Congenital Short QT Syndrome　― Review Focused on KCNQ1 p.Val141Met Variant ―

Abstract

Short QT syndrome (SQTS) is a very rare inherited arrhythmia characterized by extremely short QT intervals on electrocardiograms and sudden cardiac death in young patients. Among the genotypes of SQTS, gain-of-function variants in the potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene are accountable for SQTS type 2 (SQT2). Pathogenic variants for SQT2 are rare and, among them, the p.Val141Met is relatively prevalent. This review summarizes findings for 5 SQTS patients harboring p.Val141Met we recently encountered and compares them to another 14 patients reported in the literature.

Short QT syndrome (SQTS) is a rare primary arrhythmic disorder with a low prevalence rate that was first reported in 2000 by Gussak et al.,¹ who described 2 families with extremely short QT intervals and an increased risk of ventricular arrhythmia (VA) and cardiac death.^2–4 Pathologic variants were found in multiple genes, including the potassium voltage-gated channel subfamily H member 2 (KCNH2), potassium voltage-gated channel subfamily Q member 1 (KCNQ1), potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) and solute carrier family 4 member 3 (SLC4A3) genes. SQTS associated with variants in KCNQ1 is classified as SQT2.⁴ Since the first report by Hong et al. in 2005,⁵ KCNQ1 p.Val141Met has become the most frequently identified variant in SQT2 but is phenotypically atypical. In addition to causing SQTS, KCNQ1 p.Val141Met causes other phenotypes, such as fetal or newborn bradycardia, atrial fibrillation (AF), and bradycardia-induced heart failure.^6–16 In addition, some patients also present sinoatrial and atrioventricular node dysfunction, supraventricular arrhythmias, and atrial standstill.^3,4,16 Some also present left ventricular (LV) dilatation and are diagnosed with early-onset dilated cardiomyopathy.^5,14 From the early stages of life, patients require pacemaker implantation. However, due to atrial standstill, ventricular pacing is often required.^8,10–14,17

Some studies have reported that patients with p.Val141Met-related SQTS rarely exhibit VAs, whereas other studies have reported that SQTS patients present VAs, resulting in sudden cardiac death.^3,4 We recently reported a family harboring p.Val141Met, with the father of the proband experiencing ventricular fibrillation (VF).¹⁴ Subsequently, as reported herein, we evaluated 5 Val141Met-positive carriers (including 2 adult family members) from 3 unrelated families. We then reviewed 19 SQTS patients carrying a heterozygous Val141Met variant, including our 5 patients.

Methods

Patients

Diagnosis of SQTS was based on a previous consensus report.¹⁸ Patients underwent a genetic test using targeted gene sequencing methods (HaloPlex HS kit; Agilent Technology, CA, USA) and MiSeq system (Illumina, CA, USA),¹⁹ which included more than 45 genes. The panel included KCNH2, KCNQ1, KCNJ2, and SLC4A3, as well as other genes responsible for the inherited arrhythmia syndromes.²⁰ All identified variants were verified by Sanger sequencing.

Three probands and 2 of their family members were found to carry a heterozygous KCNQ1 p.Val141Met variant, but none in other genes that were analyzed. We surveyed their clinical background, including age, sex, clinical phenotypes, therapy, electrocardiogram (ECG) findings, and prognosis. ECG parameters included RR and QT intervals. The corrected QT interval (QTc) was calculated using Bazzet’s formula.²¹ Holter ECG data were also included, if available. An early repolarization (ER) pattern²² was defined as J-point elevation >1 mm in ≥2 contiguous leads.

This study complies with the Declaration of Helsinki. Written informed consent was obtained from all patients and guardians following the guidelines approved by the Institutional Review Board of Shiga University of Medical Science.

We also conducted a PubMed search in August 2024 to identify Val141Met-related cases of SQTS and collected detailed clinical features of all patients identified.

Results

Five Patients Harboring the KCNQ1 p.Val141Met Variant

The demographics of our 5 patients harboring the KCNQ1 p.Val141Met variant are summarized in the upper 3 rows of Table A (Probands 1–3) and in Table B (Fathers 17 and 18). Figure 1 illustrates the pedigrees of the 3 families. Genetic testing for the parents revealed that 2 of 5 patients had a de novo variant. Because genetic data on the parents of Father 17 were not available, it was unknown whether this patient’s variant is a de novo variant.

Table.

(A) Demographics of KCNQ1 Val141Met-Positive Probands, (B) Demographics of KCNQ1 Val141Met-Positive Family Members of the Probands

(A) Proband	Age at genetic testing (years)	Sex	Pattern of inheritance	Rhythm	RR (ms)	QT (ms)	QTc (ms)	Perinatal bradycardia	AF (age at onset; years)	LV dilatation	VA (age at onset; years)	Quinidine	Device therapy (age at implantation; years)	Reference
1	2	M	Paternal	SR	1,162	326	302	Yes	Yes (2)	Yes	No	No	PM (2)	14
2	1	F	Paternal	SR	1,304	358	315	Yes	Yes (0)	Yes	No	No	PM (3)	This study
3	4	M	De novo	SR	650	252	313	Yes	No	Yes	No	No	PM (4)	This study
4	0	F	De novo	SR	1,000	280	280	Yes	Yes (fetus)	No	No	No	No	6
5	3	F	ND	ND	ND	ND	<330	Yes	Yes (3)	ND	No	No	No	3
6	2	F	ND	SR	870	260	279	Yes	No	ND	No	Yes	No	9
7	6	F	ND	AF	1,000	200	292	Yes	Yes (fetus)	ND	No	Yes	PM (0)	8
8	9	F	ND	AF	675	260	317	Yes	Yes (fetus)	ND	No	No	No	8
9	10	F	Paternal	JR	938	280	293	Yes	Yes	No	No	No	PM (0)	11
10	1	F	De novo	AF	ND	ND	270	Yes	Yes	Yes	No	No	PM (2)	10
11	1	M	De novo	AF	1,160	312	290	Yes	Yes	Yes	No	Yes	PM (0)	10
12	1	F	De novo	AF	1,280	328	290	Yes	Yes	Yes	No	No	No	10
13	19	F	ND	SR	840	260	283	Yes	Yes	No	No	Yes	PM (2)	12
14	26	F	ND	SR	ND	ND	330	ND	Yes	No	No	No	PM (8) → ICD (26)	13
15	0	F	ND	ND	ND	ND	277	ND	Yes	ND	No	No	No	16
16	1	F	De novo	SR	ND	ND	330	Yes	Yes (0)	Yes	No	No	PM (1)	15
(B) Family member
17 (father of Proband 1)	37	M	ND	AF	1,065	349	339	Yes	Yes (8)	Yes	VF (42)	No	PM (20) → ICD (42)	14
18 (father of Proband 3)	34	M	De novo	JR	1,220	410	371	Yes	Yes (33)	Yes	No	No	Refused	This study
19 (father of Proband 11)	37	M	ND	AF	1,622	ND	375	ND	Yes (3)	ND	ND	ND	No	11

The probands from the present study are Probands 1–3. AF, atrial fibrillation; F, female; ICD, implantable cardioverter defibrillator; JR, junctional rhythm; KCNQ1, potassium voltage-gated channel subfamily Q member 1; LV, left ventricle; M, male; ND, not described; PM, pacemaker; SR, sinus rhythm; VA, ventricular arrhythmia.

Figure 1.

Three pedigrees of our 3 probands. Arrows indicate the probands and filled symbols indicate affected patients; (+) and (−) indicate KCNQ1 Val141Met-positive and-negative individuals, respectively. Numbers in symbols correspond to those used in Table. II-1 in Family 2 and II-1 in Family 3 were de novo mutation carriers.

The initial clinical symptoms of the 3 probands was severe bradycardia found during the perinatal stage, with ECGs taken after birth showing short QT intervals. In the 3 probands, the QTc was 302 ms (Proband 1 in Table), 315 ms (Proband 2 in Table), and 313 ms (Proband 3 in Table). The QTc was more prolonged in the 2 family members (371 and 339 ms in Fathers 17 and 18, respectively). Genetic testing was performed from the age of 1 to 37 years. By the time genetic testing was conducted, all patients presented sick sinus syndrome (SSS), AF with slow ventricular conduction (AF bradycardia), and/or atrial standstill with junctional rhythm. Four of the 5 (80%) patients underwent pacemaker implantation (PMI). No patient presented an ER pattern.²²

On echocardiography, all patients showed LV dilatation. At 4 years of age, Proband 3 had an LV end-diastolic diameter (LVDD) of 45 mm with an LVDD index of 7.38, which was partially reversed to 5.40 mL/m² after 2 years of atrial pacing (Figure 2A). Compared with the LVDD index, the left atrium showed a more rapid reverse remodeling (left atrial volume index from 64.8 to 27.4 mL/m²).

Figure 2.

(A) Four consecutive chest X-rays of Proband 3, showing partial reverse left ventricular (LV) remodeling from before (Pre-PMI) to 6 months and 1 and 2 years after pacemaker implantation. LAVI, left atrial volume index; LVDD, LV end-diastolic diameter. (B) Father 17 in Table. An electrocardiogram (ECG) strip from an automated external defibrillator record showing ventricular fibrillation (VF), which was terminated by a DC shock. (Reproduced with permission from Takechi et al.¹⁴) (C) A 12-lead ECG of Father 18 (father of Proband 3) at 34 years of age, showing a slow atrial fibrillation. The RR interval was 1,220 ms, with a QT interval of 410 ms and a QTc of 371 ms. (D) Two strips of a Holter ECG of Father 18 , showing an extremely low heart rate (HR) of ~30 beats/min, suggesting the presence of junctional rhythm (Upper panel) and a ventricular couplet (Lower panel).

The probands did not have syncope or documented VA, but Father 17 experienced an episode of VF at 42 years of age and was successfully rescued by an automated external defibrillator (Figure 2B). His pacemaker was then replaced with an implantable cardioverter-defibrillator. In infancy, he was found to have severe bradycardia. Then, at the age of 8 years, an electrophysiological study was performed showing atrial standstill, and at age 20 years, Father 17 underwent PMI. The pacing VVI mode was selected, and the pacing rate was set at 50 beats/min.

Another proband’s father (Father 18) had severe SSS and slow AF but remained asymptomatic until the age of 34 years, and a PMI was recommended but refused it. His 12-lead ECG showed slow AF with a QTc of 371 ms (Figure 2C). Holter ECG revealed a marked bradycardia (junctional rhythm) and multiple ventricular couplets (Figure 2D). Father 18 had a typical bradycardia-induced LV dilatation (LVDD 62 mm).

Clinical Characteristics of Patients Harboring the KCNQ1 p.Val141Met Variant in Published Reports

The lower rows of Table summarize details of the 14 p.Val141Met variant carriers found in previous publications (Probands 4–16 and Father 19).^8–13,15,16 Complete clinical data could not be obtained due to a lack of detailed descriptions. The median age of the probands at the time of genetic testing was 2 years (interquartile range [IQR] 1–8 years), and there were more females (n=13, 81%) than males. The median QTc was 292 ms (IQR 280–315 ms). These probands presented with perinatal bradycardia, SSS, junctional rhythm, and slow AF. Ten (63%) probands underwent PMI at a median age of 2 years (IQR 0–3 years). Seven (64%) of the 11 patients for whom data were available showed bradycardia-induced LV remodeling. Only 1 (6.3%) proband (Proband 14) underwent implantable cardioverter defibrillator implantation for the primary prevention of VF because of a prominent family history of sudden cardiac death.¹³ Only 1 proband (Proband 16) showed an ER pattern.¹⁵

Discussion

The present study reveals several unique features of SQTS associated with the KCNQ1 p.Val141Met variant. First, all patients experienced fetal bradycardia followed by SSS, AF bradycardia, and/or atrial standstill with junctional beats. Second, most patients presented LV structural remodeling. Third, unlike previous reports, our adult family members had VAs. Our 3 probands with the p.Val141Met variant had severe perinatal bradycardia and/or atrial standstill (junctional rhythm), but no VAs. All previously reported probands were also free from VA, indicating that VAs are rare in Val141Met probands. These specific features are exceptional in other SQT2 or other types of SQTS patients, raising the possibility of a unique association with the Val141Met variant.

KCNQ1 encodes the pore-forming subunit of the cardiac delayed rectifier potassium channel, which passes the delayed rectifier potassium current (I_Ks) and contributes to repolarization of the action potential. By using patch-clamp techniques, Bellocq et al.²³ demonstrated that the p.Val307Leu variant caused a significant hyperpolarizing voltage shift of the I_Ks activation curve. Hong et al.⁵ then reported that the p.Val141Met variant caused an instantaneous component to increase I_Ks, both leading to QT shortening. By using computational modeling, Whittaker et al.²⁴ showed that the p.Val141Met variant caused atrial and ventricular action potential abbreviation and cessation of pacemaking activity. Compared with other KCNQ1-related SQTS variants, only the p.Val141Met variant significantly altered the sinoatrial nodal pacemaking rate, because it has a more marked effect on I_Ks over the whole diastolic depolarization membrane potential range. In contrast, the p.Val307Leu variant,²³ for example, produced a negative-shift of the voltage-dependent activation, modestly accelerating the activation time course and slowing the deactivation time course. Such a unique functional change induced by the Val141Met variant may have led to the atypical phenotype, such as mixed AF/bradycardia (atrial standstill).

In terms of the inheritance pattern of the p.Val141Met variant, cascade family analyses revealed that 6 (38%) probands had de novo variants, and 3 were inherited from the paternal side (Table). However, heritability in the other 7 (44%) probands remains unknown. Of note, 2 adult family members (both men) showed phenotypes distinct from previously reported p.Val141Met-positive patients, namely a relatively longer QTc and the presence of VA. One (Father 17 of patient 1) experienced an episode of VF, which required an electrical DC shock to resuscitate, and the other (Father 18 of patient 2) presented ventricular couplets on the Holter ECG recording (Figure 2D). Another adult family member (Father 19), a 37-year-old father of a 10-year-old proband (Proband 9), presented a QTc of 375 ms.¹¹ It was not stated whether Father 19 had VA events and/or LV remodeling. Thus, all 3 Val141Met family members tended to have more prolonged QT intervals. Long-lasting bradycardia associated with Val141Met-related SQTS may predispose cardiac functions to electrical remodeling, which may result in QT prolongation.

In a rabbit model of complete atrioventricular block,²⁵ electrical remodeling progressed the development of structural remodeling and heart failure. Both types of remodeling were prevented by ventricular pacing at a near-physiological rate. Bradycardia produced by atrioventricular block operation downregulated delayed rectifier potassium currents, including I_Ks.²⁵ This may partially explain why QT intervals were within the normal range in adult Val141Met family members.

Early initiation of pacing at a near-physiological rate may prevent the electrophysiological remodeling of both the atrium and ventricle.²⁵ Indeed, our Proband 3 presented rapid remodeling at the age of 4 years, and the introduction of AAI pacing at rate of 80 beats/min induced reverse remodeling of both the atrium and ventricle (Figure 2A). One of our adult cases (Father 17) underwent PMI at the age of 20 years, but his pacing rate was set at 50 beats/min (VVI mode). LV remodeling was not prevented, which may have caused transmural dispersion of inhomogeneous repolarization. Father 17 experienced a VF episode at the age of 42 years. Another adult case (Father 18) refused PMI and presented a remarkably enlarged LV with a QTc of 371 ms and ventricular couplets (Figure 2C,D).

A dual-chamber pacemaker is preferable because it may fail to pace the atrium due to potential atrial standstill or slow AF. PMI is recommended as early as possible, with subsequent and careful echocardiographic evaluation of LV function.

Another difference was the association of an ER pattern,²² which has been shown to be significantly more prevalent in SQTS patients who experience life-threatening arrhythmias than in those who do not.^26,27 However, among the Val141Met-positive patients, there was only 1 proband with an ER pattern.¹⁵ We previously demonstrated that an ER pattern was observed in 6.1% of 327 hospital-based patients with a short QT interval (mean QTc 359.8 ms).²⁷ Extremely short QT intervals may result in transmural dispersion of repolarization and ER patterns, and the rarity of the ER pattern in Val141Met-positive individuals may indicate that the arrhythmogenicity is not severe, thus suggesting that VAs are rare in the probands.

Conclusions

Despite the small number of patients with SQTS, patients with the KCNQ1 Val141Met variant are relatively frequent and characterized by distinct phenotypes.

Acknowledgments

The authors thank Arisa Ikeda, Kazu Toyooka, and Madoka Tanimoto for their contributions to genetic testing.

Disclosures

The authors have no conflicts of interest to declare.

IRB Information

This study was approved by the Institutional Review Board of Shiga University of Medical Science (Approval no. 2011-128).

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