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The first case of a Caucasian child with calmodulinopathy related to CALM2 N98S mutation

Published online by Cambridge University Press:  10 February 2026

Giacomo BurattiOpen the ORCID record for Giacomo Buratti[Opens in a new window],
Dhivya Elango,
Ahmed Shakir Mohammed and
Dominic Hares
Giacomo Buratti*
Affiliation:
Paediatrics, Diana Princess of Wales Hospital, UK
Dhivya Elango
Affiliation:
Paediatrics, Diana Princess of Wales Hospital, UK
Ahmed Shakir Mohammed
Affiliation:
Paediatrics, Diana Princess of Wales Hospital, UK
Dominic Hares
Affiliation:
Department of Congenital Cardiology, Leeds General Infirmary, UK
*
Corresponding author: Giacomo Buratti; Email: giacomo.buratti2@gmail.com
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Abstract

We report the first Caucasian patient with CALM2 p. Asn98Ser, a 2-year-old girl who survived out-of-hospital cardiac arrest after emotional stress. The initial rhythm was broad-complex tachycardia degenerating into ventricular fibrillation. Normal QT intervals and absent structural disease suggest a CPVT-like presentation, highlighting diagnostic and management challenges in calmodulinopathy.

Keywords

CALM2 N98Scalmodulinopathysudden cardiac arrestgenetic mutationpaediatric arrhythmia

Information

Type
Case Report
Information
Cardiology in the Young , Volume 36 , Issue 2 , February 2026, pp. 400 - 403
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Copyright
© The Author(s), 2026. Published by Cambridge University Press

Introduction

Mutations in the calmodulin genes (CALM1, CALM2, and CALM3) are recognised causes of severe, early-onset cardiac arrhythmia syndromes. Reported phenotypes include long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, and sudden cardiac death.Reference Crotti, Spazzolini and Nyegaard1

The CALM2 N98S mutation is an extremely rare variant, with only a few cases described to date. The genotype–phenotype relationship remains complex, with long QT syndrome, Reference Jiménez-Jáimez, Palomino Doza and Ortega2,Reference Fukuyama, Horie and Kato3,Reference Makita, Yagihara and Crotti4 idiopathic ventricular fibrillation,Reference Crotti, Spazzolini and Nyegaard1 and suspected isolated catecholaminergic polymorphic ventricular tachycardiaReference Jiménez-Jáimez, Palomino Doza and Ortega2 reported in the literature.

To date, this mutation has only been reported in Hispanic, Japanese, and Moroccan patients in the literature, Reference Jiménez-Jáimez, Palomino Doza and Ortega2,Reference Makita, Yagihara and Crotti4 and never in a British Caucasian child. Additionally, no cases have been documented in children younger than 4 years, making the age of presentation in our patient another noteworthy feature.

Here, we describe the case of a 2-year-old child with CALM2 N98S who survived a cardiac arrest. This case highlights the challenges in defining the underlying arrhythmogenic mechanism in calmodulinopathy and raises the possibility of a catecholaminergic polymorphic ventricular tachycardia-like presentation in this genotype.

Case presentation

The patient is a 2-year-old previously well British Caucasian girl with no significant past medical history, apart from a recent episode of tonsillitis. She was born at term, developmentally appropriate, with no known cardiac symptoms prior to the event. There is no family history of sudden cardiac death, syncope, or arrhythmia. One evening, while at home, the child became emotionally distressed before bedtime. As she approached a safety gate separating the bedroom from the corridor, she suddenly collapsed. Her parents witnessed the event, found her unresponsive, and immediately initiated cardiopulmonary resuscitation. Emergency services arrived shortly after and confirmed a cardiac arrest. The initial recorded rhythm was a regular broad-complex tachycardia (Figure 1A), which rapidly degenerated into ventricular fibrillation (Figure 1B). A single defibrillation shock successfully restored circulation. On admission, blood tests including full biochemistry, electrolytes, and thyroid function were within normal limits. A baseline ECG obtained one hour post-arrest demonstrated sinus rhythm at a heart rate of 99 bpm with a QT interval of 420 ms, within normal limits, and no repolarization abnormalities (Figure 1C). The 24-hour Holter monitoring showed a normal sinus rhythm with an average heart rate of 92 bpm (range 69–169 bpm). An adenosine challenge led to transient complete heart block, ruling out an accessory pathway. A CT scan was normal, and an electroencephalogram was not indicated based on clinical findings. She was started on oral propranolol and discharged with an implantable loop recorder, which to date has shown a normal sinus rhythm without arrhythmic abnormalities, suggesting good control on therapy. Subsequent genetic testing identified a heterozygous pathogenic autosomal dominant CALM2 variant, c.293A > G p.(Asn98Ser), previously associated with long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, overlapping long QT syndrome / catecholaminergic polymorphic ventricular tachycardia phenotypes, and sudden unexplained death.Reference Crotti, Spazzolini and Nyegaard1,Reference Nyegaard and Overgaard5 Parental genetic testing was negative, confirming the variant to be de novo.

A recent detailed history revealed that a fire alarm, triggered by shower steam above the child’s bed had activated shortly before the arrest. This acute stressor may potentially have induced an adrenergic surge, triggering the ventricular tachycardia.

Figure 1A.

Regular broad complex tachycardia.

Figure 1B.

Into ventricular fibrillation.

Figure 1C.

No repolarisation abnormalities.

Discussion

This case highlights the significant clinical challenges in managing a very young child with a calmodulinopathy. To our knowledge, this is the youngest patient described with the CALM2 N98S variant, and importantly, the first Caucasian case reported in the literature.Reference Tsai, Chen and Rubart6 This makes the case particularly valuable, as it expands the recognised spectrum of both the genotype and phenotype associated with this mutation.

A major limitation in this age group is the difficulty of establishing the precise arrhythmic substrate. The child presented with a cardiac arrest under emotional stress, raising suspicion for either long QT syndrome or catecholaminergic polymorphic ventricular tachycardia. Unlike previously published CALM2 N98S cases, Reference Jiménez-Jáimez, Palomino Doza and Ortega2,Reference Fukuyama, Horie and Kato3,Reference Makita, Yagihara and Crotti4 she has never demonstrated QT prolongation on resting ECG or Holter monitoring, leaving the possibility of an isolated catecholaminergic polymorphic ventricular tachycardia-like or idiopathic ventricular fibrillation phenotype. However, the exact rhythm at the time of her collapse remains uncertain. Available pre-hospital recordings show a regular broad-complex tachycardia that subsequently degenerated into ventricular fibrillation. This pattern contrasts with classical catecholaminergic polymorphic ventricular tachycardia, where bidirectional and polymorphic ventricular ectopics are typical, and with long QT syndrome, which more often presents with polymorphic ventricular tachycardia. The stage of treatment during which these recordings were obtained is unclear, further limiting their diagnostic value.

Overall, the p. Asn98Ser mutation has been associated with the full spectrum of calmodulinopathy phenotypes, including long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, and overlapping long QT syndrome/catecholaminergic polymorphic ventricular tachycardia presentations. Reference Crotti, Spazzolini and Nyegaard1,Reference Nyegaard, Overgaard and Søndergaard7,Reference Nyegaard and Overgaard5 However, when considering CALM2 N98S specifically, the literature predominantly reports long QT syndrome Reference Jiménez-Jáimez, Palomino Doza and Ortega2,Reference Fukuyama, Horie and Kato3,Reference Makita, Yagihara and Crotti4 and idiopathic ventricular fibrillation,Reference Crotti, Spazzolini and Nyegaard1 with only a single case raising suspicion for catecholaminergic polymorphic ventricular tachycardia.Reference Jiménez-Jáimez, Palomino Doza and Ortega2 Interestingly, the stress-related trigger of our patient’s cardiac arrest supports catecholaminergic polymorphic ventricular tachycardia as a possible underlying mechanism, and this interpretation is further reinforced by reports of isolated catecholaminergic polymorphic ventricular tachycardia in the paralogous CALM1 N98S mutation, supporting the plausibility of a similar phenotype occurring in CALM2 N98S. Reference Fukuyama, Horie and Kato3,Reference Nyegaard, Overgaard and Søndergaard7

Further evaluation for an underlying arrhythmia is presently limited by diagnostic challenges. Formal exercise testing is not currently feasible at her age, and an epinephrine challenge is considered inappropriate due to the need for beta-blocker withdrawal and anaesthesia, both of which carry avoidable risks. Once she reaches an appropriate developmental stage, exercise provocation will form part of her evaluation.

Management decisions in such young patients are inherently complex. Implantation of an implantable cardioverter defibrillator carries significant procedural and long-term risks and has therefore not been pursued at present. Instead, she is closely monitored with a loop recorder for continuous surveillance of ventricular arrhythmias, and beta-blocker therapy (propranolol) has been initiated to reduce arrhythmic risk. At this stage, she has not been restricted in her daily activities or exercise; however, this may need to be reconsidered as she grows older and her clinical course evolves. Her treatment pathway will continue to be adapted according to her clinical course and the evolving understanding of her genetic background.

Conclusion

In summary, this case represents both the youngest patient and the first British Caucasian individual reported with the CALM2 N98S variant. While the exact arrhythmic phenotype remains unconfirmed, the documentation of a regular broad-complex tachycardia progressing to ventricular fibrillation adds a unique feature that does not align with the classical patterns described in calmodulinopathies and may suggest that calmodulinopathies can also give rise to less typical arrhythmic mechanisms.

References

Crotti, L, Spazzolini, C, Nyegaard, M, et al. Clinical presentation of calmodulin mutations: the international calmodulinopathy registry. Eur Heart J 2023; 44: 3357–3370. doi: 10.1093/eurheartj/ehad418.CrossRefGoogle ScholarPubMed
Jiménez-Jáimez, J, Palomino Doza, J, Ortega, A, et al. Calmodulin 2 Mutation N98S is associated with unexplained cardiac arrest in infants due to low clinical penetrance electrical disorders. PLoS ONE 2016; 11(4): e0153851. doi: 10.1371/journal.pone.0153851.CrossRefGoogle ScholarPubMed
Fukuyama, M, Horie, M, Kato, K, 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. doi: 10.1253/circj.CJ-23-0195.CrossRefGoogle ScholarPubMed
Makita, N, Yagihara, N, Crotti, L, et al. Novel calmodulin mutations associated with congenital arrhythmia susceptibility. Circ Cardiovasc Genet 2014; 7: 466–474. doi: 10.1161/CIRCGENETICS.113.000459.CrossRefGoogle ScholarPubMed
Nyegaard, M, Overgaard, MT. The international calmodulinopathy registry: recording the diverse phenotypic spectrum of un-CALM hearts. Eur Heart J 2019; 40: 2976–2978. doi: 10.1093/eurheartj/ehz463.CrossRefGoogle ScholarPubMed
Tsai, WC, Chen, PS, Rubart, M. Calmodulinopathy in inherited arrhythmia syndromes. Tzu Chi Med J 2021; 33: 339–344. DOI: 10.4103/tcmj.tcmj_182_20.CrossRefGoogle ScholarPubMed
Nyegaard, M, Overgaard, MT, Søndergaard, MT, et al. Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. Am J Hum Genet 2012; 91: 703–712. doi: 10.1016/j.ajhg.2012.08.015.CrossRefGoogle ScholarPubMed
Figure 0

Figure 1A.Regular broad complex tachycardia.

Figure 1

Figure 1B.Into ventricular fibrillation.

Figure 2

Figure 1C.No repolarisation abnormalities.