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A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations

Author

Listed:
  • Xiaolin Zhu
  • Raghavendra Padmanabhan
  • Brett Copeland
  • Joshua Bridgers
  • Zhong Ren
  • Sitharthan Kamalakaran
  • Ailbhe O'Driscoll-Collins
  • Samuel F Berkovic
  • Ingrid E Scheffer
  • Annapurna Poduri
  • Davide Mei
  • Renzo Guerrini
  • Daniel H Lowenstein
  • Andrew S Allen
  • Erin L Heinzen
  • David B Goldstein

Abstract

Trio exome sequencing has been successful in identifying genes with de novo mutations (DNMs) causing epileptic encephalopathy (EE) and other neurodevelopmental disorders. Here, we evaluate how well a case-control collapsing analysis recovers genes causing dominant forms of EE originally implicated by DNM analysis. We performed a genome-wide search for an enrichment of "qualifying variants" in protein-coding genes in 488 unrelated cases compared to 12,151 unrelated controls. These "qualifying variants" were selected to be extremely rare variants predicted to functionally impact the protein to enrich for likely pathogenic variants. Despite modest sample size, three known EE genes (KCNT1, SCN2A, and STXBP1) achieved genome-wide significance (p

Suggested Citation

  • Xiaolin Zhu & Raghavendra Padmanabhan & Brett Copeland & Joshua Bridgers & Zhong Ren & Sitharthan Kamalakaran & Ailbhe O'Driscoll-Collins & Samuel F Berkovic & Ingrid E Scheffer & Annapurna Poduri & D, 2017. "A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations," PLOS Genetics, Public Library of Science, vol. 13(11), pages 1-12, November.
    • Handle: RePEc:plo:pgen00:1007104
    DOI: 10.1371/journal.pgen.1007104
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    References listed on IDEAS

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    1. Brian J. O’Roak & Laura Vives & Santhosh Girirajan & Emre Karakoc & Niklas Krumm & Bradley P. Coe & Roie Levy & Arthur Ko & Choli Lee & Joshua D. Smith & Emily H. Turner & Ian B. Stanaway & Benjamin V, 2012. "Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations," Nature, Nature, vol. 485(7397), pages 246-250, May.
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