Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era

Nadine Norton, Peggy D. Robertson, Mark J. Rieder, Stephan L Zuchner, Evadnie Rampersaud, Eden R Martin, Duanxiang Li, Deborah A. Nickerson, Ray E. Hershberger

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

Background-Human exome sequencing is a recently developed tool to aid in the discovery of novel coding variants. Now broadly applied, exome sequencing data sets provide a novel opportunity to evaluate the allele frequencies of previously published pathogenic rare variants. Methods and Results-We examined the exome data set from the National Heart, Lung and Blood Institute Exome Sequencing Project and compared this data set with a catalog of 197 previously published rare variants reported as causative of dilated cardiomyopathy (DCM) from familial and sporadic cases. Of these 197, 33 (16.8%) were also present in the Exome Sequencing Project database, raising the question of whether they were uncommon polymorphisms. Supporting functional data has been published for 14 of the 33 (42%), suggesting they are unlikely to be false-positives. The frequencies of these functional variants in the Exome Sequencing Project data set ranged from 0.02 to 1.33% (median 0.04%), which when applied as a cutoff to filter variants in a DCM pedigree identified an additional DCM candidate gene. A greater proportion of sporadic DCM cases had variants that were present in the Exome Sequencing Project data set versus novel variants (ie, not in the Exome Sequencing Project; 44% versus 21%; P=0.002), suggesting some of the variants identified as disease causing in sporadic DCM are either false-positives or low penetrance alleles in human populations. Conclusions-Rare nonsynonymous variants identified in DCM subjects also present at very low frequencies in public databases are likely relevant for DCM. Allele frequencies >0.04% are of less certain pathogenicity, especially if identified in sporadic cases, although this cutoff should be viewed as preliminary.

Original languageEnglish
Pages (from-to)167-174
Number of pages8
JournalCirculation: Cardiovascular Genetics
Volume5
Issue number2
DOIs
StatePublished - Apr 1 2012

Fingerprint

Exome
Dilated Cardiomyopathy
Virulence
Gene Frequency
Databases
National Heart, Lung, and Blood Institute (U.S.)
Penetrance
Pedigree
Alleles
Datasets

Keywords

  • Cardiomyopathy
  • Genes
  • Genetics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

Cite this

Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era. / Norton, Nadine; Robertson, Peggy D.; Rieder, Mark J.; Zuchner, Stephan L; Rampersaud, Evadnie; Martin, Eden R; Li, Duanxiang; Nickerson, Deborah A.; Hershberger, Ray E.

In: Circulation: Cardiovascular Genetics, Vol. 5, No. 2, 01.04.2012, p. 167-174.

Research output: Contribution to journalArticle

Norton, N, Robertson, PD, Rieder, MJ, Zuchner, SL, Rampersaud, E, Martin, ER, Li, D, Nickerson, DA & Hershberger, RE 2012, 'Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era', Circulation: Cardiovascular Genetics, vol. 5, no. 2, pp. 167-174. https://doi.org/10.1161/CIRCGENETICS.111.961805
Norton, Nadine ; Robertson, Peggy D. ; Rieder, Mark J. ; Zuchner, Stephan L ; Rampersaud, Evadnie ; Martin, Eden R ; Li, Duanxiang ; Nickerson, Deborah A. ; Hershberger, Ray E. / Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era. In: Circulation: Cardiovascular Genetics. 2012 ; Vol. 5, No. 2. pp. 167-174.
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N2 - Background-Human exome sequencing is a recently developed tool to aid in the discovery of novel coding variants. Now broadly applied, exome sequencing data sets provide a novel opportunity to evaluate the allele frequencies of previously published pathogenic rare variants. Methods and Results-We examined the exome data set from the National Heart, Lung and Blood Institute Exome Sequencing Project and compared this data set with a catalog of 197 previously published rare variants reported as causative of dilated cardiomyopathy (DCM) from familial and sporadic cases. Of these 197, 33 (16.8%) were also present in the Exome Sequencing Project database, raising the question of whether they were uncommon polymorphisms. Supporting functional data has been published for 14 of the 33 (42%), suggesting they are unlikely to be false-positives. The frequencies of these functional variants in the Exome Sequencing Project data set ranged from 0.02 to 1.33% (median 0.04%), which when applied as a cutoff to filter variants in a DCM pedigree identified an additional DCM candidate gene. A greater proportion of sporadic DCM cases had variants that were present in the Exome Sequencing Project data set versus novel variants (ie, not in the Exome Sequencing Project; 44% versus 21%; P=0.002), suggesting some of the variants identified as disease causing in sporadic DCM are either false-positives or low penetrance alleles in human populations. Conclusions-Rare nonsynonymous variants identified in DCM subjects also present at very low frequencies in public databases are likely relevant for DCM. Allele frequencies >0.04% are of less certain pathogenicity, especially if identified in sporadic cases, although this cutoff should be viewed as preliminary.

AB - Background-Human exome sequencing is a recently developed tool to aid in the discovery of novel coding variants. Now broadly applied, exome sequencing data sets provide a novel opportunity to evaluate the allele frequencies of previously published pathogenic rare variants. Methods and Results-We examined the exome data set from the National Heart, Lung and Blood Institute Exome Sequencing Project and compared this data set with a catalog of 197 previously published rare variants reported as causative of dilated cardiomyopathy (DCM) from familial and sporadic cases. Of these 197, 33 (16.8%) were also present in the Exome Sequencing Project database, raising the question of whether they were uncommon polymorphisms. Supporting functional data has been published for 14 of the 33 (42%), suggesting they are unlikely to be false-positives. The frequencies of these functional variants in the Exome Sequencing Project data set ranged from 0.02 to 1.33% (median 0.04%), which when applied as a cutoff to filter variants in a DCM pedigree identified an additional DCM candidate gene. A greater proportion of sporadic DCM cases had variants that were present in the Exome Sequencing Project data set versus novel variants (ie, not in the Exome Sequencing Project; 44% versus 21%; P=0.002), suggesting some of the variants identified as disease causing in sporadic DCM are either false-positives or low penetrance alleles in human populations. Conclusions-Rare nonsynonymous variants identified in DCM subjects also present at very low frequencies in public databases are likely relevant for DCM. Allele frequencies >0.04% are of less certain pathogenicity, especially if identified in sporadic cases, although this cutoff should be viewed as preliminary.

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