Andersen-Tawil syndrome
Andersen-Tawil syndrome (ATS) is characterized by a triad of episodic flaccid muscle weakness (i.e., periodic paralysis), ventricular arrhythmias and prolonged QT interval, and anomalies including low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis [22]. Two types of Andersen-Tawil syndrome are distinguished by their genetic causes. Type 1, which accounts for about 60 percent of all cases of the disorder, is caused by mutations in the KCNJ2 gene [23]. The remaining 40 percent of cases are designated as type 2; the cause of these cases are as yet unknown [23].
Gene name | Transcript | Clinical sensitivity |
KCNJ2 | ENST00000535240 | ~60% [22] |
Brugada syndrome (BrS)
Brugada syndrome (BrS) is an autosomal dominantly inherited arrhythmia syndrome, with highly variable expressivity and penetrance [24]. Cardiac symptoms are characterised by abnormal findings on the electrocardiogram (ECG) in conjunction with an increased risk of ventricular arrhythmias and sudden cardiac death. It has an estimated prevalence of approximately 1:2000 [25]. There is limited data regarding the prevalence and population distribution of Brugada syndrome but data suggests significant population variance according to ethnicity, with males often being more severely affected. Brugada syndrome is thought to account for up to 4% of all sudden cardiac deaths in the setting of a structurally normal heart [26]. Loss-of-function mutations in SCN5A are the most frequent genetic alteration identified in Brugada syndrome, with pathogenic variants being identified in about 35% of cases [27].
Gene name | Transcript | Clinical sensitivity |
SCN5A | ENST00000333535 | 10-30% [26-29] |
CACNA1C | ENST00000399655 | 6-7% [27] |
CACNB2 | ENST00000377329 | 4-5% [27] |
CACNA2D1 | ENST00000356860 | <1% [29] |
GPD1L | ENST00000828541 | <1% [27,29] |
KCND3 | ENST00000315987 | <1% [29] |
SCN1B | ENST00000262631 | 1-2% [27] |
PKP2 | ENST00000070846 | n/a |
HCN4 | ENST00000261917 | <1% [27,29] |
KCNE3 | ENST00000310128 | <1% [27,29] |
RANGRF | ENST00000226105 | <1% [29] |
SCN3B | ENST00000392770 | <1% [27,29] |
Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by cardiac electrical instability exacerbated by acute activation of the adrenergic nervous system [30]. If untreated, the disease can be lethal, as approximately 30% of those affected experience at least one cardiac arrest [30]. Patients usually present before the age of 10 [25]. The true prevalence of CPVT in the population is not known but is estimated at approximately 1:10,000 [30]. Autosomal dominantly inherited pathogenic variants in RYR2 (most common) and recessively inherited CASQ2 pathogenic variants account for most genetic causes. Causative allelic variants are identified in approximately 55%-65% of individuals with CPVT [28].
Gene name | Transcript | Clinical sensitivity |
CALM1 | ENST00000356978 | <1% [30] |
CALM2 | ENST00000272298 | |
CALM3 | ENST00000291295 | |
CASQ2 | ENST00000261448 | 2-5% [28,30] |
RYR2 | ENST00000366574 | 50-60% [28,30,31] |
TRDN | ENST00000398178 | n/a |
Long QT syndrome
Long QT Syndrome (LQTS) is an autosomal dominantly inherited disorder of ventricular repolarisation, with an estimated prevalence of 1:2000 [25]. It is characterised by a prolonged QT interval on ECG and predisposition to cardiac arrhythmia, syncope and sudden death. LQTS is a genetically heterogenous condition, but the most common causes are heterozygous pathogenic variants in the KCNQ1, KCNH2, and SCN5A genes. A causal variant is found in approximately 75% of LQTS patients with a definitive diagnosis [32]. Around 15% of these pathogenic variants are de novo, and compound heterozygous pathogenic variants are found in 10% of genotype-positive patients, often presenting with a more severe clinical manifestation [32]. Variable penetrance may be observed within families. The autosomal recessive syndromic form of LQTS, known as Jervell and Lange-Nielsen syndrome, probably affects less than 1 in a million people and is accompanied by sensorineural deafness. It is caused by biallelic pathogenic variants in the KCNQ1 or KCNE1 genes [28].
Gene name | Transcript | Clinical sensitivity |
KCNQ1 | ENST00000155840 | 30-55% [24,25,28,32,33] |
KCNH2 | ENST00000262182 | 25-45% [24,25,28,32,33] |
SCN5A | ENST00000333535 | 5-13% [24,25,28,32,33] |
KCNE1 | ENST00000399289 | 1-1.7% [25,33] |
KCNE2 | ENST00000290310 | 0.7-1% [25,33] |
ANK2 | ENST00000264366 | ~1% [25] |
CACNA1C | ENST00000399655 | n/a |
CALM1 | ENST00000356978 | n/a |
CAV3 | ENST00000343849 | n/a |
KCNJ2 | ENST00000353240 | n/a |
KCNJ5 | ENST00000529694 | n/a |
RYR2 | ENST00000366574 | n/a |
SCN4B | ENST00000324727 | n/a |
SNTA1 | ENST00000217381 | n/a |
Short QT syndrome
Short QT syndrome (SQTS) is marked by a shortened QT interval and an increased risk of atrial and/or ventricular arrhythmias [25], however the severity of clinical manifestations is highly variable. It is autosomal dominantly inherited and genetically heterogeneous [28]. Gain-of-function variants in KCNH2, KCNQ1, and KCNJ2 are the principal genetic causes of SQTS [27]. As SQTS is rare, data on its prevalence and demographics are limited. The identification of a pathogenic variant causing SQTS ranges from 18% to 40% in the literature but the yield of clinical genetic testing is likely to be much lower due to a publication bias for more severe cases [27].
Gene name | Transcript | Clinical sensitivity |
KCNH2 | ENST00000262182 | 18-33% [27] |
KCNJ2 | ENST00000353240 | <5% [27] |
KCNQ1 | ENST00000155840 | <5% [27] |
CACNA1C | ENST00000399655 | n/a |
CACNA2D1 | ENST00000356860 | n/a |
CACNB2 | ENST00000377329 | n/a |
SLC22A5 | ENST00000435065 |
Other genes included under all arrhythmia
Gene name | Transcript | Clinical sensitivity |
ABCC9 | ENST00000261201 | n/a |
AKAP9 | ENST00000356239 | n/a |
DSC2 | ENST00000280904 | n/a |
EMD | ENST00000369842 | n/a |
GJA5 | ENST00000271348 | n/a |
JPH2 | ENST00000372980 | n/a |
KCNA5 | ENST00000252321 | n/a |
LMNA | ENST00000368300 | n/a |
MYH6 | ENST00000356287 | n/a |
NKX2-5 | ENST00000329198 | n/a |
NPPA | ENST00000376480 | n/a |
SCN10A | ENST00000449082 |
Clinical genetics and genomics laboratory
Ground floor (level 2), Sydney wing, Royal Brompton Hospital, Sydney Street, London, SW3 6NP
Telephone: +44(0)207 352 8121, ext 83009
Email: rbh-tr.genomics@nhs.net or geneticslab@rbht.nhs.uk
Opening hours: Monday to Friday, 9am to 5pm
Head of laboratory: Dr Deborah Morris-Rosendahl
Useful documents
Molecular genetic testing request and consent form (pdf, 431KB)
Non-NHS molecular genetic testing request and consent form (pdf, 493KB)