Sudden death

Panel testing recommended at Breda Genetics for this condition:

Sudden death (ABCC9, ACTN2, AKAP9, ANK2, CACNA1C, CACNA2D1, CACNB2, CALM1, CALM2, CASQ2, CAV3, CSRP3, DES, DPP6, DSC2, DSG2, DSP, DTNA, FBN1, FGF12, GJA5, GPD1L, CN4, JPH2, JUP, KCNA5, KCND2, KCND3, KCNE1, KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1, LAMP2, LDB3, LMNA, LRP6, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, NEXN, NPPA, NUP155, PKP2, PLN, PRKAG2, RANGRF, RBM20, RYR2, SCN10A, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SEMA3A, SLMAP, SNTA1, TCAP, TGFB3, TGFBR2, TNNC1, TNNI3, TNNT2, TPM1, TRPM4, TTN, VCL)

Summary

Sudden death syndrome or Sudden Unexplained Death Syndrome (SUDS) is the first cause of unexpected death and without clinical explanation in developed countries.

The syndrome is common especially among the populations of Southeast Asia, and can affect both adults under the age of 40/45 years (Sudden Adult Death Syndrome-SADS) and infants and children (Sudden Infant Death Syndrome-SIDS, also commonly known such as “cot death”) or fetuses (Sudden Unexplained IntraUuterine Death Syndrome-SIUDS) apparently healthy. It mainly affects males, often during sleep (Sudden Unexpected/Unexplained Nocturnal Death Syndrome-SUNDS), without any warning and without leaving traces on post-mortem autopsy examination.

The first case described dates back to 1917 in the Philippines but until 1981 this condition has not aroused the interest of the scientific community. From the beginning of the 1980s and for the next 20 years, instead, numerous studies have come in succession in order to correlate the pathogenesis of the syndrome to environmental factors. Only in 2002 the first genetic cause of sudden death has been identified, consisting of a single nucleotide variant in the SCN5A gene, which code for a voltage-gated sodium channel expressed in the heart.

The identification of patients at high risk and the prevention of this rare disorder are now possible but require knowledge of the cause and mechanism underlying its onset.

The first cause of sudden death is linked to ventricular cardiac arrhythmia (Sudden Arrhythmias Death Syndrome- SADS), which arises in the absence of structural organ anomalies. These arrhythmias represent the main clinical manifestation of a group of dysfunctions called “channelopathies”, which are caused in the vast majority of cases by mutations in the nucleotide sequence of one of the genes among those responsible the synthesis of ion channel mainly located in the heart.

Detailed clinical description

Channelopathies comprise many different clinical conditions, due to mutations in different groups of genes:

Long QT syndrome
It is a rare cardiac disorder that affects 1/2.500 individuals and causes the elongation of the depolarization/repolarization time of ventricles. This results in an increase in the time necessary for ventricular relaxation after a first contraction, in preparation for the next one. The origin of the defect is an anomaly in the conduction of electrical signals of the myocardium, linked to an abnormality of the potassium or, to a lesser extent, sodium ion channels. When symptomatic, the syndrome can manifest with syncope, palpitations and epilepsy. The diagnostic test on which the diagnosis is based is electrocardiogram: the name “long QT” is linked to a peculiarity in the ECG profile.

Long QT syndrome can be inherited or acquired.

Inherited long QT syndrome is caused by mutations in at least 15 known genes (AKAP9, ANK2, CACNA1C, CALM1, CALM2, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A,  SNTA1) and can be transmitted by one of the parents to the offspring. In about 80% of cases, the genes involved are KCNQ1 (subtype LQT1), KCNH2 (LQT2) and SCN5A (LQT3). Regarding inheritance, both autosomal dominant and autosomal recessive forms of long QT syndrome exist: autosomal dominant (Romano-Ward syndrome) is quite frequent and has 50% of chance to be transmitted; autosomal recessive is rarer and can be associated with deafness (Jervell and Lange-Nielsen syndrome). In this case, parents are healthy carriers of the mutation and reproductive risk is 25% each pregnancy.

The acquired long QT syndrome is, on the other hand, a secondary condition triggered by a primary factor, sometimes identifiable with certain drug consumption to which the patient is sensitive: antibiotics, antidepressants, antipsychotics, antihistaminics, diuretics, antiarrhythmics, statins.

Short QT syndrome
Very rare cardiopathy characterized by the association between a short QT interval (QT and QTc 300 ms) and a high risk of syncope or sudden death due to ventricular arrhythmia. This syndrome mainly affects young adults and newborns. Mutations in the KCNQ1, KCNH2 and KCNJ2 genes, which code for potassium ion channels, have been reported. Inheritance is autosomal dominant. Nowadays, the only effective treatment for the prevention of sudden death is the automatic implantable defibrillator.

Brugada syndrome
It consists of an alteration in the electrical activity of the heart, which can cause dangerous ventricular arrhythmia episodes, in some cases lethal. It’s one of the main causes of sudden cardiac death in adult males. Patients with Brugada syndrome have a peculiar sign in the ECG profile, known as the Brugada sign, which is not associated with evident clinical manifestation. In other words, the Brugada sign is completely asymptomatic and can only be identified with a specific cardiological examination. Also for this disease, a hereditary and an acquired form exist.

Among the genes responsible for Brugada syndrome, the most studied and well-known is SCN5A. Other involved genes are GPD1L, CACNA1 e CACNB2, SCN1B, SCN10A and HEY2. The inheritance is dominant.

Hypothesized non-genetic causes are: drug abuse, particularly cocaine, hypertension (high blood pressure), angina pectoris, blood electrolyte imbalance, medication consumption.

Catecholaminergic polymorphic ventricular tachycardia (CPVT)
It’s a severe genetic arrhythmogenic disease, characterized by ventricular tachycardia induced by adrenergic stress, which manifests with syncope and sudden death. The age of onset is between 7 and 9 years of life and there is no difference in the frequency between sexes.

The two most important genes that cause CPVT are RYR2 and CASQ2. RYR2 mutations (autosomal dominant inheritance) account for about 55%-65% of cases, while CASQ2 mutations (autosomal recessive inheritance) are observed in only 2% of patients. Some mutations in the KCNJ2 gene, which is usually associated with Andersen syndrome (long QT), can also cause CPVT, with adrenergic-dependent bidirectional tachycardia in the absence (or moderate presence) of other disease signs.

Progressive familial heart block (PFHB)
A hereditary disease that can evolve into complete atrioventricular (AV) block with fatal outcome. This condition can be both asymptomatic and symptomatic (dyspnea, dizziness, syncope, abdominal pain, heart failure or sudden death). In most cases, the contractile function of the heart and cardiac structure are normal, but the complete AV block can sometimes lead to left ventricular dilation and heart failure.

The disease is in most cases due to mutations in one of three genes: SCN5A, SCN1B and TRPM4. In familiar PFHB associated with heart failure, mutations can also be in the NKX2, TBX5, PRKAG2 and LMNA genes. Moreover, there is a candidate gene, GJA5, which has been associated with severe early-onset PFHB. Inheritance is autosomal dominant with incomplete penetrance and variable expressivity. Recessive or sporadic forms are very rare.

Idiopathic ventricular fibrillation non-Brugada (IVF)
Ventricular fibrillation is a heartbeat alteration due to ventricular impairment, which contracts rapidly and in a disorderly manner. As a result, the heartbeat and contractions also change, leading to increased frequency and speed, irregularity and lack of coordination, variable intensity and mechanical ineffectiveness. When ventricular fibrillation occurs in the absence of other obvious pathologies or causes, it is called idiopathic ventricular fibrillation.

IVF estimated incidence is 1% of total out-of-hospital cardiac arrest, of 3%-9% of ventricular fibrillation not related to myocardial infarction and of 14% of ventricular fibrillation in patients under 40 years of age.

Pathogenic mutations have been identified in the DPP6 and SCN5A genes. However, it is plausible that mutations occur also in other genes, not yet associated with IVF, since genetic confirmation can be obtained only in a small number of patients.

Timothy syndrome (TS)
It is a rare genetic disorder that can be associated with several clinical manifestations, such as arrhythmias, seizures, immunodeficiency and autism. The likelihood of surviving the first few years of life is very low. The disorder is caused by a single nucleotide mutation in the gene CACNA1C, which codes for a calcium channel. This syndrome is not hereditable because patients dye before reaching the fertile age, but it is equally genetic, being caused by de novo mutations.

Wolff-Parkinson-White syndrome
It is a disorder characterized by abnormal conduction of the electrical impulse, ensured by the presence of one or more accessory atrio-ventricular bundles that can give rise to episodes of sporadic tachycardia. The disease affects 1 in 450 persons; 70% of patients are males, especially young males, and occurs sporadically in the vast majority of cases. The familial form has an autosomal dominant inheritance. the disease can be completely clinically silent (asymptomatic). Familial cases are due to mutations in the PRKAG2 gene.

Other SADS-related clinical conditions underlie structural heart abnormalities. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DM) are all conditions that can lead to sudden arrest of cardiac function.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)
It is a disease due to the replacement of the myocardium (normal cardiac muscle tissue) with adipose of fibro-adipose tissue. 30%-50% of cases have a genetic cause, with both autosomal dominant and recessive inheritance. This disorder has variable expressivity. Nowadays, the known genes are TGFB3, RYR2, TMEM43, DSP, PKP2, DSG2, DSC2, JUP.

Hypertrophic cardiomyopathy (HCM)
It is a condition characterized by thickening (hypertrophy) and hardening of the heart muscle, which consequently becomes stiff. The disorder is quite common, affecting 1 in 500 people in the general population. The inheritance is autosomal dominant. Currently, mutations in at least 13 genes are known, all coding for proteins of the contractile apparatus of the cardiomyocyte. The most frequent mutations happen in MYH7 and MYBPC3 genes (50% of cases). Other known genes are TNNT2, TNNI3, TPM1, MYL3, MYL2, MYH6, TNNC, ACTC, CSRP3, ACTN2, TTN, PLN, CAV3, TCAP, JPH2, LBD3.

Dilated cardiomyopathy (DCM)
It is a heart muscle disease characterized by decreased contractility and dilation of the left ventricle or both ventricles. DCM is a quite common cause of heart failure in industrialized countries and represents one of the main indications for transplantation, which is currently the only therapy.

Genetic forms are very common (20%-50% of cases). The most frequent is the autosomal dominant form involving only the heart. Most of the mutations have been identified in the TTN, LMNA, MYH7, MYH6, SCN5A, MYBPC3, TNNT2, BAG3 and ANKRD1 genes. The X-linked form is due to DMD mutations.

Recommended genetic strategy

Due to the high genetic heterogeneity of sudden death, a Next Generation Sequencing panel is recommended. Breda Genetics offers this panel on the basis of whole exome or whole genome sequencing.

Panel testing recommended at Breda Genetics for this condition:

Sudden death (ABCC9, ACTN2, AKAP9, ANK2, CACNA1C, CACNA2D1, CACNB2, CALM1, CALM2, CASQ2, CAV3, CSRP3, DES, DPP6, DSC2, DSG2, DSP, DTNA, FBN1, FGF12, GJA5, GPD1L, CN4, JPH2, JUP, KCNA5, KCND2, KCND3, KCNE1, KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1, LAMP2, LDB3, LMNA, LRP6, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, NEXN, NPPA, NUP155, PKP2, PLN, PRKAG2, RANGRF, RBM20, RYR2, SCN10A, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SEMA3A, SLMAP, SNTA1, TCAP, TGFB3, TGFBR2, TNNC1, TNNI3, TNNT2, TPM1, TRPM4, TTN, VCL)

References

Elijah R Behr. “When a young person dies suddenly”. Cardiac Risk in the Young – CRY. Archived from the original on 2014-07-20.

Eckart, Robert E.; Shry, Eric A.; Burke, Allen P.; McNear, Jennifer A.; Appel, David A.; Castillo-Rojas, Laudino M.; Avedissian, Lena; Pearse, Lisa A.; Potter, Robert N. “Sudden Death in Young Adults”. Journal of the American College of Cardiology. 58 (12): 1254–1261.

Alders M, Bikker H, Christiaans I. Long QT Syndrome. 2003 Feb 20 [Updated 2018 Feb 8]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Lilly L.S., Pathophysiology of Heart Disease., 2007ª ed., Baltimore: Lippincott Williams & Wilkins, ISBN 978-1-60547-723-7.

Brugada R, Campuzano O, Sarquella-Brugada G, et al. Brugada Syndrome. 2005 Mar 31 [Updated 2016 Nov 17]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Napolitano C, Priori SG, Bloise R. Catecholaminergic Polymorphic Ventricular Tachycardia. 2004 Oct 14 [Updated 2016 Oct 13]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington,

Baruteau AE, Probst V, Abriel H. Inherited progressive cardiac conduction disorders. Curr Opin Cardiol. 2015 Jan;30(1):33-9.

Mark E. Josephson, Josephson’s Clinical Cardiac Electrophysiology, 5 ed., Lippincott Williams&Wilki, 2015, ISBN 978-1451187410

Napolitano C, Splawski I, Timothy KW, et al. Timothy Syndrome. 2006 Feb 15 [Updated 2015 Jul 16]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Wolff-Parkinson-White syndrome. Genetics Home Reference (GHR). June 2017;

McNally E, MacLeod H, Dellefave-Castillo L. Arrhythmogenic Right Ventricular Cardiomyopathy. 2005 Apr 18 [Updated 2017 May 25]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Ali J. Marian, Eugene Braunwald. Hypertrophic Cardiomyopathy. Circ Res. 2017;121:749-770.

Hershberger RE, Morales A. Dilated Cardiomyopathy Overview. 2007 Jul 27 [Updated 2015 Sep 24]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

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