• Login
    View Item 
    •   UMB Digital Archive
    • UMB Open Access Articles
    • UMB Open Access Articles
    • View Item
    •   UMB Digital Archive
    • UMB Open Access Articles
    • UMB Open Access Articles
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    KCNQ1 and Long QT Syndrome in 1/45 Amish: The Road from Identification to Implementation of Culturally Appropriate Precision Medicine

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Author
    Streeten, E.A.
    See, V.Y.
    Jeng, L.B.J.
    Maloney, K.A.
    Lynch, M.
    Glazer, A.M.
    Yang, T.
    Roden, D.
    Pollin, T.I.
    Daue, M.
    Ryan, K.A.
    Van Hout, C.
    Gosalia, N.
    Gonzaga-Jauregui, C.
    Economides, A.
    Perry, J.A.
    O’Connell, J.
    Beitelshees, A.
    Palmer, K.
    Mitchell, B.D.
    Shuldiner, A.R.
    Show allShow less

    Date
    2020-11-03
    Journal
    Circulation: Genomic and Precision Medicine
    Publisher
    Lippincott Williams and Wilkins
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1161/CIRCGEN.120.003133
    Abstract
    Background: In population-based research exome sequencing, the path from variant discovery to return of results is not well established. Variants discovered by research exome sequencing have the potential to improve population health. Methods: Population-based exome sequencing and agnostic ExWAS were performed 5521 Amish individuals. Additional phenotyping and in vitro studies enabled reclassification of a KCNQ1 variant from variant of unknown significance to pathogenic. Results were returned to participants in a community setting. Results: A missense variant was identified in KCNQ1 (c.671C>T, p.T224M), a gene associated with long QT syndrome type 1, which can cause syncope and sudden cardiac death. The p.T224M variant, present in 1/45 Amish individuals is rare in the general population (1/248 566 in gnomAD) and was highly associated with QTc on electro-cardiogram (P=5.53E-24, β=20.2 ms/allele). Because of the potential importance of this variant to the health of the population, additional phenotyping was performed in 88 p.T224M carriers and 54 noncarriers. There was stronger clinical evidence of long QT syndrome in carriers (38.6% versus 5.5%, P=0.0006), greater history of syncope (32% versus 17%, P=0.020), and higher rate of sudden cardiac death in first degree relatives<age 30 (4.5% versus 0%, P=0.026). Expression of p.T224M KCNQ1 in Chinese hamster ovary cells showed near complete loss of protein function. Our clinical and functional data enabled reclassification of p.T224M from a variant of unknown significance to pathogenic. Of the 88 carriers, 93% met criteria for beta-blocker treatment and 5/88 (5.7%) were on medications that may further prolong QTc. Carriers were provided a Clinical Laboratory Improvement Amendments confirmed report, genetic counseling, and treatment recommendations. Follow-up care was coordinated with local physicians. Conclusions: This work provides a framework by which research exome sequencing can be rapidly translated in a culturally appropriate manner to directly benefit research participants and enable population precision health. Copyright 2020 Cambridge University Press. All rights reserved.
    Keyword
    exome
    genetic counseling
    human
    population health
    syncope
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/14619
    ae974a485f413a2113503eed53cd6c53
    10.1161/CIRCGEN.120.003133
    Scopus Count
    Collections
    UMB Open Access Articles

    entitlement

    Related articles

    • Biophysical properties of 9 KCNQ1 mutations associated with long-QT syndrome.
    • Authors: Yang T, Chung SK, Zhang W, Mullins JG, McCulley CH, Crawford J, MacCormick J, Eddy CA, Shelling AN, French JK, Yang P, Skinner JR, Roden DM, Rees MI
    • Issue date: 2009 Aug
    • Genotype-based clinical manifestation and treatment of Chinese long QT syndrome patients with KCNQ1 mutations - R380S and W305L.
    • Authors: Zhou H, Lai W, Zhu W, Xie J, Liu X, Shen Y, Yuan P, Liu Y, Cao Q, He W, Hong K
    • Issue date: 2016 Apr
    • Biophysical properties of mutant KCNQ1 S277L channels linked to hereditary long QT syndrome with phenotypic variability.
    • Authors: Aidery P, Kisselbach J, Schweizer PA, Becker R, Katus HA, Thomas D
    • Issue date: 2011 Apr
    • Identification of a Novel KCNQ1 Frameshift Mutation and Review of the Literature among Iranian Long QT Families
    • Authors: Amirian A, Zafari Z, Karimipoor M, Kordafshari A, Dalili M, Saber S, Farjam Fazelifar A, Zeinali S
    • Issue date: 2019 May
    • Further evidence of the association between LQT syndrome and epilepsy in a family with KCNQ1 pathogenic variant.
    • Authors: Tiron C, Campuzano O, Pérez-Serra A, Mademont I, Coll M, Allegue C, Iglesias A, Partemi S, Striano P, Oliva A, Brugada R
    • Issue date: 2015 Feb
    DSpace software (copyright © 2002 - 2022)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.