Which came first: validity or clinical testing? The example of long QT genes

Abstract

Aim: To investigate the potential relationship between the strength of evidence for a gene-disease association and inclusion of the gene on a targeted, indication-based gene panel test for hereditary long QT syndrome (LQTS) and to explore factors that may influence laboratory decisions about the inclusion or exclusion of genes from these clinical tests.

Methods: A comprehensive literature search was performed to quantify existing evidence supporting putative LQTS gene-disease associations. This evidence included the year that the gene was first implicated in LQTS, the total number of published cases of LQTS attributed to the gene, and the presence of published segregation and functional data for the gene. To explore the possible relationship between the published evidence for clinical validity of each gene and availability of clinical genetic testing, semi-structured interviews were conducted with key laboratory stakeholders. Representatives from nine US laboratories offering clinical LQTS gene testing agreed to be interviewed regarding decision-making about when and why genes comprising their clinical LQTS test offerings were added.

Results: Genes associated with LQTS before 2006 generally had more reported cases of LQTS and the greatest amount of supporting segregation and functional data prior to being offered as a clinical test. For genes first linked to LQTS after 2006, these trends are less linear and the timeframe between initial report and inclusion on clinical test menus decreased substantially. Advances in technology, lifting of patents, clinician request, and literature searches were cited as the main factors that influence composition of LQTS gene panel tests. Paradoxically, one lab director noted that it may require more evidence to remove a gene than to add a gene to a clinical test panel.

Conclusion: Our evaluation of the LQTS genes illustrates the nuanced relationship between published evidence supporting a gene-disease association and availability of clinical testing. Expert assessment of clinical validity of gene-disease associations may help laboratories to determine gene panel content. The ultimate impact of such information on the composition of clinical gene tests as well as their utilization by clinicians and coverage by health insurance policies remains to be seen.

Keywords

Clinical validity / NGS tests / long QT syndrome / gene panels / PanelApp / ClinGen

References

[1] ChongJX,JhangianiSN,SobreiraN,HarrellTM,WiszniewskW,AkdemirZHC,ScottAF,ChakravartiA,MathewsD,LingH,WatkinsL,ReinierF,MuznyD,BilguvarK,SuttonRV,LealSM,ManeS,BoerwinkleE,ShendureJ,LiftonRP,NickersonDA.The genetic basis of mendelian phenotypes: discoveries, challenges, and opportunities.Am J Hum Genet2015;97:199-215 PMCID:PMC4573249

[2] RehmHL,BrooksLD,EvansJP,LedbetterDH,MartinCL,PlonSE,SherryST,ClinGen..ClinGen - The Clinical Genome Resource.N Engl J Med2015;372:2235-42 PMCID:PMC4474187

[3] Transforming Genetic Medicine Initiative (TGMI) online resource. GEMSTAR. Available from: http://www.thetgmi.org//gemstar/. [Last accessed on 24 Jun 2018]

[4] Genomics England PanelApp online resource. Long QT syndrome (Version 1.5). Available from: https://panelapp.genomicsengland.co.uk/panels/76/. [Last accessed 24 Jun 2018]

[5] ShahSR.Long QT syndrome: a comprehensive review of the literature and current evidence.Curr Probl Cardiol2018;18:30051-3

[6] AminAS.Genetic screening in acquired long QT syndrome? Caution: proceed carefully.Eur Heart J2016;37:1465-8 PMCID:PMC4914884

[7] RohatgiRK,BosJM,AsirvathamSJ,OwenHJ,KruisselbrinkT.Contemporary outcomes in patients with LQTS.J Am Coll Cardiol2017;70:453-62

[8] MossAJ,CramptonRS,LocatiEH,HallWJ,VincentGM,RobinsonJL,ChoiS.The long QT syndrome. Prospective longitudinal study of 328 families..Circulation1991;84:1136-44

[9] Fernández-FalguerasA,BrugadaJ,CampuzanoO.Cardiac channelopathies and sudden death: recent clinical and genetic advances.Biology (Basel).2017;6.pii:E7 PMCID:PMC5372000

[10] ItohH,AibaT,DenjoyI,HayashiK,OhnoS,WuJ,MastantuonoE,PedrazziniM,BerthetM,ShimizuW,SchwartzPJ.The genetics underlying acquired long QT syndrome: impact for genetic screening.Eur Heart J2016;37:1456-64 PMCID:PMC4914885

[11] PrioriSG,HorieM,BehrER,BlomN,ChiangCE,KannankerilP,LeenhardtA,SchwartzPJ,TomaselliG.Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes.Heart Rhythm2013;10:e85-108

[12] GiudicessiJR,AckermanMJ.The genetic architecture of long QT syndrome: a critical reappraisal.Trends Cardiovasc Med2018;

[13] Van DriestSL,StallingsS,GordonA,KimJH,JarvikGP,RalstonJD,BielinskiSJ,YeZ,Abul-HusnNS,BottingerE,ConnollyJ,HakonarsonH,PanV,SmithM,KitchnerTE,BrilliantMH,DohenyKF,LiR,CallisTE,WilliamsMS,KapplingerJD,RitchieMD,RodenDM.Association of arrhythmia-related genetic variants with phenotypes documented in electronic medical records.JAMA2016;315:47-57 PMCID:PMC4758131

[14] PrioriSG,MazzantiA,BorggrefeM,ElliottPM,HatalaR,KirchhofP,KuckKH,NikolaouN,SpauldingC.2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.Rev Esp Cardiol (Eng Ed).2016;69:176

[15] CzosekRJ,CassedyAE,VetterVL,Wernovksy,WrayJ.Quality of life of pediatric patients with long QT syndrome.Am J Cardiol2016;117:605-10

[16] GiuffreRM,CrawfordSG.Fears and anxiety in children with long-QT syndrome compared to children with asthma.J Natl Med Assoc2008;100:420-4

[17] VattaM,YeB,UghanzeEE,TesterDJ,FoellJD,KampTJ.Mutant Caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.Circulation2006;114:2104-12

[18] YeB,VattaM,AckermanMJ.Molecular and functional characterization of novel CAV3-encoded caveolin-3 mutations in congenital long QT syndrome.Heart Rhythm2006;3:S1

[19] Medeiros-DomingoA,TesterDJ,IttyA,ValdiviaC,Canizales-QuinterosS,MakielskiJC.SCN4B-encoded sodium channel 4 subunit in congenital long-QT syndrome.Circulation2007;116:134-42 PMCID:PMC3332546

[20] ChenL,TesterDJ,AckermanMJ.Mutation of an A-kinase-anchoring protein causes long-QT syndrome.Proc Natl Acad Sci USA2007;104:20990-5 PMCID:PMC2409254

[21] MaltesePE,KrasikovaE,CheremisinaA,SalminaA,BonizzatoA,ZuntiniM,BertelliM.Gene-targeted analysis of clinically diagnosed long QT Russian families.Int Heart J2017;58:81-7

[22] ShimizuW.Clinical impact of genetic studies in lethal inherited cardiac arrhythmias.Circ J2008;72:1926-36

[23] AngristM,HeaneyC.Impact of gene patents and licensing practices on access to genetic testing for long QT syndrome.Genet Med2010;12:S111-54 PMCID:PMC3021512

[24] StrandeNT,BuchananAH,DiStefanoM,GoldsteinJ,SeifertBA,WrightMW,CherryJM,MurrayMF,RamosEM,ScottAF,RehmHL,BergJS.Evaluating the clinical validity of gene-disease associations: an evidence-based framework developed by the clinical genome resource.Am J Hum Genet2017;100:895-906 PMCID:PMC5473734

[25] National human genome research institute (NHGRI) online resource. Available from: www.genome.gov/10002335/regulation-of-genetic-tests/. [Last accessed on 25 Jun 2018]

[26] OkurV.The impact of hereditary cancer gene panels on clinical care and lessons learned.Cold Spring Harb Mol Case Stud2017;3:a002154 PMCID:PMC5701305

[27] KurianAW,HamiltonAS,HawleyST,McLeodMC,KatzSJ.Gaps in incorporating germline genetic testing into treatment decision-making for early-stage breast cancer.J Clin Oncol2017;35:2232-9 PMCID:PMC5501363

[28] Wooderchak-DonahueW,TvrdikT,LewisT,RaneyJA,BergA,YetmanAT,MesleyR,CollinsRT,RobertsA,WoernerA,Bayrak-ToydemirP.Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy.Am J Med Genet A2015;167A:1747-57