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

Publication ,  Journal Article
Zhu, X; Padmanabhan, R; Copeland, B; Bridgers, J; Ren, Z; Kamalakaran, S; O'Driscoll-Collins, A; Berkovic, SF; Scheffer, IE; Poduri, A; Mei, D ...
Published in: PLoS Genet
November 2017

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<2.68×10-6). In addition, six of the 10 most significantly associated genes are known EE genes, and the majority of the known EE genes (17 out of 25) originally implicated in trio sequencing are nominally significant (p<0.05), a proportion significantly higher than the expected (Fisher's exact p = 2.33×10-17). Our results indicate that a case-control collapsing analysis can identify several of the EE genes originally implicated in trio sequencing studies, and clearly show that additional genes would be implicated with larger sample sizes. The case-control analysis not only makes discovery easier and more economical in early onset disorders, particularly when large cohorts are available, but also supports the use of this approach to identify genes in diseases that present later in life when parents are not readily available.

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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

November 2017

Volume

13

Issue

11

Start / End Page

e1007104

Location

United States

Related Subject Headings

  • Potassium Channels, Sodium-Activated
  • Potassium Channels
  • Nerve Tissue Proteins
  • NAV1.2 Voltage-Gated Sodium Channel
  • Mutation
  • Munc18 Proteins
  • Male
  • Humans
  • Genome-Wide Association Study
  • Genes, Dominant
 

Citation

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Zhu, X., Padmanabhan, R., Copeland, B., Bridgers, J., Ren, Z., Kamalakaran, S., … Goldstein, D. B. (2017). A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations. PLoS Genet, 13(11), e1007104. https://doi.org/10.1371/journal.pgen.1007104
Zhu, Xiaolin, Raghavendra Padmanabhan, Brett Copeland, Joshua Bridgers, Zhong Ren, Sitharthan Kamalakaran, Ailbhe O’Driscoll-Collins, et al. “A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations.PLoS Genet 13, no. 11 (November 2017): e1007104. https://doi.org/10.1371/journal.pgen.1007104.
Zhu X, Padmanabhan R, Copeland B, Bridgers J, Ren Z, Kamalakaran S, et al. A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations. PLoS Genet. 2017 Nov;13(11):e1007104.
Zhu, Xiaolin, et al. “A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations.PLoS Genet, vol. 13, no. 11, Nov. 2017, p. e1007104. Pubmed, doi:10.1371/journal.pgen.1007104.
Zhu X, Padmanabhan R, Copeland B, Bridgers J, Ren Z, Kamalakaran S, O’Driscoll-Collins A, Berkovic SF, Scheffer IE, Poduri A, Mei D, Guerrini R, Lowenstein DH, Allen AS, Heinzen EL, Goldstein DB. A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations. PLoS Genet. 2017 Nov;13(11):e1007104.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

November 2017

Volume

13

Issue

11

Start / End Page

e1007104

Location

United States

Related Subject Headings

  • Potassium Channels, Sodium-Activated
  • Potassium Channels
  • Nerve Tissue Proteins
  • NAV1.2 Voltage-Gated Sodium Channel
  • Mutation
  • Munc18 Proteins
  • Male
  • Humans
  • Genome-Wide Association Study
  • Genes, Dominant