title: Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records.
abstract: OBJECTIVE
  Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants.
  
  
  OBJECTIVE
  To determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes.
  
  
  METHODS
  This prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014.
  
  
  METHODS
  One or more variants designated as pathogenic in SCN5A or KCNH2.
  
  
  METHODS
  Arrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review.
  
  
  RESULTS
  Among 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen κ = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds.
  
  
  CONCLUSIONS
  Among laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise questions about the implications of notifying patients of incidental genetic findings.
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Van Driest
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Quinn S
authors.initials: QS
authors.lastname: Wells
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Sarah
authors.initials: S
authors.lastname: Stallings
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee2Case Western Reserve University, Cleveland, Ohio.
authors.forename: William S
authors.initials: WS
authors.lastname: Bush
authors.affiliation: University of Washington, Seattle.
authors.forename: Adam
authors.initials: A
authors.lastname: Gordon
authors.affiliation: University of Washington, Seattle.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: University of Washington, Seattle.
authors.forename: Jerry H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: University of Washington, Seattle.
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.affiliation: University of Washington, Seattle.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.affiliation: Group Health Research Institute, Seattle, Washington.
authors.forename: David S
authors.initials: DS
authors.lastname: Carrell
authors.affiliation: Group Health Research Institute, Seattle, Washington.
authors.forename: James D
authors.initials: JD
authors.lastname: Ralston
authors.affiliation: Group Health Research Institute, Seattle, Washington.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Suzette J
authors.initials: SJ
authors.lastname: Bielinski
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Olson
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Zi
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Iftikhar J
authors.initials: IJ
authors.lastname: Kullo
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Noura S
authors.initials: NS
authors.lastname: Abul-Husn
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Scott
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Erwin
authors.initials: E
authors.lastname: Bottinger
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Berta
authors.initials: B
authors.lastname: Almoguera
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: John
authors.initials: J
authors.lastname: Connolly
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Rosetta
authors.initials: R
authors.lastname: Chiavacci
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania8Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Rasmussen-Torvik
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Vivian
authors.initials: V
authors.lastname: Pan
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Persell
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Maureen
authors.initials: M
authors.lastname: Smith
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Rex L
authors.initials: RL
authors.lastname: Chisholm
authors.affiliation: Marshfield Clinic Research Foundation, Marshfield, Wisconsin.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Kitchner
authors.affiliation: Marshfield Clinic Research Foundation, Marshfield, Wisconsin.
authors.forename: Max M
authors.initials: MM
authors.lastname: He
authors.affiliation: Marshfield Clinic Research Foundation, Marshfield, Wisconsin.
authors.forename: Murray H
authors.initials: MH
authors.lastname: Brilliant
authors.affiliation: Pennsylvania State University, University Park.
authors.forename: John R
authors.initials: JR
authors.lastname: Wallace
authors.affiliation: Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: M Benjamin
authors.initials: MB
authors.lastname: Shoemaker
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Rongling
authors.initials: R
authors.lastname: Li
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Teri A
authors.initials: TA
authors.lastname: Manolio
authors.affiliation: Transgenomic, New Haven, Connecticut.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Callis
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Macaya
authors.affiliation: Geisinger Health System, Danville, Pennsylvania.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Williams
authors.affiliation: Geisinger Health System, Danville, Pennsylvania.
authors.forename: David
authors.initials: D
authors.lastname: Carey
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Jamie D
authors.initials: JD
authors.lastname: Kapplinger
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.affiliation: Pennsylvania State University, University Park16Geisinger Health System, Danville, Pennsylvania.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001145:Arrhythmias, Cardiac / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D053840:Brugada Syndrome / Q000235:genetics; D000072237:ERG1 Potassium Channel; D057286:Electronic Health Records; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000592:standards; D014644:Genetic Variation; D023281:Genomics; D006579:Heterozygote; D006801:Humans; D033162:Incidental Findings; D007753:Laboratories / Q000592:standards*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype; D011446:Prospective Studies; D011897:Random Allocation; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human