Sudden unexplained deaths in apparently healthy individuals (newborn through adult) pose a vexing challenge to medical examiners, law enforcement and society as a whole. Recent advances in “molecular autopsies” have begun to uncover the mystery surrounding sudden unexplained deaths by identifying mutations that can result in or predispose an apparently healthy individual to sudden death. Genetic risks of sudden unexplained deaths have been studied from several different perspectives, and categorized generally by systems, including: cardiac, nervous, immune, and metabolic. This article reviews the genetic risks in sudden unexplained deaths, presents the current state and challenges of molecular investigations, and sheds light on future directions in sudden unexplained death investigations.
MathewsT.J.MininoA.M.OstermanM.J.. Annual summary of vital statistics: 2008.Pediatrics.2011 Jan; 127(1): 146–57.
2.
AckermanM.J.TesterD.J.DriscollD.J.Molecular autopsy of sudden unexplained death in the young.Am J Forensic Med Pathol.2001 Jun; 22(2): 105–11.
3.
SchwartzP.J.PrioriS.G.DumaineR.. A molecular link between the sudden infant death syndrome and the long-QT syndrome.N Engl J Med.2000 Jul 27; 343(4): 262–7.
4.
SchwartzP.J.Stramba-BadialeM.SegantiniA.. Prolongation of the QT interval and the sudden infant death syndrome.N Engl J Med.1998 Jun 11; 338(24): 1709–14.
5.
CerroneM.PrioriS.G.Genetics of sudden death: focus on inherited channelopathies.Eur Heart J.2011 Apr 9.
6.
PrioriS.G.The fifteen years of discoveries that shaped molecular electrophysiology: time for appraisal.Circ Res.2010 Aug 20; 107(4): 451–6.
7.
Van NorstrandD.W.ValdiviaC.R.TesterD.J.. Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) mutations in sudden infant death syndrome.Circulation.2007 Nov 13; 116(20): 2253–9.
8.
ArnestadM.CrottiL.RognumT.O.. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome.Circulation.2007 Jan 23; 115(3): 361–7.
9.
AckermanM.J.SiuB.L.SturnerW.Q.. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.JAMA.2001 Nov 14; 286(18): 2264–9.
10.
MillatG.KugenerB.ChevalierP.. Contribution of long-QT syndrome genetic variants in sudden infant death syndrome.Pediatr Cardiol.2009 May; 30(4): 502–9.
11.
ChungS.K.MacCormickJ.M.McCulleyC.H.. Long QT and Brugada syndrome gene mutations in New Zealand.Heart Rhythm.2007 Oct; 4(10): 1306–14.
12.
KoenigX.DysekS.KimbacherS.. Voltage-gated ion channel dysfunction precedes cardiomyopathy development in the dystrophic heart.PLoS One.2011; 6(5): e20300.
13.
McNairW.P.SinagraG.TaylorM.R.. SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism.J Am Coll Cardiol.2011 May 24; 57(21): 2160–8.
14.
DuncanJ.R.PatersonD.S.HoffmanJ.M.. Brainstem serotonergic deficiency in sudden infant death syndrome.JAMA.2010 Feb 3; 303(5): 430–7.
15.
LavezziA.M.CasaleV.OnedaR.. Sudden infant death syndrome and sudden intrauterine unexplained death: correlation between hypoplasia of raphe nuclei and serotonin transporter gene promoter polymorphism.Pediatr Res.2009 Jul; 66(1): 22–7.
16.
NaritaN.NaritaM.TakashimaS.. Serotonin transporter gene variation is a risk factor for sudden infant death syndrome in the Japanese population.Pediatrics.2001 Apr; 107(4): 690–2.
17.
PatersonD.S.RiveraK.D.BroadbeltK.G.. Lack of association of the serotonin transporter polymorphism with the sudden infant death syndrome in the San Diego Dataset.Pediatr Res.2010 Nov; 68(5): 409–13.
18.
Weese-MayerD.E.Berry-KravisE.M.MaherB.S.. Sudden infant death syndrome: association with a promoter polymorphism of the serotonin transporter gene.Am J Med Genet A.2003 Mar 15; 117A(3): 268–74.
19.
OpdalS.H.RognumT.O.The IL6 -174G/C polymorphism and sudden infant death syndrome.Hum Immunol.2007 Jun; 68(6): 541–3.
20.
CourtsC.MadeaB.No association of IL-10 promoter SNP -592 and -1082 and SIDS.Forensic Sci Int.2011 Jan 30; 204(1-3): 179–81.
21.
OpdalS.H.OpstadA.VegeA.RognumT.O.IL-10 gene polymorphisms are associated with infectious cause of sudden infant death.Hum Immunol.2003 Dec; 64(12): 1183–9.
22.
HighetA.R.BerryA.M.GoldwaterP.N.Distribution of interleukin-1 receptor antagonist genotypes in sudden unexpected death in infancy (SUDI); unexplained SUDI have a higher frequency of allele 2.Ann Med.2010; 42(1): 64–9.
23.
HighetA.R.GibsonC.S.GoldwaterP.N.Variant interleukin 1 receptor antagonist gene alleles in sudden infant death syndrome.Arch Dis Child.2010 Dec; 95(12): 1009–12.
24.
MoscovisS.M.GordonA.E.HallS.T.. Interleukin 1-beta responses to bacterial toxins and sudden infant death syndrome.FEMS Immunol Med Microbiol.2004 Sep 1; 42(1): 139–45.
SchneiderP.M.WendlerC.RiepertT.. Possible association of sudden infant death with partial complement C4 deficiency revealed by post-mortem DNA typing of HLA class II and III genes.Eur J Pediatr.1989 Dec; 149(3): 170–4.
27.
BennettM.J.PowellS.Metabolic disease and sudden, unexpected death in infancy.Hum Pathol.1994 Aug; 25(8): 742–6.
28.
BennettM.J.RinaldoP.The metabolic autopsy comes of age.Clin Chem.2001; 47(7): 1145–6.
29.
RashedM.S.OzandP.T.BennettM.J.. Inborn errors of metabolism diagnosed in sudden death cases by acylcarnitine analysis of postmortem bile.Clin Chem.1995 Aug; 41(8 Pt 1): 1109–14.
30.
RinaldoPHahnS.MaternD.Clinical biochemical genetics in the twenty-first century.Acta Paediatr Suppl.2004 May; 93(445): 22–6; discussion 27.
31.
ManoukianA.A.HaC.E.SeaverL.H.BhagavanN.V.A neonatal death due to medium-chain acyl-CoA dehydrogenase deficiency: utilization of the neonatal metabolic screen in a functional approach to sudden unexplained infant death.Am J Forensic Med Pathol.2009 Sep; 30(3): 284–6.
32.
AkarF.G.O'RourkeB.Mitochondria are sources of metabolic sink and arrhythmias.Pharmacol Ther.2011 Sep; 131(3): 287–94.
33.
ArnestadM.OpdalS.H.MusseM.A.. Are substitutions in the first hypervariable region of the mitochondrial DNA displacement-loop in sudden infant death syndrome due to maternal inheritance?Acta Paediatr.2002; 91(10): 1060–4.
34.
OpdalS.H.RognumT.O.VegeA.. Increased number of substitutions in the D-loop of mitochondrial DNA in the sudden infant death syndrome.Acta Paediatr.1998 Oct; 87(10): 1039–44.
35.
OpdalS.H.VegeA.ArnestadM.. Mitochondrial tRNA genes and flanking regions in sudden infant death syndrome.Acta Paediatr.2007 Feb; 96(2): 211–4.
36.
OpdalS.H.VegeA.EgelandT.. Possible role of mtDNA mutations in sudden infant death.Pediatr Neurol.2002 Jul; 27(1): 23–9.
37.
HofmannS.JakschM.BezoldR.. Population genetics and disease susceptibility: characterization of central European haplogroups by mtDNA gene mutations, correlation with D loop variants and association with disease.Hum Mol Genet.1997 Oct; 6(11): 1835–46.
38.
TorunerG.A.KurvathiR.SugalskiR.. Copy number variations in three children with sudden infant death.Clin Genet.2009 Jul; 76(1): 63–8.
39.
SotoodehniaN.IsaacsA.de BakkerP.I.. Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.Nat Genet.2010 Dec; 42(12): 1068–76.
40.
RichardsC.S.BaleS.BellissimoD.B.. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.Genet Med.2008 Apr; 10(4): 294–300.
41.
ZengJ.LauritaK.R.RosenbaumD.S.RudyY.Two components of the delayed rectifier K+ current in ventricular myocytes of the guinea pig type. Theoretical formulation and their role in repolarization.Circ Res.1995 Jul; 77(1): 140–52.
42.
FerreiraS.CrumbW.J.Jr.CarltonC.G.ClarksonC.W.Effects of cocaine and its major metabolites on the HERG-encoded potassium channel.J Pharmacol Exp Ther.2001 Oct; 299(1): 220–6.
43.
BerthetM.DenjoyI.DongerC.. C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.Circulation.1999 Mar 23; 99(11): 1464–70.
44.
PrioriS.G.NapolitanoC.SchwartzP.J.Low penetrance in the long-QT syndrome: clinical impact.Circulation.1999 Feb 2; 99(4): 529–33.
45.
GeorgeA.L.Jr.VarkonyT.A.DrabkinH.A.. Assignment of the human heart tetrodotoxin-resistant voltage-gated Na+ channel alpha-subunit gene (SCN5A) to band 3p21.Cytogenet Cell Genet.1995; 68(1-2): 67–70.
46.
MohlerP.J.SchottJ.J.GramoliniA.O.. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death.Nature.2003 Feb 6; 421(6923): 634–9.
47.
SplawskiI.ShenJ.TimothyK.W.. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.Circulation.2000 Sep 5; 102(10): 1178–85.
48.
PlasterN.M.TawilR.Tristani-FirouziM.. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.Cell.2001 May 18; 105(4): 511–9.
49.
SplawskiI.TimothyK.W.DecherN.. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.Proc Natl Acad Sci U S A.2005 Jun 7; 102(23): 8089–96; discussion 8086-8.
50.
CronkL.B.YeB.KakuT.. Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3.Heart Rhythm.2007 Feb; 4(2): 161–6.
ChenL.MarquardtM.L.TesterD.J.. Mutation of an A-kinase-anchoring protein causes long-QT syndrome.Proc Natl Acad Sci U S A.2007 Dec 26; 104(52): 20990–5.
53.
UedaK.ValdiviaC.Medeiros-DomingoA.. Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex.Proc Natl Acad Sci U S A.2008 Jul 8; 105(27): 9355–60.
54.
YangY.LiangB.LiuJ.. Identification of a Kir3.4 Mutation in Congenital Long QT Syndrome.Am J Hum Genet.2010 Jun 2.
55.
TesterD.J.WillM.L.HaglundC.M.AckermanM.J.Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.Heart Rhythm.2005 May; 2(5): 507–17.
56.
UedaK.HiranoY.HigashiuesatoY.. Role of HCN4 channel in preventing ventricular arrhythmia.J Hum Genet.2009 Feb; 54(2): 115–21.
57.
HuD.Barajas-MartinezH.BurashnikovE.. A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype.Circ Cardiovasc Genet.2009 Jun; 2(3): 270–8.
58.
DelponE.CordeiroJ.M.NunezL.. Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome.Circ Arrhythm Electrophysiol.2008 Aug; 1(3): 209–18.
59.
WatanabeH.KoopmannT.T.Le ScouarnecS.. Sodium channel beta1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans.J Clin Invest.2008 Jun; 118(6): 2260–8.
60.
AntzelevitchC.PollevickG.D.CordeiroJ.M.. Loss-of-function mutations in the cardiac calcium channel under lie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.Circulation.2007 Jan 30; 115(4): 442–9.
61.
LondonB.MichalecM.MehdiH.. Mutation in glycerol-3-phosphatedehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias.Circulation.2007 Nov 13; 116(20): 2260–8.
62.
ChenQ.KirschG.E.ZhangD.. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.Nature.1998 Mar 19; 392(6673): 293–6.
63.
di BarlettaM.R.Viatchenko-KarpinskiS.NoriA.. Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia.Circulation.2006 Sep 5; 114(10): 1012–9.
64.
PrioriS.G.NapolitanoC.TisoN.. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia.Circulation.2001 Jan 16; 103(2): 196–200.
65.
PrioriS.G.PanditS.V.RivoltaI.. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene.Circ Res.2005 Apr 15; 96(7): 800–7.
66.
BellocqC.van GinnekenA.C.BezzinaC.R.. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome.Circulation.2004 May 25; 109(20): 2394–7.
67.
GaitaF.GiustettoC.BianchiF.. Short QT Syndrome: a familial cause of sudden death.Circulation.2003 Aug 26; 108(8): 965–70.
GollobM.H.GreenM.S.TangA.S.. Identification of a gene responsible for familial Wolff-Parkinson-White syndrome.N Engl J Med.2001 Jun 14; 344(24): 1823–31.
70.
Schulze-BahrE.NeuA.FriederichP.. Pacemaker channel dysfunction in a patient with sinus node disease.J Clin Invest.2003 May; 111(10): 1537–45.
71.
TingleyW.G.PawlikowskaL.ZaroffJ.G.. Gene-trapped mouse embryonic stem cell-derived cardiac myocytes and human genetics implicate AKAP10 in heart rhythm regulation.Proc Natl Acad Sci U S A.2007 May 15; 104(20): 8461–6.
72.
KruseM.Schulze-BahrE.CorfieldV.. Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.J Clin Invest.2009 Sep; 119(9): 2737–44.
HoffmannB.Schmidt-TraubH.PerrotA.. First mutation in cardiac troponin C, L29Q, in a patient with hypertrophic cardiomyopathy.Hum Mutat.2001 Jun; 17(6): 524.
75.
KimuraA.HaradaH.ParkJ.E.. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.Nat Genet.1997 Aug; 16(4): 379–82.
76.
WatkinsH.ConnerD.ThierfelderL.. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy.Nat Genet.1995 Dec; 11(4): 434–7.
77.
ThierfelderL.WatkinsH.MacRaeC.. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.Cell.1994 Jun 3; 77(5): 701–12.
78.
Geisterfer-LowranceA.A.KassS.TanigawaG.. A molecular basis for familial hypertrophic cardio-myopathy: a beta cardiac myosin heavy chain gene missense mutation.Cell.1990 Sep 7; 62(5): 999–1006.
79.
SinkovecM.PetrovicD.VolkM.PeterlinB.Familial progressive sinoatrial and atrioventricular conduction disease of adult onset with sudden death, dilated cardiomyopathy, and brachydactyly. A new type of heart-hand syndrome?Clin Genet.2005 Aug; 68(2): 155–60.
80.
TisoN.StephanD.A.NavaA.. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2).Hum Mol Genet.2001 Feb 1; 10(3): 189–94.
81.
KlaassenS.ProbstS.OechslinE.. Mutations in sarcomere protein genes in left ventricular non-compaction.Circulation.2008 Jun 3; 117(22): 2893–901.
82.
Ben YaouR.ToutainA.ArimuraT.. Multitissular involvement in a family with LMNA and EMD mutations: Role of digenic mechanism?Neurology.2007 May 29; 68(22): 1883–94.
83.
GlasscockE.YooJ.W.ChenT.T.. Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy.J Neurosci.2010 Apr 14; 30(15): 5167–75.
84.
WanM.LeeSS.ZhangX.. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.Am J Hum Genet.1999 Dec; 65(6): 1520–9.
85.
PhilippeC.AmsallemD.FrancannetC.. Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females.J Med Genet.2010 Jan; 47(1): 59–65.
86.
KalscheuerV.M.TaoJ.DonnellyA.. Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation.Am J Hum Genet.2003 Jun; 72(6): 1401–11.
87.
SekulE.A.MoakJ.P.SchultzR.J.. Electrocardiographic findings in Rett syndrome: an explanation for sudden death?J Pediatr.1994 Jul; 125(1): 80–2.
88.
AmielJ.LaudierB.Attie-BitachT.. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypo-ventilation syndrome.Nat Genet.2003 Apr; 33(4): 459–61.
89.
SasakiA.KanaiM.KijimaK.. Molecular analysis of congenital central hypoventilation syndrome.Hum Genet.2003 Dec; 114(1): 22–6.
