Genetic Causes of Cardiac Disease

407 Pages·2019·7.581 MB·English

by  Jeanette Erdmann, Alessandra Moretti

Cardiac and Vascular Biology 7
Editor-in-chief: Markus Hecker
Jeanette Erdmann
Alessandra Moretti Editors
Genetic
Causes of
Cardiac
Disease
Cardiac and Vascular Biology
Volume 7
Editor-in-Chief
MarkusHecker
Inst.ofPhysiology&Pathophysiology,HeidelbergUniversity,Heidelberg,
Baden-Württemberg,Germany
SeriesEditors
JohannesBacks
DepartmentofMolecularCardiologyandEpigenetics,HeidelbergUniversity,
Heidelberg,Baden-Württemberg,Germany
MarcFreichel
InstituteofPharmacology,HeidelbergUniversity,Heidelberg,Germany
ThomasKorff
Inst.ofPhysiology&Pathophysiology,HeidelbergUniversity,Heidelberg,
Germany
DierkThomas
DepartmentofCardiologyandHCR,UniversityHospitalHeidelberg,Heidelberg,
Germany
Thebookseriesgivesanoverviewonallaspectsofstate-of-the-artresearchonthe
cardiovascular system in health and disease. Basic research aspects of medically
relevant topics are covered and the latest advances and methods covering diverse
disciplines as epigenetics, genetics, mechanobiology, platelet research or stem cell
biology are featured. The book series is intended for researchers, experts and
graduates, both basic and clinically oriented, that look for a carefully selected
collectionofhighqualityreviewarticlesontheirrespectivefieldofexpertise.
Moreinformationaboutthisseriesathttp://www.springer.com/series/13128
Jeanette Erdmann (cid:129) Alessandra Moretti
Editors
Genetic Causes of Cardiac
Disease
Editors
JeanetteErdmann AlessandraMoretti
IIEG IMedicalDept(Cardiology)
UniversityofLubeck KlinikumRechtsderIsaroftheTechnical
Lübeck,Germany UniversityMunich
München,Bayern,Germany
ISSN2509-7830 ISSN2509-7849 (electronic)
CardiacandVascularBiology
ISBN978-3-030-27370-5 ISBN978-3-030-27371-2 (eBook)
https://doi.org/10.1007/978-3-030-27371-2
#SpringerNatureSwitzerlandAG2019
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Contents
1 GeneticsofAdultandFetalFormsofLongQTSyndrome. . . . . 1
LiaCrotti,AliceGhidoni,andFedericaDagradi
2 TheGeneticLandscapeofCardiomyopathies. . . . . . . . . . . . . . . 45
BrendaGerull,SabineKlaassen,andAndreasBrodehl
3 GeneticBasisofMitochondrialCardiomyopathy. . . . . . . . . . . . 93
ElisaMastantuono,CordulaMariaWolf,andHolgerProkisch
4 TheGeneticsofCoronaryHeartDisease. .. . . .. . . .. . . . .. . . . 141
JeanetteErdmannandMariaLoretoMuñozVenegas
5 ComplexGeneticsandtheEtiologyofHumanCongenital
HeartDisease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
RichardW.KimandPeterJ.Gruber
6 FamilialHypercholesterolemia. . . . . . . . . . . . . . . . . . . . . . . . . . 185
AshishSarrajuandJoshuaW.Knowles
7 LongNoncodingRNAsinCardiovascularDisease. . . . . . . . . . . 199
LescaM.Holdt,AlexanderKohlmaier,andDanielTeupser
8 MouseModelstoStudyInheritedCardiomyopathy. . . . . . . . . . 289
MohammadBakhtiarHossain,MohammadBohlooly-Y,
andRalphKnöll
9 InterrogatingCardiovascularGeneticsinZebrafish. . . . . . . . . . 313
JiandongLiu,MarcRenz,andDavidHassel
10 HumanInducedPluripotentStemCellsasPlatformforFunctional
ExaminationofCardiovascularGeneticsinaDish. . . . . . . . . . . 341
RalfDirschinger,TatjanaDorn,andAlessandraMoretti
v
vi Contents
11 SystemsMedicineasaTransformingToolforCardiovascular
Genetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
MelanieBoerriesandTanjaZeller
12 SexDifferencesinPrevalentCardiovascularDisease
intheGeneralPopulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
DanielEngler,NataschaMakarova,andRenateB.Schnabel
1
Genetics of Adult and Fetal Forms of Long
QT Syndrome
Lia Crotti, Alice Ghidoni, and Federica Dagradi
Contents
1.1 Introduction................................................................................. 2
1.2 PartI:GeneticsofAdultFormsofLongQTSyndrome.................................. 4
1.2.1 MajorLQTSGenes................................................................. 4
1.2.2 MinorLQTSGenes................................................................ 6
1.2.3 GeneticModifiersofLongQTSyndrome......................................... 8
1.3 PartII:GeneticsofPerinatalFormsofLongQTSyndrome.............................. 12
1.3.1 SodiumandPotassiumChannels................................................... 15
1.3.2 CalciumChannelComplex......................................................... 23
1.3.3 SuddenInfantDeathSyndrome(SIDS)andIntrauterineFetalDeath(IUFD):Role
ofLongQTSyndrome............................................................. 29
1.4 Conclusions................................................................................. 32
References......................................................................................... 32
Abstract
Long QT syndrome (LQTS) is an inherited cardiac disease characterized by
prolongation of QT interval at surface ECG, T-wave abnormalities, and high
risk of life-threatening arrhythmias in otherwise healthy young individuals.
Currently the LQTS diagnosis is genetically confirmed in nearly 75–85% of
LQTS patients, revealing agoodknowledge of thegeneticbases ofthedisease.
L.Crotti(*)
IstitutoAuxologicoItaliano,IRCCS,LaboratoryofCardiovascularGenetics,CenterforCardiac
ArrhythmiasofGeneticOrigin,Milan,Italy
DepartmentofMedicineandSurgery,UniversityofMilano-Bicocca,Milan,Italy
IstitutoAuxologicoItaliano,IRCCS,DepartmentofCardiovascular,NeuralandMetabolic
Sciences,SanLucaHospital,Milan,Italy
A.Ghidoni·F.Dagradi
IstitutoAuxologicoItaliano,IRCCS,LaboratoryofCardiovascularGenetics,CenterforCardiac
ArrhythmiasofGeneticOrigin,Milan,Italy
#SpringerNatureSwitzerlandAG2019 1
J.Erdmann,A.Moretti(eds.),GeneticCausesofCardiacDisease,Cardiacand
VascularBiology7,https://doi.org/10.1007/978-3-030-27371-2_1
2 L.Crottietal.
The main LQTS genes are KCNQ1, KCNH2, and SCN5A encoding potassium
and sodium cardiac ion channels responsible of the cardiac action potential
duration. Minor contributors of LQTS genetic background include genes
encodingothercardiacionchannels,ancillarysubunits,andproteincomponents
formingchannels’macromolecularcomplexes.
FetalandneonatalformsofLQTSarethemostaggressiveformofthedisease,
frequently associated with typical ECG features as very prolonged QTc, 2:1
functional atrioventricular block, T-wave alternans, and life-threatening
arrhythmias. The genetic basis of these early-onset cases is peculiar. Indeed,
while potassium channel mutations are the most commonly observed causes of
adultLQTS,fetalandneonatalformsofthediseasearemainlyduetoaggressive
sodiumchannelmutationsortomutationsaffectingcalciumchannelactivity,as
in Timothy syndrome, triadin knockout syndrome, and calmodulin-LQTS.
Aggressive forms of LQTS can also cause sudden infant death syndrome
(SIDS)orintrauterinefetaldeath.
1.1 Introduction
Long QT syndrome (LQTS) is an inherited cardiac disease characterized by
prolongation of QT interval at surface ECG, T-wave abnormalities (biphasic or
notchedTwaves),andhighriskoflife-threateningarrhythmias.Thetypicalventric-
ulartachyarrhythmiathatunderliescardiaceventsinLQTSisthetorsadesdepointes
(TdP).Thistypeofventriculartachycardiacanproducetransientsyncope,whenitis
self-limited,orcandegenerateintoventricularfibrillationandcardiacarrest,mainly
precipitatedbyemotionalorphysicalstress.Asignofmajorelectricalinstabilityin
LQTS patients is represented by T-wave alternans, a beat-to-beat alteration in
polarity, and amplitude of the T wave [1]. Long QT syndrome is considered one
oftheleadingcausesofsuddendeathinyoung(<35years)[2].Unfortunately,the
diseasecanremainclinicallysilentforalongtime,andsuddencardiacdeath(SCD)
maybethefirstmanifestationinsomecases.
The congenital form of the disease has been largely studied over the years and
includestwomainhereditaryvariants.TheRomano-Ward(RW)variant,described
forthefirsttimein1964[3],representstheautosomaldominantformofthedisease,
anditisrelativelycommon,withaprevalenceof1:2000livebirths[4].TheJervell
and Lange-Nielsen (JLN) syndrome is an extremely severe form of the disease,
associated with congenital deafness and higher mortality [5, 6]. The JLN has an
autosomalrecessivemodeofinheritance,morefrequentlyassociatedwithhomozy-
gousandrarelycompoundheterozygousmutations.Thissyndromeisveryrareand
affectsaround2–3outof1000individualswithcongenitaldeafness[6].
Since the main feature of LQTS is the prolongation of QT interval, it is not
surprisingthatcardiacionchannelsresponsibleforactionpotential(AP)durationare
themainmolecularplayersofthesyndrome.
In particular, three genes (KCNQ1, KCNH2, SCN5A), encoding cardiac sodium
and potassium channels, are the major genetic contributors underlying LQTS.
1 GeneticsofAdultandFetalFormsofLongQTSyndrome 3
effect Onlinecionic
unctional IKsIKrINa2+[Ca]iIKsIKrIK1ICaLINaINaIKsINaIKAChICaLICaLICaLICaL gene,theoncardia
F# # " " # # # " " " # " # " " " " hns
co
eaati
nit Formut
u
βnel4-sub n syndrome.actofgene
Protein K7.1VK11.1VNa1.5VAnkyrinB MinK MiRP1 Kir2.1 Ca1.2VCaveolin-3 Sodiumchan Yotiaoα1-Syntrophi Kir3.4 CaM CaM CaM Trisk32 TSe,Timothyeffectandimp
mal
on
veLQTS-associatedgenes OMIMIDLocus *60754211p15.5-p15.4 *1524277q36.1 *6001633p22.2 *1064104q25-q26 *17626121q22.12 *60379621q22.11 *60068117q24.3 *11420512p13.33 *6012533p25.3 *60825611q23.3 *6040017q21.2 *60101720q11.21 *60073411q24.3 *11418014q32.11 *1141822p21 *11418319q13.32 *6032836q22.31 ATSme,Andersen-Tawilsyndredproteinarereported.Functio"nctionorgainoffunction
Table1.1LongQTsyndromevarianttypessofardescribedandrelati LQTSvarianttypeSyndromeGeneKCNQ1LQT1RWS,JLNSKCNH2LQT2RWSSCN5ALQT3RWSANKBLQT4RWS,ANKBsyndromeKCNE1LQT5RWS,JLNSKCNE2LQT6RWSKCNJ2LQT7ATSCACNA1CLQT8TSCAV3LQT9RWSSCN4BLQT10RWSAKAP9LQT11RWSSNTA1LQT12RWSKCNJ5LQT13RWSCALM1LQT14CalmodulinopathyCALM2LQT15CalmodulinopathyCALM3LQT16CalmodulinopathyTRDNLQT17TRDNknockoutsyndrome RWSJLNSRomano-Wardsyndrome,JervellandLange-NielsensyndroMendelianInheritanceinMan(OMIM)geneID,thelocus,andtheencod#currentderivedfrominvitrocellularstudiesarereportedaslossoffu