|Year : 2022 | Volume
| Issue : 2 | Page : 41-45
Rare genetic mutations associated with long QT syndrome in Hong Kong chinese patients
Oscar Hou In Chou1, Jeremy Man Ho Hui1, Yan Hiu Athena Lee1, Simon Siyuan Li1, Keith Sai Kit Leung1, Teddy Tai Loy Lee1, Leonardo Roever1, Yunlong Xia2, Qiang Liu3, Sharen Lee1, Gary Tse1, Khalid Bin Waleed4
1 Cardiac Electrophysiology Unit, Cardiovascular Analytics Group, Hong Kong, China
2 Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
3 Department of Cardiology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
4 Cardiac Electrophysiology Unit, Cardiovascular Analytics Group, Hong Kong; Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Department of Cardiology, St. George's University Hospitals NHS Foundation Trust, London, United Kingdom
|Date of Submission||22-Mar-2022|
|Date of Decision||29-Sep-2022|
|Date of Acceptance||03-Oct-2022|
|Date of Web Publication||07-Dec-2022|
Cardiac Electrophysiology Unit, Cardiovascular Analytics Group, Laboratory of Cardiovascular Physiology, Hong Kong
Dr. Sharen Lee
Cardiac Electrophysiology Unit, Cardiovascular Analytics Group, Hong Kong
Source of Support: None, Conflict of Interest: None
Congenital long QT syndrome (LQTS) is a type of cardiac ion channelopathy that increases the susceptibility of the affected individuals to spontaneous ventricular tachycardia/fibrillation or even sudden cardiac death. More than 17 subtypes have been identified. This was a systematic review of the published case series or reports on the clinical characteristics, genetic basis, and patient outcomes from Hong Kong with rare genetic variants of LQTS which fall outside the traditional LQTS classification system. PubMed and Zenodo were searched from the corresponding inception until January 15, 2022. Twenty-four studies were identified. Of these, one article met the inclusion criteria. The article included a case series of six patients from a cohort with 134 patients. They had either asymptomatic LQTS with HCN4 mutations (n = 1, c.1471G>A, QTc: 420 ms with prolonged QTc of 670 ms during the recovery phase of treadmill test), RYR2 (n = 1, c.7060G>A, QTc: 480 ms) or SCN10A (n = 2, c.3542C>T, QTc: 439 ms–480 ms), or LQTS with multiorgan syndromes with GATA3 mutations (n = 1, c. 815C>T, Barakat syndrome: Sensorineural deafness, hypoparathyroidism, and renal disease, QTc: 450–489 ms), or SLC6A8 (n = 1, c.691_693del; X-linked creatine transporter deficiency, with c.6065A>G mutation in AKAP9, known modifier of LQTS; QTc: 485 ms). In addition, rare genetic variants in non-LQTS causative genes were identified. Future studies should be conducted to compare the variants and investigate their functional consequences.
Keywords: AKAP9, genetic variants, HCN4, long QT syndrome, RYR2, SCN10A
|How to cite this article:|
In Chou OH, Ho Hui JM, Athena Lee YH, Li SS, Kit Leung KS, Loy Lee TT, Roever L, Xia Y, Liu Q, Lee S, Tse G, Waleed KB. Rare genetic mutations associated with long QT syndrome in Hong Kong chinese patients. Ann Clin Cardiol 2022;4:41-5
|How to cite this URL:|
In Chou OH, Ho Hui JM, Athena Lee YH, Li SS, Kit Leung KS, Loy Lee TT, Roever L, Xia Y, Liu Q, Lee S, Tse G, Waleed KB. Rare genetic mutations associated with long QT syndrome in Hong Kong chinese patients. Ann Clin Cardiol [serial online] 2022 [cited 2023 May 29];4:41-5. Available from: http://www.onlineacc.org/text.asp?2022/4/2/41/362956
| Introduction|| |
Long QT syndrome (LQTS) describes a heterogeneous group of diseases that result in T-wave abnormalities and QT prolongation on electrocardiogram (ECG). It has both congenital and acquired causes and is characterized by palpitations, syncope, and sudden cardiac death (SCD). The manifestations can be due to polymorphic ventricular tachycardia/ventricular fibrillation (PMVT/VF). Genetic testing is routinely used to evaluate patients with suspected LQTS, as it identifies potentially pathogenic variants and aids the risk stratification and management of these patients. More than 17 genes are found to be potentially LQTS causative (definitive: KCNQ1, KCNH2, and SCN5A; strong/definitive: CALM1, CALM2, CALM3, and TRDN; moderate evidence: CACNA1C; and limited/disputed evidence: AKAP9, ANK2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, and SNTA1). Variants in other genes that encode for pore-forming or ancillary subunits of ion channels, such as SCN1B, SCN10A, and HCN4 have also been implicated. Cohort studies from Hong Kong, China, have been conducted, among which patients who were not part of LQTS subtypes 1–17 were excluded from the study.
This study aims to review the existing works on the clinical characteristics, genetic basis, and patient outcomes from Hong Kong with LQTS-associated genetic variants falling outside the traditional LQTS classification system.
| Case Load of Long QT Syndrome in Hong Kong|| |
Previously, the outcomes of 121 patients diagnosed with congenital LQTS between 1997 and 2019 were reported in a territory-wide study on searching the public hospital system-managed electronic health records, which serve a population of approximately 7.5 million individuals. In line with the 2013 Heart Rhythm Society Expert Consensus Statement (Priori, 2013 #1), congenital LQTS was diagnosed if any of the following criteria were satisfied: (i) Schwartz LQTS score ≥3.5 points; (ii) an unequivocally pathogenic mutation in one of the LQTS genes; and (iii) corrected QT interval ≥500 ms on repeated 12-lead ECG without any secondary causes for QT prolongation.
| Rare Genetic Variants Falling Outside of LQTS 1–17 Subtypes|| |
The case reports or case series were searched using PubMed and Zenodo on patients with mutations outside the classical LQTS 1–17 subtypes from Hong Kong using the search terms (“Long QT syndrome” AND “Hong Kong”) from their inception to January 15, 2022. Twenty-four entries were identified. Only one article met the inclusion criteria. This was case series of six patients identified from a cohort of 121 patients. They either presented with isolated cardiac ion channelopathy-like features with mutations in HCN4, RYR2, or SCN10A or presented with multiorgan syndromes with LQTS features with mutations in SLC6A8/AKAP9 or GATA3.
The first case was a 21-year-old female patient with a QTc interval of 420 ms. ECG screening in the family illustrated QTc intervals of 400 and 442 ms for her father and mother, respectively. Her aunt suffered from bradycardia. The patient presented with syncope without palpitations. Twenty-four-hour Holter showed sinus bradycardia of heart rates between 35 and 45 bpm with ventricular ectopics. The treadmill test found a maximum QTc of 670 ms during recovery. Genetic analysis identified the c.1471G>A, p. Asp491Asn mutation at exon 4 in the HCN4 gene. An implantable cardioverter-defibrillator (ICD) was inserted, and on follow-up, the patient did not have any arrhythmias.
Case two was a 12-year-old female who had syncope without any exercise-induced arrhythmias or exertional symptoms. She previously suffered from a syncope lasting 2 min, resulting to a head injury. She had a positive family history of LQTS. Her elderly sister had asymptomatic LQTS, and her father had asymptomatic Wolff–Parkinson–White syndrome with a normal QTc interval. Meanwhile, her younger brother had a normal QTc interval. In the family screening ECG, her father had a QTc of 440 ms with delta waves and flattened T-waves, her sister had a QTc of 490 ms with bifid T-waves, and her brother with a QTc of 446–473 ms with peaked T-waves. Her initial ECG illustrated a QTc of 480 ms with peaked T-waves but without T-wave inversion. Her repeated ECGs showed QTc between 500 and 520 ms. Her echocardiography and 24-h Holter test were unremarkable, whereas the treadmill demonstrated prolonged QTc during recovery. Genetic analysis identified the c.7060G>A mutation at exon 46 in the RyR2 gene. She was treated with atenolol and later switched to nadolol. During follow-up, the patient did not have arrhythmias.
Case three was a 37-year-old male patient with a QTc of 439 ms. His daughter was the proband who had Turner's syndrome presenting with hypoplastic arch, coarctation of the aorta, valvular aortic stenosis, and LQTS. She had a variant of uncertain significance with low clinical significance (c. 3542C>T, p. Thr1181Met) in SCN10A at exon 20. The mutation was expected to affect the extracellular domain. The patient also underwent next-generation sequencing (NGS) and was found to have the same mutation. However, the patient appeared to be an asymptomatic carrier. He was treated with propranolol without any arrhythmias during the follow-up.
Case four was a female patient who started to have convulsions and recurrent dizziness at 5 years old. She was initially diagnosed with epilepsy and prescribed anticonvulsant medications. In the family ECG screening, her asymptomatic father had a QTc of 490 ms, whereas her mother had a QTc of 410 ms. The patient was treated with metoprolol but later presented with increased frequency of dizziness episodes associated with palpitations. Since her 13 years old, the patient had already suffered from four episodes of syncope associated with generalized tonic-clonic seizures, which resolved spontaneously within a minute. Subsequently, the patient was admitted with dizziness, persistent palpitations, irritability, and behavioral change. The patient also had ECG showing PMVT with QTc up to 600 ms. Metoprolol was then switched to atenolol, yet two more episodes of polymorphic VT occurred. The patient was inserted with an ICD, complicated by ventricular bigeminy which later progressed into VF. The ICD was switched to atrial demand pacing mode; thereafter, the patient remained asymptomatic. A left thoracoscopic sympathectomy was performed on the left side without complications. Genetic analysis identified a variant in SCN10A as well as a variant of unknown significance in KCNH2, and the precise mutations were not reported.
Case five was a male patient diagnosed with Barakat syndrome (presented with hypoparathyroidism, sensorineural deafness, and renal disease; heterozygous for GATA3 c.815C>T leading to p. Thr272Ile). The patient had ECG showing QTc between 450 and 489 ms without T-waves changes. The patient initially presented with a prolonged QTc of 460 ms during hypocalcemia. Later, despite a normal calcium level, he was found to have persistent QTc prolongation. The family ECG screening of the patient was unremarkable, and he had no family history of SCD.
Case six was a 6-year-old male who presented with developmental delay, epilepsy, and moderate intellectual disability. The patient had an initial QTc of 485 ms. The patient did not recall any family history of SCD. He had T-wave inversion in the chest leads V1–V3, in accompanied by notched and slow-rising T-waves in V4–V6. The echocardiography result did not show any structural abnormalities. His father had a 52 bpm sinus bradycardia with a normal QTc interval of 380 ms, and his mother had a 49 bpm sinus bradycardia with a normal QTc of 409 ms in the family ECG screening. The patient's paternal uncle had a history of attention deficit hyperactivity disorder but without any electrocardiographic abnormalities or epilepsy. Genetic analysis identified c. 6065A>G (p. Gln2022Arg) in AKAP9 and c.691_693del (p. Leu231del) in SLC6A8. The patient was subsequently identified to be an X-linked creatine transporter deficiency patient. He was then treated with atenolol without any arrhythmias during subsequent follow-up.
| Broader Perspectives|| |
LQTS predisposes the affected individuals to ventricular arrhythmias through both the reentrant and nonreentrant mechanisms.,, The condition can be inherited and acquired.,, Inherited LQTS is a group of heterogeneous diseases with genotype-specific features. The LQTS risk stratification involves genetic testing, clinical assessment, and electrocardiography.,,,, LQTS may present either as an isolated cardiac ion channelopathy or multiorgan syndromes. As it is now possible to screen the patients for genetic variants using NGS,, potentially pathogenic genetic mutants for LQTS and other cardiac ion channelopathies can now be identified.,,, In this case series, LQTS patients with genetic variants not classified in the 1–17 LQTS subtypes were described.
| Rare Genetic Mutations Associated with Long QT Phenotype|| |
The hyperpolarization-activated cyclic-nucleotide-gated channel isoform in pacemaker tissue was encoded in HCN4. HCN4 mutation could result in various arrhythmic disorders, including tachycardia–bradycardia syndrome, asymptomatic and symptomatic sinus bradycardia, atrial fibrillation, and atrioventricular node block., In case one, the patient had a c.1471G>A mutation at exon 4 in the HCN4 gene, in which the asparagine at the extracellular domain (p. Asp491Asn) replaced the original aspartic acid residue at codon 491. While this mutation was reported with unknown significance by ClinVar (VCV000404133.1), in the Functional Analysis through Hidden Markov Models the mutation was predicted to be pathogenic. Given the clear clinical phenotype in accompanied by the absence of other LQTS-related mutations, this case suggested classifying this variant as pathogenic. Indeed, most HCN4-mutated patients presented with bradycardic complications despite normal QTc intervals. Meanwhile, another case report identified a D553N mutant associated with QT prolongation in ECG, recurrent syncope, PMVT, and torsade de points.
The RYR2 encodes the ryanodine receptor 2. Mutation of RYR2 is associated with catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). It was also recently implicated in LQTS. On studying 117 probands, 12 variants were diagnosed with LQTS, with over half of these patients being symptomatic. In case 2, the female patient did not have features of CPVT or ARVD/C, but she presented with prolonged QTc interval of 480 ms with syncope. Genetic testing found the c.7060G>A mutation in exon 46 of RYR2 gene, in which the alanine residue at codon 2354 was replaced with threonine. This replacement affects the cytoplasmic domain (p. Ala2354Thr); however, the RYR2 mutation pathogenicity remains unknown. An analysis of RYR2 mutations demonstrated that among 155 patients, 14 (31%) patients had a positive mutation in RYR2.
SCN10A encodes the Nav1.8 channel alpha subunit. The Nav1.8 channel plays a fundamental role in cardiac conduction.,, In case three, the LQTS patients were found to have frameshift and missense variants in SCN10A. Interestingly, the daughter was diagnosed with Turner's syndrome. QT prolongation was previously found in 20% of adults and 33% of children with Turner's syndrome with a high prevalence of LQTS gene mutations. The second patient in case four had variants in both SCN10A and KCNH2 genes. Unfortunately, further details on the precise mutations were not available.
GATA3 encodes for the zinc–finger transcription factor. In case five, the patient was initially suspected of an incomplete DiGeorge syndrome. However, the patient was later diagnosed with Barakat Syndrome. Barakat Syndrome is attributed to c.815C>T (p. Thr272Ile) mutation in the GATA3 gene and is characterized by hypoparathyroidism, sensorineural deafness, and nephropathy. While hypocalcemia secondary to hypoparathyroidism can cause prolonged QTc, the patient had a QTc of 474 despite an unremarkable calcium level. This suggested patients with GATA3 mutation had an inherent predisposition to QT prolongation.
A mutation in SLC6A8, which codes for the creatine transporter, causes X-linked creatine deficiency. In case six, a young boy had intellectual disabilities and epileptic seizures. The patient's genetic testing illustrated an additional AKAP9 gene mutation of c.6065A>G (p. Gln2022Arg). The AKAP9 encodes for kinase anchor protein-9, an LQTS genetic modifier. Loss-of-function mutations in the AKAP9 gene have been associated with type 11 congenital LQTS. While creatine transporter deficiency male patients may have a rare interrelation with LQTS, the patient may also have additional QTc prolongation. However, future studies are needed to confirm any functional connection.
| Conclusions|| |
This case series recapitulated the clinical characteristics and genetics, and patient outcomes from Hong Kong with rare variants involving genes outside of the traditional LQTS system. Future studies are needed to determine their functional effects.
Khalid Bin Waleed and Oscar Hou In Chou: Systematic search, data collection, study screening, data analysis, manuscript drafting, and manuscript critical revision. Jeremy Man Ho Hui, Yan Hiu Athena Lee, Simon Siyuan Li, Teddy Tai Loy Lee, Keith Sai Kit Leung, Leonardo Roever, Yunlong Xia, and Qiang Liu: Data analysis, manuscript drafting, and manuscript critical revision. Sharen Lee and Gary Tse: Systematic search, study screening, genetic analysis and interpretation, ECG analysis, manuscript drafting, manuscript critical revision.
Khalid Bin Waleed acknowledged and dedicated this work to the European Society of Cardiology and European Heart Rhythm Association for fellowship award and learning opportunity at St. George's University Hospitals NHS Foundation Trust, London, United Kingdom.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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