef; Bruat, Vanessa; Saillour, Virginie; Healy, Jasmine; Grenier, Jean-Christophe; de Malliard, Thibault and Busche, Stephan, et al. (2013) In Genome Research 23(3). p.30-419
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... (More)

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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Adolescent, Alleles, Child, Child, Preschool, Cohort Studies, Crossing Over, Genetic, Exome, Female, Gene Frequency, Gene Rearrangement, Genomic Instability, Histone-Lysine N-Methyltransferase/genetics, Humans, Infant, Leukemia, Biphenotypic, Acute/genetics, Male, Meiosis, Microarray Analysis, Mutation, Pedigree, Polymorphism, Single Nucleotide, Recombination, Genetic, Sequence Analysis, DNA, Translocation, Genetic
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Genome Research
volume
23
issue
3
pages
12 pages
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Cold Spring Harbor Laboratory Press
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  • scopus:84874615220
ISSN
1549-5469
DOI
10.1101/gr.144188.112
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English
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cb4bf941-8a38-4832-91b7-443087a5acde
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2019-06-19 14:04:18
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2019-09-26 04:38:13
@article{cb4bf941-8a38-4832-91b7-443087a5acde,
  abstract     = {<p>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.</p>},
  author       = {Hussin, Julie and Sinnett, Daniel and Casals, Ferran and Idaghdour, Youssef and Bruat, Vanessa and Saillour, Virginie and Healy, Jasmine and Grenier, Jean-Christophe and de Malliard, Thibault and Busche, Stephan and Spinella, Jean-François and Larivière, Mathieu and Gibson, Greg and Andersson, Anna and Holmfeldt, Linda and Ma, Jing and Wei, Lei and Zhang, Jinghui and Andelfinger, Gregor and Downing, James R and Mullighan, Charles G and Awadalla, Philip},
  issn         = {1549-5469},
  keyword      = {Adolescent,Alleles,Child,Child, Preschool,Cohort Studies,Crossing Over, Genetic,Exome,Female,Gene Frequency,Gene Rearrangement,Genomic Instability,Histone-Lysine N-Methyltransferase/genetics,Humans,Infant,Leukemia, Biphenotypic, Acute/genetics,Male,Meiosis,Microarray Analysis,Mutation,Pedigree,Polymorphism, Single Nucleotide,Recombination, Genetic,Sequence Analysis, DNA,Translocation, Genetic},
  language     = {eng},
  number       = {3},
  pages        = {30--419},
  publisher    = {Cold Spring Harbor Laboratory Press},
  series       = {Genome Research},
  title        = {Rare allelic forms of PRDM9 associated with childhood leukemogenesis},
  url          = {http://dx.doi.org/10.1101/gr.144188.112},
  volume       = {23},
  year         = {2013},
}