Clinical Impact of Genetic Testing for Long QT Syndrome　― Evidence From a Nationwide LQTS Registry in Japan ―

Abstract

Background: Genetic testing for long QT syndrome (LQTS) is useful for diagnosis, risk stratification, and therapeutic strategies. This study investigated the clinical impact of genetic testing for LQTS patients.

Methods and Results: Total 3,851 patients (proband: 2,316 [60%]; female: 2,283 [59%]; median age: 14 years [interquartile range 9–36 years]) diagnosed with LQTS (LQTS score ≥3.5, QTc ≥500 ms, pathogenic variants in LQTS-associated genes, or unexplored syncope with QTc 480–499 ms) were enrolled in this study. Of these patients, 1,146 (29.8%) experienced syncope and 322 (8.5%) experienced ventricular fibrillation (VF) or cardiopulmonary arrest (CPA) at ≤70 years of age. Genetic testing using a next-generation sequencing panel and/or Sanger sequencing was performed for 3,770 (98%) patients, genotype was then identified in the following LQTS-associated genes: KCNQ1 (45%), KCNH2 (34%), SCN5A (8%), KCNE1 (0.1%), KCNE2 (0.03%), KCNJ2 (2.7%), CACNA1C (1.2%), and CALM1,2 (0.3%). Forty-seven (1.2%) patients had double or compound heterozygous variants in LQTS-associated genes, whereas the genotype remained unknown in 220 (5.8%) patients. When comparing phenotype with genotype, QTc was significantly longer in CALM1,2 patients than in others except for CACNA1C, whereas QTc was almost normal in KCNJ2 patients. The incidence of the first cardiac event (syncope, VF/CPA) differed among the genotypes, and prognosis was significantly worse for CALM1,2 patients.

Conclusions: Comprehensive genetic testing, including non-major LQTS genes, is important for diagnosis and risk stratification of LQTS.

Long QT syndrome (LQTS) is characterized by a prolonged QT interval on electrocardiogram (ECG) and a polymorphic ventricular tachycardia, known as torsade de pointes (TdP), triggered primarily by exercise or stress, resulting in syncope or sudden cardiac death (SCD).^1,2 The first symptoms usually occur in children or adolescents, but in some cases may occur in the adult or older population. Continuous medical care from childhood/adolescence to adulthood is important for those with LQTS.

Most cases of congenital LQTS are autosomal dominant inherited (Romano-Ward syndrome). Pathogenic variants in the genes encoding cardiac ion channels or their associated proteins have been identified in approximately 70% of patients with LQTS.³ Previous studies have demonstrated genotype-^4–6 or variant-specific^7–11 differences in prognosis and therapeutic strategies in LQTS, suggesting that genetic testing is extremely important for patients with LQTS and their families. More than 17 genes have been reported as causative or associated genes for LQTS. The Clinical Genome Resource (ClinGen) Working Group for LQTS has classified the LQTS-associated genes as definitive, strong, and moderate,¹² with these classifications being cited in the 2022 European Heart Rhythm Association/Heart Rhythm Society/Asia Pacific Heart Rhythm Society/Latin American Heart Rhythm Society expert consensus statement.¹³ However, the clinical impact of genetic testing for LQTS based on the recent statement is still unexplored.

In this study, we enrolled nearly 4,000 patients with LQTS using a nationwide Japanese LQTS registry and then investigated the clinical impact of genetic testing, as well as the association between the genotype and phenotype, for patients with LQTS.

Methods

Patients

This multicenter registry retrospectively enrolled patients with LQTS and their families who had been diagnosed with LQTS at 19 Japanese institutions (National Cerebral and Cardiovascular Center, Saitama Medical University International Medical Center, Tsukuba University, Kagoshima Medical Center, Shiga University of Medical Science, Kanazawa University, Okayama University, Gunma University, Niigata University, Shinshu University, Osaka City General Hospital, Hokkaido Children’s Hospital, Teine-Keijinkai Hospital, Yamagata University, Nagoya University, Tokushima University, Fukuoka Children Hospital, and Yokohama City University). The number of enrollments from each institution are presented in Supplementary Table 1.

LQTS was diagnosed if any of the following criteria were met:

• LQTS risk score (“Schwartz score”) ≥3.5¹⁴

• QTc ≥500 ms on repeated ECG recordings after excluding secondary LQTS

• the presence of pathogenic or likely pathogenic (P/LP) variants in LQTS-associated genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNJ2, CACNA1c, CALM1–3 and TRDN) regardless of QT interval.

A diagnosis of LQTS was also made for those who had unexplained syncope and a QTc of 480–499 ms on repeated ECGs after excluding secondary LQTS.

Written informed consent was obtained from all patients, or from the parents or legal guardians of minors, for both clinical and molecular screening, as well as study participation. This study conformed to the Declaration of Helsinki and was approved by the Ethics Committee of the National Cerebral and Cardiovascular Center (R22006-5).

Clinical Characteristics and ECG Parameters

All clinical characteristics, including age at diagnosis, sex, previous cardiac events, such as syncope, ventricular fibrillation (VF), cardiopulmonary arrest (CPA) or SCD, a family history of LQTS and SCD, and ECG parameters were obtained from the electronic data capture system. For the ECG parameters, the QT and RR intervals were measured in lead II or V5, and the QT interval was corrected for heart rate (QTc) according to Bazett’s formula. In addition, data was collected in the registry for the QTc 4 min after recovery from an exercise stress test (if applicable), the presence or absence of TdP, T wave alternans (TWA), notched T wave in 3 leads, and bradycardia for age.¹⁴

Genetic Testing

Genetic testing for at least the major LQTS genes, such as KCNQ1, KCNH2 and SCN5A, was performed locally at each institution using standard technologies. However, some probands had undergone more recent comprehensive genetic testing using next-generation sequencing (NGS) targeting not only the major LQTS genes but also relatively rare LQTS genes, such as CALM1–3, KCNE1, KCNE2, TRDN, CACNA1c, and KCNJ2. Family members underwent genetic screening focused on the disease-causing variant identified in the probands. Variant pathogenicity was evaluated using ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and Franklin ACMG classification (https://franklin.genoox.com/). The variant position was based on the transcript ID NM_000218 (KCNQ1), NM_000238 (KCNH2), and NM_001099404 or NM_198056 (SCN5A).

Statistical Analysis

Continuous variables are presented as the mean±SD or median with interquartile range (IQR), as appropriate, and categorical variables are presented as numbers and percentages. The significance of differences in baseline characteristics between probands and family members were compared using Student’s t-test or the Wilcoxon rank-sum test for continuous variables, and the Chi-squared test or Fisher’s exact test for categorical variables, as appropriate. Differences among patients in the major 3 LQTS genotypes, namely KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), were compared using analysis of variance (ANOVA) or the Kruskal-Wallis test for continuous variables, and the Chi-squared test or Fisher’s exact test for categorical variables, as appropriate. We described QTc (ms) at diagnosis using violin plots for better visualization of the distribution of QTc among genotypes. We used ANOVA to compare mean QTc values among genotypes and Tukey’s honestly significant difference test for multiple comparisons. The cumulative incidences of the primary and secondary outcomes were calculated using the Kaplan-Meier method. The follow-up period was defined as from birth to the age of initial diagnosis. The primary endpoint was the time from birth until the first syncope event up to age 70 years, and the secondary endpoint was VF or CPA up to age 70 years. All reported P values are 2-tailed, and P<0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.4 and JMP version 14 (SAS Institute Inc., Cary, NC, USA).

Results

LQTS Diagnosis

In total, 4,006 patients with LQTS were recorded in this registry from 19 institutions in Japan. Of these 4,006 patients, 155 who were not compatible with the diagnostic criteria for LQTS were excluded,³ leaving 3,851 patients who met the LQTS diagnosis in this study. Figure 1A shows the number of patients in whom LQTS was diagnosed using the different diagnostic criteria. Specifically, 1,300 patients had a QTc ≥500 ms on ECG, and 1,160 (89.2%) of these patients were genotype positive; another 2,265 patients had a Schwartz score ≥3.5, with 2,006 (88.6%) being genotype positive. However, 1,439 patients did not completely meet these diagnostic criteria (QTc ≥500 ms or Schwartz score ≥3.5) and were diagnosed with LQTS on the basis of a positive genetic test; almost 60% of these patients were family members of the probands.

Figure 1.

(A) Overlap pie chart showing the number of patients diagnosed with long QT syndrome (LQTS) with the various diagnostic criteria in this registry. (B) Age and (C) QTc at diagnosis distribution in probands and family members in this registry.

As shown in Figure 1B, the age of the probands peaked before 20 years, but the age distribution was extremely broad, indicating that LQTS can be diagnosed not only in children/adolescents but also in adults and older populations.¹⁵ Conversely, the age of family members (Figure 1B) showed a bimodal distribution because, in many familial cases, a child (proband) was first diagnosed with LQTS and the parents or siblings were then diagnosed with LQTS by cascade screening.

As indicated in Table 1, 1,161 (30%) patients had a history of syncope, with 1,146 being aged ≤70 years old, of whom a higher proportion were probands (40%) than family members (14%). Not all syncope in this registry was due to TdP; however, 16% of probands experienced TdP. Furthermore, 322 (8.5%) patients had a history of VF/CPA at age ≤70 years, with a significantly higher proportion among probands than their families (12.6% vs. 2.0%). Thus, some probands could be diagnosed with LQTS when they experienced a cardiac event such as syncope, TdP, or VF/CPA.

Table 1.

Clinical Characteristics of Patients With LQTS at Diagnosis

	Overall (n=3,851)	Probands (n=2,316)	Family members (n=1,535)	P value
Age at diagnosis (years)	14 [9–36]	13 [9–24]	27 [9–43]	<0.001
Female sex	2,283 (59.3)	1,435 (62.0)	848 (55.2)	<0.001
Symptom
Syncope	1,161 (30.2)	938 (40.5)	223 (14.5)	<0.001
First syncope at age ≤70 years	1,146 (29.8)	924 (39.9)	222 (14.5)	<0.001
VF/CPA	333 (8.6)	300 (13.0)	33 (2.1)	<0.001
First VF/CPA at age ≤70 years	322 (8.5)	291 (12.6)	31 (2.0)	<0.001
ECG parameters
RR (ms)	890±191	903±184	870±199	<0.001
QT (ms)	455±65	470±63	434±61	<0.001
QTc (B) (ms)	486±49	497±48	469±44	<0.001
T wave alternans	112 (2.9)	92 (4.0)	20 (1.3)	<0.001
Notched T wave	966 (25.1)	664 (28.7)	302 (19.7)	<0.001
TdP	391 (10.2)	367 (15.9)	24 (1.6)	<0.001
Bradycardia	316 (8.2)	246 (10.6)	70 (4.6)	<0.001
Deafness	23 (0.6)	17 (0.7)	6 (0.4)	0.175
Treadmill exercise testing	967 (25.1)	796 (34.4)	171 (11.1)	<0.001
QTc 4 min after exercise testing (ms)	503±53	505±53	496±49	0.034
Family history
Definitive LQTS		942 (40.7)	N/A
SCD at age <30 years		190 (8.2)	N/A
Schwartz score	3.8±2.0	4.3±2.0	3.0±1.8	<0.001

Continuous variables are presented as the mean±SD or median [interquartile range]. Categorical variables are presented as n (%). CPA, cardiopulmonary arrest; ECG, electrocardiogram; LQTS, long QT syndrome; QTc, QT corrected for heart rate; SCD, sudden cardiac death; VF, ventricular fibrillation.

The QTc was longer in probands than in the family members, but its distribution was also broad (Figure 1C). Moreover, the presence of other ECG parameters, such as TWA, notched T wave, and bradycardia for age, was also higher among probands than their family members. Therefore, the Schwartz score was significantly higher among probands than their family members (Table 1).

Genotype Identification

Genetic testing was performed in 3,770 (97.9%) patients. Among the probands, 2,250 (97.2%) underwent genetic testing, with 670 (29.8%) undergoing NGS; after testing, 2,035 (90.4%) probands were diagnosed as genotype-positive LQTS. Conversely, among family members (n=1,535), 1,520 (99.0%) underwent genetic testing, with 1,448 (95.3%) undergoing Sanger sequencing targeting the variant that had already been identified in the probands (Table 2; Figure 2A).

Table 2.

Genetic Testing and LQTS Genotype

	Overall (n=3,851)	Probands (n=2,316)	Family members (n=1,535)	P value
Genetic testing performed	3,770 (97.9)	2,250 (97.2)	1,520 (99.0)
Sanger only	3,009 (79.8)	1,561 (69.4)	1,448 (95.3)	<0.0001
NGS only	222 (5.9)	194 (8.6)	28 (1.8)
NGS+Sanger	505 (13.4)	476 (21.2)	29 (1.9)
Unknown/others	34 (0.9)	19 (0.8)	15 (1.0)
Genotype				<0.001
KCNQ1	1,710 (45.4)	948 (42.1)	762 (50.1)
KCNH2	1,293 (34.3)	737 (32.8)	556 (36.6)
SCN5A	314 (8.3)	186 (8.3)	128 (8.4)
KCNE1	4 (0.1)	4 (0.2)	0 (0.0)
KCNE2	1 (0.03)	1 (0.04)	0 (0.0)
KCNJ2	100 (2.7)	60 (2.7)	40 (2.6)
CACNA1C	58 (1.5)	40 (1.8)	18 (1.2)
CALM1	3 (0.1)	3 (0.1)	0 (0.0)
CALM2	10 (0.3)	10 (0.4)	0 (0.0)
CALM3	0 (0.0)	0 (0.0)	0 (0.0)
TRDN	0 (0.0)	0 (0.0)	0 (0.0)
Double or compound hetero	47 (1.3)	36 (1.6)	11 (0.7)
OthersA	10 (0.3)	10 (0.4)	0 (0.0)
Unknown	220 (5.8)	215 (9.6)	5 (0.3)

Unless indicated otherwise, data are given as n (%). ^AOther genotypes included ANK2 (n=3), structural abnormalities of chromosome 7 (n=3), RYR2 (n=1), KCNJ5 (n=1), HCN4 (n=1), and MYBPC3 (n=1). Double or compound hetero, double or compound heterozygous variants in long QT syndrome [LQTS]-associated genes; NGS, next-generation sequencing.

Figure 2.

(A) Number of patients who underwent genetic testing, and the methods of genetic testing. NGS, next-generation sequencing methods, including targeted sequencing panel, whole-exome sequencing, and whole-genome sequencing. (B) Genotypes identified in the long QT syndrome (LQTS) registry. double/compound hetero, double or compound heterozygous variants in LQTS-associated genes; UN, unknown.

Finally, in total, there were 1,710 (45.3%) patients with KCNQ1 variants (LQT1; including 8 homozygous for a KCNQ1 variant), 1,293 (34.3%) with KCNH2 variants (LQT2), 314 (8.3%) with SCN5A variants (LQT3), 4 (0.1%) with KCNE1 variants (LQT5), 1 (0.03%) with a KCNE2 variant (LQT6), 100 (2.7%) with KCNJ2 variants (LQT7; Andersen–Tawil syndrome [ATS]), 58 (1.5%) with CACNA1C variants (LQT8; including 5 with Timothy syndrome [TS]), and 13 (0.3%), all probands, with CALM1 (n=3) and CALM2 (n=10) variants enrolled in this registry. Moreover, 47 patients had more than 2 variants (double or compound heterozygous) of the LQTS genes. Variants not related to LQTS (i.e., ANK2, RYR2, KCNJ5, HCN4, and MYBPC3) were identified in 7 patients, and 3 patients had structural abnormalities of chromosome 7. Finally, P/LP variants in the LQTS genes were not identified in 220 patients (genotype unknown; Table 2; Figure 2B).

Genotype-Phenotype Association

The QTc distribution at diagnosis for each genotype is shown in Figure 3. Among genotyped LQTS patients, QTc was significantly longer for those with the CALM1,2 genotype than for those with the major 3 LQTS genotypes (i.e., KCNQ1, KCNH2, and SCN5A). In contrast, the QTc was shorter (and nearly normal) in those with the KCNJ2 genotype compared with the other genotypes.

Figure 3.

Violin plot of QTc at diagnosis for each long QT syndrome (LQTS) genotype. *P<0.01 (ANOVA with Tukey’s honestly significant difference test).

Kaplan-Meier analysis was used to investigate the cumulative incidence of the first cardiac event, such as syncope (Figure 4A) and VF/CPA (Figure 4B), for each genotype. Patients with CALM1,2 variants had the worst prognosis among all the genotypes. However, when CALM-LQTS was excluded from consideration, syncope events in the other genotyped patients also increased after adolescence. In particular, the incidence of syncope after puberty was higher among patients with LQT2 than among those with other types of LQTS.

Figure 4.

Kaplan-Meier curves for (A) the first syncope event and (B) the first ventricular fibrillation (VF) or cardiopulmonary arrest (CPA) event.

Furthermore, the frequency of VF/CPA in patients with KCNH2 (LQT2), SCN5A (LQT3), and CACNA1C (LQT8 or TS) was nearly 20% when they reached middle age if they were untreated, which is higher than among those with KCNQ1 (LQT1) and KCNJ2 (LQT7 or ATS) variants.

Genotype-Phenotype in LQT1–3

The 3 major genes (i.e., KCNQ1, KCNH2, and SCN5A) were found in 3,317 (86%) patients. We therefore focused on patients with LQT1–3. As indicated in Table 3, the age at diagnosis was younger for those with LQT1 and LQT3 than for those with LQT2. Female sex was more common in the LQT1 and LQT2 groups than in the LQT3 group (60.9% and 60.6% vs. 46.8%, respectively). Syncope events at age ≤70 years were more common in the LQT2 group than in the LQT1 and LQT3 groups. However, the occurrence of VF/CPA at age ≤70 years was higher in the LQT3 and LQT2 groups than in the LQT1 group.

Table 3.

Clinical Characteristics of Patients With Variants in the 3 Major LQTS Genes

	LQT1 (KCNQ1; n=1,710)	LQT2 (KCNH2; n=1,293)	LQT3 (SCN5A; n=314)	P value
Age at diagnosis (years)	13 [8–37]	17 [11–38]	13 [8–34]	<0.001
Female sex	1,041 (60.9)	784 (60.6)	147 (46.8)	<0.001
Symptom
Syncope	473 (27.7)	481 (37.2)	78 (24.8)	<0.001
First syncope at age ≤70 years	464 (27.2)	478 (37)	77 (24.5)	<0.001
Age at first syncope (years)	10 [7–14]	16 [12–25]	13.5 [7–27.5]	<0.001
VF/CPA	78 (4.6)	151 (11.7)	41 (13.1)	<0.001
First VF/CPA at age ≤70 years	73 (4.3)	146 (11.5)	41 (13.2)	<0.001
Age at first VF/CPA (years)	17 [10–46]	23 [16–38]	12 [1–25]	0.001
ECG parameters
RR (ms)	885±176	906±198	913±222	0.003
QT (ms)	450±56	464±71	459±75	<0.001
QTc (B) (ms)	481±43	490±51	484±56	<0.001
T wave alternans	30 (1.8)	40 (3.1)	24 (7.7)	<0.001
Notched T wave	122 (7.2)	629 (48.7)	53 (16.9)	<0.001
Bradycardia	100 (5.9)	97 (7.5)	60 (19.1)	<0.001
Deafness	14 (0.8)	6 (0.5)	0 (0.0)	0.160
TdP	67 (3.9)	235 (18.2)	36 (11.5)	<0.001
Treadmill exercise test	491 (28.7)	265 (20.5)	86 (27.4)	<0.001
QTc(B) 4 min after exercise test (ms)	521±47	489±44	471±46	<0.001
Family history
LQTS	1,094 (64.1)	889 (68.8)	188 (60.1)	0.002
SCD	104 (6.1)	149 (11.5)	41 (13.1)	<0.001
Schwartz score	3.5±1.9	4.3±2.1	3.5±2.2	<0.001

Continuous variables are presented as the mean±SD or median [interquartile range]. Categorical variables are presented as n (%). TdP, torsade de pointes. Other abbreviations as in Table 1.

With regard to ECG parameters, the QTc at diagnosis was longer in the LQT2 group than in the LQT1 and LQT3 groups. In addition, a notched T wave and TdP were more often observed and a family history of LQTS was more common in the LQT2 group than in the LQT1 and LQT3 groups. Conversely, the QTc at 4 min after exercise testing was significantly longer in the LQT1 group than in the LQT2 and LQT3 groups, and the incidence of bradycardia and TWA was higher in the LQT3 group than in the other 2 groups. Together with clinical parameters, the ECG findings contributed to a higher Schwartz score in the LQT2 group than in the LQT1 and LQT3 groups (Table 3).

Triggers for the first syncope event are shown in Figure 5A. In the LQT1 group, many (70%) syncope events occurred during exercise and/or swimming. In contrast, exercise as a trigger of first syncope was rare in the LQT2 and LQT3 groups, as reported previously.⁵ In the LQT2 group, 23% of syncope events occurred during some emotional stress or arousal stimuli, but they occurred more (44%) often during sleep or when waking up in the morning, similar to findings in the LQT3 group. These results mirror the triggers for VF/CPA (Figure 5B): almost half the VF/CPA events in the LQT1 group occurred during exercise, whereas more than half the events in the LQT2 and LQT3 groups occurred during rest or sleep.

Figure 5.

Triggers of the first cardiac event occurring at age ≤70 years in patients with LQT1, LQT2, and LQT3: (A) syncope and (B) ventricular fibrillation (VF) or cardiopulmonary arrest (CPA).

Variants in LQT1–3

In total, 243 variants were identified in 948 LQT1 probands (Supplementary Table 2), including 719 (75.8%) patients with missense variants, 106 (11.2%) with splicing errors, 49 (5.2%) with frameshifts, 34 (3.6%) with nonsense variants, 30 (3.2%) with deletions, 4 with insertions/deletions, 2 with duplications, and 4 with copy number variants. Among 737 LQT2 probands, 417 variants were identified (Supplementary Table 3), including missense variants in 425 (57.7%) patients, splicing errors in 29 (3.9%), frameshifts in 201 (27.3%), nonsense variants in 53 (7.2%), deletions in 20 (2.7%), insertions/deletions in 2, duplications in 5, and copy number variants in 1. There were 74 variants identified in 186 LQT3 probands (Supplementary Table 4), including 174 (93.6%) patients with missense variants, 9 (4.8%) with deletions, and 2 with duplications (1 unknown). None of the LQT3 patients had splicing errors, or nonsense and frameshift variants.

According to the Franklin ACMG classification, patients with P/LP variants were higher in the order of KCNQ1 (95.3%), KCNH2 (88.1%), and SCN5A (76.3%). Using ClinVar, there was still a high proportion of P or LP variants (67.6% in KCNQ1, 53.2% in SCN5A, but only 36.2% in KCNH2), but many variants were classified as conflicting with pathogenicity, as a variant of unknown significance (VUS), or were not provided in ClinVar (Supplementary Figure).

Discussion

Major Findings

This study enrolled 3,851 patients with LQTS, comprising 2,316 probands and 1,535 families, in Japan; as of January 2025, this was the largest LQTS cohort in any study, not only in Japan but also worldwide.^16,17 As detailed in this registry, genetic testing was performed in 3,770 (98%) patients, with 1,710 LQT1, 1,293 LQT2, and 314 LQT3 patients and families identified in total. The number of LQT1 and LQT2 patients enrolled in this registry is also higher than in previous international LQTS studies. Most notably, this registry also identified some minor genotypes, such as KCNE1, CACNA1C, KCNJ2 and CALM1,2 genes, as well as detailed variant information for LQT1–3. Recently, comprehensive genetic testing for all LQTS-associated genes has become available as a routine diagnostic tool, and our data including all genotyped LQTS patients will be helpful for clinical practice.

Genetic Background in LQTS

In LQTS, the causative gene has been identified in 70–80% of patients with a clinical diagnosis of congenital LQTS. Because this registry enrolled patients who had already been diagnosed with congenital LQTS, it is impossible to determine directly how many genotype-positive cases there were among patients clinically diagnosed (or suspected) with LQTS. However, in total, 2,111 of 2,409 (87.6%) patients with clinically confirmed LQTS (QTc ≥500 ms and/or Schwartz score ≥3.5) were genotype positive (Figure 1A). Moreover, among the genotype-positive patients (n=3,550), most affected genes were identified as either KCNQ1, KCNH2, or SCN5A (total n=3,317; 93.4%).

In addition to these 3 genes, CALM1–3 encoding calmodulin, a Ca²⁺-binding protein, is also an important causative gene for LQTS.^12,13 The Japanese Circulation Society/JCC/JSPCCS 2024 guideline on genetic testing and counseling strongly recommends genetic testing in LQTS for genes that are certain to cause LQTS (i.e., KCNQ1, KCNH2, SCN5A and CALM1–3).³ In our LQTS registry, there were 13 patients with CALM-LQTS (3 CALM1 and 10 CALM2). All 13 patients were probands and their QTc was significantly longer than for the other genotypes, except for CACNA1C (Figure 3); in addition, most individuals had experienced a lethal cardiac event at age <20 years (Figure 4B). The severe prognosis of CALM-LQTS patients is similar to that reported in the international registry data for calmodulin mutations,¹⁸ which cause several arrhythmic disorders in addition to LQTS, such as catecholaminergic polymorphic ventricular tachycardia (CPVT) and idiopathic VF, that may be called “calmodulinopathies.” Fukuyama et al. have already reported some calmodulinopathies in Japanese children (n=10), including 5 with LQTS, 3 with CPVT, and 2 with overlapping phenotypes.¹⁹

TRDN variants are a possible cause in homozygous patients with recessive LQTS, but there were no TRDN homozygous variants in our registry. In addition, KCNQ1 and KCNE1 are thought to cause Jervell and Lange-Nielsen syndrome, and KCNE1 and KCNE2 are associated with acquired LQTS.^3,13 In our LQTS registry, there were 8 patients with KCNQ1 homozygous variants and 4 with KCNE1 heterozygous variants. The D85N variant of KCNE1 is a susceptibility variant that affects QT prolongation,²⁰ but is not included in the genotypes in our registry because it is essentially a benign variant (Japanese minor allele frequency=0.01 on the 8.3KJPN Japanese whole-genome reference panel). These susceptibility gene variants are also an issue for future studies.

Other LQTS or LQTS-related diseases include TS and non-TS (LQT8) or ATS (LQT7). Several investigators have already reported the genetic and clinical aspects of ATS in Japan,^21–23 and in an international cohort.²⁴ Moreover, Fukuyama et al. reported on LQT8 in Japan.^25,26 In our registry, there were 5 patients with TS, 53 with non-TS LQT8, 100 with ATS, and 47 with double or compound heterozygous variants.

Furthermore, a phenotypic overlap of LQT3 with Brugada syndrome is observed in some carriers of variants in the Na channel gene SCN5A.²⁷ In our LQTS registry, there were 16 patients (median age 30 years, 75% male) with phenotypic overlap of LQTS with Brugada syndrome. These patients had a variant in the SCN5A (n=12), KCNQ1 (n=2), KCNH2 (n=1) and CACNA1C (n=1) genes, but in most cases (n=10; 63%) the variant was c.5350G>A p.E1784K in SCN5A. Details of each genotyped LQTS and other phenotypes, such as calmodulinopathy, TS, non-TS LQT8, ATS, and overlap with Brugada syndrome, were not investigated in this study, but they will be identified in future studies.

Genotype-Phenotype Association in LQT1–3

Since 1985, when Schwartz²⁸ and Moss et al.² first reported more than 100 patients with LQTS, many LQTS registry studies have revealed considerable information about the genotype–phenotype association in LQTS. Most of these studies have focused on LQT1–3, investigating triggers of cardiac events,^5,17 age and sex differences in arrhythmic risk,^6,29,30 genotype and variant location-specific risk stratification,^8,9,31 and genotype-specific pharmacological therapy.^32–34

The results of our LQTS registry are similar to those of studies in previous international cohorts. The primary difference is that the present study is not an international study, but a domestic study in Japan (albeit a multicenter registry in Japan), so most of the participants were Japanese. Thus, the frequency of gene variants reflects race-specific differences. For example, the KCNQ1 A344A splicing variant is the most commonly found variant in LQT1 in the Japanese population.³⁵ Furthermore, in terms of the triggers of cardiac events (e.g., syncope or VF/CPA), rest or sleep (including waking up in the morning) was the most common in LQT2 patients (Figure 5A), and was found more often than emotional or auditory stress, as previously reported. This was particularly true for VF/CPA, with 59% of events occurring during rest or sleep, and was similar in the case of LQT3 (Figure 5B).

Previous studies on LQTS enabled early diagnosis, risk stratification, and appropriate medical therapies for most LQTS patients and families. The prognosis for patients with LQTS has improved significantly since the first reports.³⁶ However, some severe cases of LQTS, particularly in women with the LQT2 genotype, are refractory to β-blocker treatment, and alternative medication or non-pharmacological therapies other than β-blockers have not been fully elucidated. To begin with, the rate of β-blocker adherence is lower among Japanese patients with LQTS than in the Europe.³⁷ It is still unclear to what extent the diagnosis and treatment of LQTS based on current practical guidelines actually contribute to improving a patient’s prognosis and preventing SCD. It is therefore essential to follow the prognosis of patients enrolled in our registry.

Study Limitations

This study has some limitations. First, this study was a retrospective study, and has some selection bias because many of the patients with LQTS were enrolled from institutions that treated many cardiovascular diseases and arrhythmias in children or adults, but not from general hospitals or clinics. Therefore, there was a high rate of genetic testing and there may be more severe cases included than for actual LQTS.

Second, this study has only provided clinical and genetic data at diagnosis, and has not included follow-up results after diagnosis. The quality of life, transitional care, and long-term prognosis of patients with congenital LQTS after diagnosis are not well understood. The effects of exercise restriction and allowing competitive sports for genotypes other than LQT1 are also not known.³⁸ To clarify these unresolved issues in LQTS, further investigations are needed into follow-up results of all patients after LQTS diagnosis.

Conclusions

The phenotype of patients with LQTS differs according to genotype, as well as age, sex, and probands/families, thus comprehensive genetic testing, including for non-major LQTS genes, is important for diagnosis and risk stratification of LQTS. The evidence from this registry study is expected to play an important role in the future treatment of LQTS and other inherited arrhythmias.

Acknowledgments

The authors are grateful to Kazue Nakajima for technical assistance with REDCap electronic data capture constructions and data management; Hiroshi Hasegawa, Kota Suzuki, Masafumi Utsumi, Hideki Kobayashi, and Tomomi Yamaguchi for data input; Nozomi Nakashima and Yuka Hiraoka for data and registry office management; and Rieko Osawa, Kaori Kugo, and Madoka Tanimoto for technical assistance with the genetic analysis.

Sources of Funding

This study was supported, in part, by Health Science Research Grants from the Ministry of Health, Labor and Welfare of Japan (21FC1004 and 23FC1003 to T.A.).

Disclosures

W.S. is a member of Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to declare.

IRB Information

This study was approved by the Ethics Committee of the National Cerebral and Cardiovascular Center (Reference no. R22006-5).

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-25-0105

References

• 1.   Schwartz PJ. 1970–2020: 50 years of research on the long QT syndrome: From almost zero knowledge to precision medicine. Eur Heart J 2021; 42: 1063–1072.
• 2.   Moss AJ, Schwartz PJ, Crampton RS, Locati E, Carleen E. The long QT syndrome: A prospective international study. Circulation 1985; 71: 17–21.
• 3.   Imai Y, Kusano K, Aiba T, Ako J, Asano Y, Harada-Shiba M, et al. JCS/JCC/JSPCCS 2024 guideline on genetic testing and counseling in cardiovascular disease. Circ J 2024; 88: 2022–2099, doi:10.1253/circj.CJ-23-0926.
• 4.   Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Robinson JL, Priori SG, et al. Influence of the genotype on the clinical course of the long-QT syndrome: International Long-QT Syndrome Registry Research Group. N Engl J Med 1998; 339: 960–965.
• 5.   Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, et al. Genotype–phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias. Circulation 2001; 103: 89–95.
• 6.   Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003; 348: 1866–1874.
• 7.   Shimizu W, Horie M, Ohno S, Takenaka K, Yamaguchi M, Shimizu M, et al. Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: Multicenter study in Japan. J Am Coll Cardiol 2004; 44: 117–125.
• 8.   Shimizu W, Moss AJ, Wilde AA, Towbin JA, Ackerman MJ, January CT, et al. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol 2009; 54: 2052–2062.
• 9.   Schwartz PJ, Moreno C, Kotta MC, Pedrazzini M, Crotti L, Dagradi F, et al. Mutation location and I_Ks regulation in the arrhythmic risk of long QT syndrome type 1: The importance of the KCNQ1 S6 region. Eur Heart J 2021; 42: 4743–4755.
• 10.   Aizawa T, Wada Y, Hasegawa K, Huang H, Imamura T, Gao J, et al. Non-missense variants of KCNH2 show better outcomes in type 2 long QT syndrome. Europace 2023; 25: 1491–1499.
• 11.   Kashiwa A, Itoh H, Makiyama T, Wada Y, Ozawa J, Kato K, et al. Clinical characterization of type 1 long QT syndrome caused by C-terminus Kv7.1 variants. Heart Rhythm 2024; 21: 1113–1120.
• 12.   Adler A, Novelli V, Amin AS, Abiusi E, Care M, Nannenberg EA, et al. An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome. Circulation 2020; 141: 418–428.
• 13.   Wilde AAM, Semsarian C, Marquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. J Arrhythm 2022; 38: 491–553.
• 14.   Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation 2011; 124: 2181–2184.
• 15.   Tomidokoro D, Nakamura T, Oka S, Miyazaki Y, Wakamiya A, Ueda N, et al. Yield of genetic testing for long-QT syndrome in elderly patients with torsades de pointes. Circ Genom Precis Med 2024; 17: e004671.
• 16.   Goldenberg I, Moss AJ, Peterson DR, McNitt S, Zareba W, Andrews ML, et al. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation 2008; 117: 2184–2191.
• 17.   Younis A, Bos JM, Zareba W, Aktas MK, Wilde AAM, Tabaja C, et al. Association between syncope trigger type and risk of subsequent life-threatening events in patients with long QT syndrome. JAMA Cardiol 2023; 8: 775–783.
• 18.   Crotti L, Spazzolini C, Nyegaard M, Overgaard MT, Kotta MC, Dagradi F, et al. Clinical presentation of calmodulin mutations: The International Calmodulinopathy Registry. Eur Heart J 2023; 44: 3357–3370.
• 19.   Fukuyama M, Horie M, Kato K, Aoki H, Fujita S, Yoshida Y, et al. Calmodulinopathy in Japanese Children: Their cardiac phenotypes are severe and show early onset in fetal life and infancy. Circ J 2023; 87: 1828–1835.
• 20.   Nishio Y, Makiyama T, Itoh H, Sakaguchi T, Ohno S, Gong YZ, et al. D85N, a KCNE1 polymorphism, is a disease-causing gene variant in long QT syndrome. J Am Coll Cardiol 2009; 54: 812–819.
• 21.   Haruna Y, Kobori A, Makiyama T, Yoshida H, Akao M, Doi T, et al. Genotype-phenotype correlations of KCNJ2 mutations in Japanese patients with Andersen-Tawil syndrome. Hum Mutat 2007; 28: 208.
• 22.   Kimura H, Zhou J, Kawamura M, Itoh H, Mizusawa Y, Ding WG, et al. Phenotype variability in patients carrying KCNJ2 mutations. Circ Cardiovasc Genet 2012; 5: 344–353.
• 23.   Miyamoto K, Aiba T, Kimura H, Hayashi H, Ohno S, Yasuoka C, et al. Efficacy and safety of flecainide for ventricular arrhythmias in patients with Andersen-Tawil syndrome with KCNJ2 mutations. Heart Rhythm 2015; 12: 596–603.
• 24.   Mazzanti A, Guz D, Trancuccio A, Pagan E, Kukavica D, Chargeishvili T, et al. Natural history and risk stratification in Andersen-Tawil syndrome type 1. J Am Coll Cardiol 2020; 75: 1772–1784.
• 25.   Fukuyama M, Wang Q, Kato K, Ohno S, Ding WG, Toyoda F, et al. Long QT syndrome type 8: Novel CACNA1C mutations causing QT prolongation and variant phenotypes. Europace 2014; 16: 1828–1837.
• 26.   Fukuyama M, Ohno S, Ozawa J, Kato K, Makiyama T, Nakagawa Y et al. High prevalence of late-appearing T-wave in patients with long QT syndrome type 8. Circ J 2020; 84: 559–568.
• 27.   Makita N, Behr E, Shimizu W, Horie M, Sunami A, Crotti L, et al. The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. J Clin Invest 2008; 118: 2219–2229.
• 28.   Schwartz PJ. Idiopathic long QT syndrome: Progress and questions. Am Heart J 1985; 109: 399–411.
• 29.   Locati EH, Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Lehmann MH, et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: Findings from the International LQTS Registry. Circulation 1998; 97: 2237–2244.
• 30.   Mazzanti A, Trancuccio A, Kukavica D, Pagan E, Wang M, Mohsin M, et al. Independent validation and clinical implications of the risk prediction model for long QT syndrome (1-2-3-LQTS-Risk). Europace 2022; 24: 614–619.
• 31.   Moss AJ, Shimizu W, Wilde AA, Towbin JA, Zareba W, Robinson JL, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation 2007; 115: 2481–2489.
• 32.   Abu-Zeitone A, Peterson DR, Polonsky B, McNitt S, Moss AJ. Efficacy of different beta-blockers in the treatment of long QT syndrome. J Am Coll Cardiol 2014; 64: 1352–1358.
• 33.   Mazzanti A, Maragna R, Faragli A, Monteforte N, Bloise R, Memmi M, et al. Gene-specific therapy with mexiletine reduces arrhythmic events in patients with long QT syndrome type 3. J Am Coll Cardiol 2016; 67: 1053–1058.
• 34.   Crotti L, Neves R, Dagradi F, Musu G, Giannetti F, Bos JM, et al. Therapeutic efficacy of mexiletine for long QT syndrome type 2: Evidence from human induced pluripotent stem cell-derived cardiomyocytes, transgenic rabbits, and patients. Circulation 2024; 150: 531–543.
• 35.   Itoh H, Dochi K, Shimizu W, Denjoy I, Ohno S, Aiba T, et al. A common mutation of long QT syndrome type 1 in Japan. Circ J 2015; 79: 2026–2030.
• 36.   Rohatgi RK, Sugrue A, Bos JM, Cannon BC, Asirvatham SJ, Moir C, et al. Contemporary outcomes in patients with long QT syndrome. J Am Coll Cardiol 2017; 70: 453–462.
• 37.   Shimamoto K, Dagradi F, Ohno S, Spazzolini C, Crotti L, Giovenzana FLF, et al. Clinical features, long-term prognosis, and clinical management of genotype-negative long QT syndrome patients. JACC Clin Electrophysiol 2024; 10: 2584–2596.
• 38.   Shimamoto K, Aiba T. How can we evaluate arrhythmic risk in children with long QT syndrome? Circ J 2024; 88: 1185–1186.