Compound heterozygous mutations in KCNJ2 and KCNH2 in a patient with severe Andersen-Tawil syndrome

Background

Andersen-Tawil syndrome (ATS, Online Mendelian Inheritance in Man database indentifier #170390) is a rare channelopathy presenting with heart rhythm disturbances (arrhythmia), periodic paralysis and facial and/or skeletal dysmorphic features.1 ATS is often referred to as long QT syndrome (LQTS) type 7, because of the prolongation of the QT interval in the patients. However, arrhythmias in ATS are not limited to QTc prolongation and can also include palpitations, ventricular tachyarrhythmias and prominent or enlarged U-waves. ATS is considered to have a milder clinical course2 when compared to other cardiac channelopathies and fatal arrhythmias, syncope and sudden cardiac death are uncommon among patients with ATS.

ATS is an autosomal dominant condition with about 70% of cases caused by pathogenic genetic variants in the potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) gene.1 The frequency of ATS is estimated to be 1 in 1 million people worldwide3; however, only approximately 200 patients with ATS have been described so far.3 Given the rarity of the condition and a relatively small number of known cases, genotype–phenotype correlations are still unreliable and based on one or several families.4 5

Variable penetrance6 and intrafamilial heterogeneity7 of symptoms have both been noted for ATS. At least some of the intrafamilial variability in cardiovascular symptoms of patients with ATS might be explained by additional genetic variants or modifier mutations in other genes encoding ion channels. All genetic variants detected should be considered during genetic counselling. While ATS is inherited in autosomal dominant manner with a 50% risk of inheritance, additional genetic variants that are inherited independently could influence the risk of passing the channelopathy to the offspring. In this paper, we present a case of a female patient with a severe clinical manifestation of ATS and complex genetic background.

Case presentation

We observed a 23-year-old female patient who was referred to our hospital. She had a history of syncope since the age of 13. Her medical history included QTc prolongation of over 600 ms. At the age of 22, her condition worsened and she experienced a lasting episode of unconsciousness followed by pronounced muscle weakness. Later, she also experienced an episode of sudden cardiac arrest followed by resuscitation and implantable cardioverter-defibrillator (ICD) implantation. The patient was prescribed a beta-blocker (metoprolol) at a dose of 100 mg daily. At the time of hospitalisation, the patient presented with episodes of dizziness and repetitive ICD shocks despite beta-blocker therapy.

The patient underwent routine examination (blood and urine tests, ECG, echocardiography and 24-hour Holter monitoring, and chest radiography), and was also referred to a clinical geneticist because of her QTc prolongation.

The patient also presented with the following clinical features: small stature (height: 153 cm, weight: 43 kg and body mass index: 18.4), mild scoliosis, shield-shaped thorax, clinodactyly of fifth fingers and toes, partial cutaneous syndactyly of the second and third toes, and sandal gap. Skeletal features along with QTc prolongation and a history of periodic paralysis were suggestive of ATS. The patient’s family history was inconclusive as both parents passed away at a young age in the accidents unrelated to cardiac arrhythmia. No living relatives had a history of syncope or cardiac arrests and no ECGs were available for the family members (figure 1).

The patient was diagnosed with ATS based on the diagnostic criteria.1

Investigations

The patient’s echocardiography and chest radiography were unremarkable. We noticed that the right ventricular shock lead was fixed in the middle third of the interventricular septum, with a loop in the region of the inferior vena cava. The lead was tested to be functionally active, but the stimulation threshold was slightly increased. However, the position of the lead coincided with post-implantation radiography, so its displacement was ruled out. It was impossible to exclude the provoking arrhythmogenic component from the side of the excessive lead loop.

The patient’s heart rhythm was partly sinus, partly artificial (DDD mode) with a medium heart rate of 73 beats/minute. No pauses of heart rhythm were detected. The patient’s ECG recorded QTc interval prolongation up to 650 ms. During Holter monitoring, we detected ventricular ectopic activity (10 521 ventricular extrasystole episodes) and runs of ventricular tachycardia (up to 17 complexes) mostly during daylight hours. Through blood tests, a mild hypopotassemia was detected with a potassium concentration of 3.4 mmol/L.

The patient’s ICD check-up revealed frequent inappropriate shocks, including ventricular extrasystoles (bigeminy type) and short runs of ventricular tachycardia.

Genetic counselling was conducted and the patient was informed of methods, possibilities and limitations of DNA diagnostics. Informed consent on the storage and usage of biomaterial (venous blood) was taken according to the Declaration of Helsinki. Extended mutational screening of a panel of 11 genes was performed, rather than targeting only KCNJ2, with Sanger sequencing considering the patient’s prominent QTc prolongation and recurrent syncope.

The DNA diagnostics was performed by high-throughput semiconductor sequencing of the gene panel on the Ion Torrent platform. The gene panel included 11 genes, most commonly associated with cardiac channelopathies—KCNQ1, KCNH2, KCNE1, KCNE2, KCNE3, KCNJ2, SCN5A, SNTA1, SCN1B, SCN3B and SCN4B. This panel does not cover the entire continuously expanding spectrum of genes responsible for LQTS; however, mutations in KCNQ1, KCNH2 and SCN5A genes are detected in 75%–90%8 of mutation-positive cases, making other genetic subtypes quite rare. All potentially significant genetic variants revealed by next generation sequencing were confirmed by PCR-based automatic bidirectional Sanger sequencing.

We detected two heterozygous genetic variants in the patient: p.R218Q in the KCNJ2 gene and p.T983I in the KCNH2 gene (figure 2). The p.R218Q variant in the KCNJ2 gene has been previously described as a pathogenic variant in patients with ATS. The variant is absent in Genome Aggregation Database (gnomAD) and 1000 Genomes database, and is known to segregate with ATS in several unrelated families. Functionally, the variant alters the channel’s current.9 Systemic phenotypic manifestation in the patient was typical for ATS. We observed distinctive skeletal and facial features and the patient presented with unexplained episodes of muscle weakness. However, heart rhythm disturbances were unusually severe for classical ATS.

The genetic variant p.T983I in the KCNH2 gene has also been previously described in databases with conflicting interpretations.10 Only 40 heterozygous carriers of this variant (and no homozygous cases) are reported in gnomAD11 with an overall population frequency of 0.0144%.12 In the Human Genome Mutations Database, the variant is reported as a mutation (CM055295). The computational interpretation of pathogenicity was controversial (Sorting Intolerant From Tolerant (SIFT) predictions: tolerated, Polymorphism Phenotyping version 2 (PolyPhen-2): probably damaging and MutationTaster: disease-causing). However, Garg et al reported a functional study13 of induced pluripotent stem cells (iPSC-derived cardiomyocytes) with the KCNH2 gene’s p.T983I variant obtained from a patient with QTc prolongation and a history of presyncope. Patch-clamp technique revealed prolongation of action potential duration and reduced rapidly activating delayed rectifier K+ current density in T983I cardiomyocytes.13 Our patient’s phenotype is consistent with that in the study, and the results of this functional study allow us to classify the p.T983I variant as likely pathogenic.

We could not perform the cascade familial screening due to the patient’s family history. Living relatives were unavailable for genetic testing.

Differential diagnosis

We considered ATS and other molecular types of LQTS as differential diagnoses. The diagnosis of ATS was confirmed after DNA diagnostic tests revealed the genetic variant p.R218Q in KCNJ2 gene, as this variant is linked to ATS. We also detected a p.T983I genetic variant in the KCNH2 gene, a gene involved in LQTS type 2. We assume that the patient’s severe clinical manifestation is a result of this complex genetic background—a combination of two pathogenic genetic variants in genes encoding potassium ion channels.

Treatment

Oral correction of the detected hypokalaemia and magnesium levels was performed. The patient’s dose of beta-blocker (metoprolol) was increased under blood pressure, ECG and Holter monitoring guidance up to 175 mg daily.

Because of the patient’s frequent inappropriate ICD shocks, the implantation of a new shock lead was performed. The old right ventricular shock lead was removed, and a new lead was implanted on a previous dual-chamber ICD in right ventricular chamber. The surgery was uneventful as all electrical parameters of leads were normal (figure 3). The patient’s ICD was transferred to the DDI operating mode, with a basic heart rate of 70 beats/minute.

Our patient carried a likely pathogenic genetic variant in the KCNH2 gene that may be associated with LQTS, so she was informed on lifestyle modifications, risk factors and specific triggers of cardiac events relevant to patients with LQTS type 2. In particular, she was provided with a list of medications to avoid and informed of the possibility of hypokalaemia, auditory evoked events and postpartum events.

Genetic counselling after DNA diagnostics was performed and the patient was informed of genetic risk in her case. The genetic risk and special aspects of inheritance will be discussed in the outcome and follow-up section.

Outcome and follow-up

After the treatment given, we recorded a significant decrease in ventricular extrasystoles and only a few short runs of ventricular tachycardia were noted during Holter monitoring (figure 4). The patient was discharged for further observation by a local cardiologist. The recommended drug therapy included beta-blocker (metoprolol 175 mg daily) and potassium and magnesium per os with the local control of potassium level in blood.

During DNA diagnostics, two pathogenic genetic variants were detected. ATS is an autosomal dominant disorder with a 50% risk of transmission; additional genetic variants in the KCNH2 gene may influence the overall genetic risk for offspring.

The genetic variants in KCNJ2 and KCNH2 genes are inherited independently; therefore, to evaluate the genetic risk of ATS and other disorders, all inheritance options must be considered (figure 5).

The patient has a 25% chance of transmitting both genetic variants to her child. In this case, the child will have both ATS and a similar severe cardiac phenotype as in the patient. The chance of transmitting ATS only is also 25%; in this case, the child will have ATS with appropriate clinical features (such as skeletal/facial malformations), but heart rhythm disturbances would likely be milder and more typical of classic ATS. The chance of transmitting the p.T983I-KCNH2 genetic variant alone is also 25%. The p.T983I-KCNH2 variant will not cause ATS, but the LQTS type 2 phenotype is possible. It is not possible to predict the severity of the clinical features, but all the recommendations for patients with LQTS will be relevant in this case. Finally, there is a 25% chance that neither of the genetic variants will be transmitted to the child. Both ATS and LQTS will be excluded in the child in this case.

The patient was interested in genetic counselling and DNA diagnostic for her future children. She was informed of genetic risks and of the possibility of prenatal or early genetic testing in order to organise appropriate follow-up of the pregnancy and newborn.

During the course of follow-up, the patient became pregnant and gave birth to a son. Through the pregnancy, her dose of beta-blockers was corrected to avoid atrioventricular block in the fetus; the metoprolol dose was lowered to 25 mg daily. However, the dose decline leads to the reappearance of frequent ventricular extrasystoles (up to 15 000 daily). As a result, the patient received a dose of 100 mg daily of metoprolol during pregnancy and for 2 months postpartum. The delivery was in-term and uncomplicated. Important option to consider is a way of feeding. It is known that beta-blockers excrete with breast milk and may be associated with bradycardia and growth restriction in fetus, and faster clearance of drug in mother.14 The patient decided to breastfeed her son for 2 months before switching to formula feeding to avoid heart rhythm disturbances due to the presence of beta-blockers in the breast milk.

Early DNA diagnostics were performed for patient’s son and neither of the p.R218Q-KCNJ2 or p.T983I-KCNH2 genetic variants was detected. Therefore, both ATS and LQTS were excluded in patient’s son.

Careful clinical evaluation and extended DNA diagnostic allowed us to establish a correct diagnosis, organise the correct follow-up for the patient and perform an early testing for her son. So far, the patient’s son has no heart rhythm disturbances and is in good health.

The dose of beta-blockers in the patient remains the same; she now receives 100 mg of metoprolol and 600 mg of potassium daily. No ICD shocks were recorded during the follow-up period.