1. NGS panel - Genetic testing for hereditary Arrhythmia

Arrhythmia, hereditary

April 11, 2017

Clinical features

Sudden unexplained death is a major source of mortality in developed countries; the major causes (in the absence of the structural heart disease) are primary cardiac arrhythmia syndromes or electrical cardiac diseases ("channelopathies")1.

A sudden unexplained death is explained as a primary arrhythmic disorder without any involvement of structural heart disease. Thus, the death is ascribed to be the result of the lethal abnormality of cardiac ion channel function, caused either by a mutation in one of the genes encoding channel-associated proteins or by mutations in genes encoding channel-interacting proteins which are essential for ion channel function. Diseases caused by one or more of these mutations are named "channelopathies" and they include the following:

It is believed that “channelopathies” are responsible for 10-15% of cases of sudden unexplained death in young adults and children 2.

The hallmark of LQTS is the finding of QT prolongation on surface electrocardiography (ECG), in association with a risk of ventricular arrhythmias, syncope, or sudden death. LQTS was the first inherited arrhythmia disorder in the absence of structural heart disease to be described, with a population prevalence of 1/2,000 3. Mutations affecting KCNQ1, KCNH2, and SCN5A are responsible for over 90% of genetically defined cases of LQTS 4.

SQTS is characterized by an abbreviated QT interval and a risk of both atrial and ventricular arrhythmias. Sudden death syndrome was reported in 33% and atrial fibrillation in 18% of patients 5. In the most common form of SQT (SQTS1), a gain-of-function mutation in KCNH2 impairs the voltage-dependent inactivation of IKr, and causes increased current flow through the channel, shortening duration and potential of QT interval 5. SQTS is also associated with mutations in the genes CACNAB2, CACNA1C, KCNQ1 and others.

Mutations in CASQ2 and other genes are also associated with CPVT. CASQ2 mutations are identified in only 1-2% of all patients with CPVT 7. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by the onset of ventricular arrhythmias and syncope with physical exercise, emotional stress, or catecholamine administration, in the absence of structural heart disease. Syncope during exercise is typically the presenting symptom. If untreated, the CPVT condition has very high mortality rate, with more than 50% of affected by the age of 30 years 6.

Brugada syndrome, also known as sudden unexpected nocturnal death syndrome, is characterized by cardiac conduction abnormalities such as ST-segment elevation in leads V1-V3 on ECG and a high risk of ventricular arrhythmias. Additional conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome 8. Several genes have been associated with Brugada syndrome. Heterozygous pathogenic variants in the SCN5A gene account for 15-30% of Brugada syndrome cases 9. Additional genes include CACNA1C, CACNB2, GPD1L, KCNE3, and others.

Management of patients with hereditary arrhythmia consists of treatment with beta-blockers, implantable cardioverter-defibrillator (ICD) implantation, and left cardiac sympathetic denervation (LCSD). Prevention of intensive exercise and avoidance of QT-prolonging drugs are important issues in life-style modification.

CENTOGENE experts have designed the Arrhythmia, hereditary panel which includes the genes: AKAP9, ANK2, CACNA1C, CACNB2, CASQ2, CAV3, DSC2, DSG2, DSP, GPD1L, JUP, KCNA5, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNQ1, NPPA, PKP2, PLN, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SNTA1, TGFB3, TMEM43 (see Table 1). CENTOGENE offers Arrhythmia, hereditary panel, including full gene sequencing and deletion/duplication analysis of selected genes (DSG2, SCN5A, CAV3, PKP2, KCNQ1, KCNE2, DSC2, RYR2, KCNE1, KCNH2, TGFB3, JUP, KCNJ2, DSP). In addition, any of the genes in the Arrhythmia, hereditary panel can also be ordered individually, for full gene sequencing and deletion/duplication analysis.

Differential diagnosis

The differential diagnosis of hereditary arrhythmia-related disorders – depending on the major symptoms in the initial case – includes the following diseases1, 3:

  • Sudden infant death syndrome (SIDS)
  • Vasovagal (neurally mediated) syncope, orthostatic hypotension
  • Seizures
  • Familial ventricular fibrillation
  • Subtle cardiomyopathies (HCM, DCM, ARVC)
  • Anomalous coronary artery
  • Drug-induced QT prolongation
  • Hypokalemia
  • Certain neurologic conditions including subarachnoid bleeding

Overview of the genes in CENTOGENE´s Arrhythmia, hereditary panel

chr. Locus
Protein % of mutations Allelic disorders
AKAP9 604001
A-kinase anchor 9 Rare 1 LQT11, BRGDA, SCFI
ANK2 106410
Ankyrin-2 1-2% 1, 10 LQT4, BRGDA, SCID, SCFI, SSS
CACNA1C 114205
Ca-channel V1C <1% of all LQTS 1, 3 BRGDA3, LQT8, SCFI
CACNB2 600003
Ca-channel VB2 Rare 1 BRGDA4
CASQ2 114251
Calsequestrin 2 2%-5% of all CPVT 18 CPVT2, BRGDA, CMH
CAV3 601253
Caveolin-3 >1% 1, 17
2/905 3
DSC2 125645
Desmocollin 2 1%-13% of all ARVD 19 ARVD11, CMD, ARVC
DSG2 125671
Desmoglein 2 3%-19% for ARVD 19 ARVD10, CMD1BB
DSP 125647
Desmoplakin 1%-16% for ARVD 19 ARVD8, DCWHK, EBLA, PPKS2, SFWHS
GPD1L 611778
Glycerol-3-phosphate dehydrogenase <1% 15, 16 BRGDA2, SCFI
JUP 173325
Plakoglobin Rare ARVD12, Naxos disease, CMD, EBLA
KCNA5 176267
Potassium channel 1 Rare ATFB7
KCNE1 176261
Potassium voltage-gated channel E1 1–3%4, 14 LQT5; JLNS2
KCNE2 603796
Potassium voltage-gated channel subfamily E2 Rare LQT6; ATFB4
KCNH2 152427
Potassium voltage-gated channel subfamily H2 25%-30%5, 6, 12 LQT2; SQT1, BRGDA, SCFI, ATFB, SCFI
KCNJ2 600681
Inward rectifier potassium channel 2 Rare LQT7 (Andersen syndrome); SQT3; ATFB9
KCNQ1 607542
Potassium voltage-gated channel subfamily KQT member 1 30%-35%5, 6, 11 LQT1; SQT2; JLNS1; ATFB3, CMD, SCID, SCFI
NPPA 108780
Cardionatrin Rare ATFB6, ATRST2, CMD
PKP2 602861
Plakophilin 2 10%-52% for ARVD 19, 20 ARVD9, CMD, CMH, SCFI, BRGDA
PLN 172405
Phospholamban Rare CMD1P, CMH18, BRGDA
RYR2 180902
Ryanodine receptor 2 50%-55% of all CPVT 6 ARVD2, CPVT1, LQTS, BRGDA, SCFI
SCN1B 600235
Sodium channel beta-1 15%-30% of all BRGDA 9 ATFB13, BRGDA5, GEFSP1, EIEE52, SCFI
SCN3B 608214
Sodium channel beta-3 Rare BRGDA7, ATFB16, SIDS
SCN4B 608256
Sodium channel subunit beta-4 Rare LQT10; ATFB17
SCN5A 600163
Sodium channel alpha-5 5%-10%5, 6, 13 LQT3; ATFB10; BRGDA1; CMD1E; PFHB1A; SSS1; VF1; SIDS, SCFI
TGFB3 190230
Transforming growth factor beta-3 Rare ARVD1, LDS5, SCFI, Aortic aneurism
TMEM43 612048
Transmembrane protein 43 Rare ARVD5, EDMD7, SCFI

Abbreviations: LQT: Long QT syndrome; CPVT: catecholaminergic polymorphic ventricular tachycardia; CMH: hypertrophic cardiomyopathy; LGMD: limb-girdle muscular dystrophy; MPDT: Tateyama type of distal myopathy; RMD: Rippling muscle disease; JLNS: Jervell and Lange-Nielsen syndrome; ATFB: familial atrial fibrillation; HALD: familial hyperaldosteronism; CMD: cardiomyopathy dilated; PFHB: progressive familial heart block; SSS: sick sinus syndrome; VF: paroxysmal familial ventricular fibrillation; SIDS: sudden infant death syndrome; ARVD: arrhythmogenic right ventricular dysplasia.; DCWHK: cardiomyopathy dilated with woolly hair and keratoderma; EBLA: lethal acantholytic epidermolysis bullosa; PPKS2: keratosis palmoplantaris striata II; SFWHS: skin fragility-woolly hair syndrome; ATRST: atrial standstill; SCFI: sudden cardiac failure, infantile; GEFSP: generalized epilepsy with febrile seizures plus; EIEE: epileptic encephalopathy, early infantile; LDS: Loeys-Dietz syndrome; EDMD: Emery-Dreifuss muscular dystrophy.

Testing strategy

CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for hereditary Arrhythmia using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the hereditary Arrhythmia panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the hereditary Arrhythmia panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.

Referral reasons

The following individuals are candidates for this particular gene testing

  • Individuals with a family history of disease and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling this disease
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected for this particular phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management.

Genetic counseling can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.

More information on CENTOGENE´s hereditary Arrhythmia panel can be found in our genetic test catalogue.