Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

General Comment

The authors present a rare and clinically interesting case of a 14-year-old girl with persistent atrial fibrillation, markedly shortened QT interval, and a heterozygous KCNJ2 variant, interpreted as short QT syndrome type 3. The case is potentially valuable because genetically confirmed pediatric SQTS cases are uncommon, and atrial fibrillation may be an early or predominant manifestation.

Nevertheless, the manuscript requires major clarification and strengthening. The authors should provide more rigorous evidence for the diagnosis, variant pathogenicity, QT measurement, treatment rationale, and long-term management plan.

Major Comments

1. Pathogenicity and novelty of the KCNJ2 variant need stronger evidence.
The authors describe NM_000891.2:c.896A>C, p.Glu299Ala as a “pathogenic” and “novel” KCNJ2 mutation. However, the manuscript does not provide sufficient supporting evidence. Please clarify whether this variant is absent from population databases such as gnomAD and whether it has been reported in ClinVar, HGMD, LOVD, or other variant databases. The authors should also provide ACMG/AMP classification criteria, in silico prediction results, conservation data, and whether Sanger confirmation was performed. If no functional validation or segregation analysis is available, the wording should be softened to “likely pathogenic” or “variant associated with suspected SQTS type 3,” depending on the available evidence.

2. Genetic testing methodology is insufficiently described.
Please provide details of the genetic test, including the platform used, gene panel composition, sequencing depth/coverage, variant calling method, confirmation method, and whether copy-number analysis was included. The manuscript states that parental ECGs were normal, but this does not establish whether the variant was de novo. Were both parents genetically tested for the KCNJ2 variant? This is important for interpretation, counseling, and cascade screening.

3. QT/QTc measurement during atrial fibrillation and rapid ventricular response requires clarification.
The diagnosis relies heavily on a QT of 200 ms and QTc of 250 ms measured during atrial fibrillation with rapid ventricular response. QT measurement in AF is challenging because of beat-to-beat RR variability, and Bazett correction can be problematic at high heart rates. Please describe exactly how QT was measured: number of beats averaged, leads used, RR interval selection, correction formula, and whether Fridericia or Framingham correction was also calculated. Serial ECG examples at lower ventricular rates would strengthen the diagnosis. A high-resolution ECG figure with QT measurement annotation is strongly recommended.

4. Diagnostic criteria for SQTS should be explicitly applied.
The authors should apply established diagnostic criteria, such as the Gollob score or current consensus criteria, and show how this patient fulfills the diagnosis of SQTS. A small table summarizing QTc, clinical history, family history, genetic findings, and exclusion of secondary causes would improve clarity. The authors should also more clearly exclude secondary causes of short QT, including electrolyte abnormalities, hypercalcemia, acid-base disturbance, hyperthermia, drug effects, and other acquired causes.

5. Treatment rationale needs substantial clarification.
The manuscript reports quinidine therapy up to 1.6 g/day, addition of metoprolol, subsequent biventricular systolic dysfunction, discontinuation of quinidine, and initiation of amiodarone. Please provide the patient’s body weight, mg/kg dosing, monitoring strategy, adverse effects, and QT response over time. It is also unclear whether rhythm control, electrical cardioversion, or catheter ablation was considered. The reason for choosing amiodarone in this setting should be justified, especially since the QT interval reportedly remained short.

6. The mechanism of transient biventricular dysfunction is unclear.
The authors state that moderate biventricular dysfunction developed after 14 days of quinidine and metoprolol therapy and was “probably due to inadequate heart rate control with this drug.” This explanation is not clear. Was this tachycardia-induced cardiomyopathy, drug-related negative inotropy, or another mechanism? Please provide serial heart rates, echocardiographic parameters, timing of recovery, and NT-proBNP changes. The causal interpretation should be more cautious unless supported by objective data.

7. Anticoagulation and antiplatelet strategy require reconsideration.
The manuscript states that anticoagulation was replaced with antiplatelet therapy based on a CHA₂DS₂-VASc score of 1 due to female sex. However, CHA₂DS₂-VASc is not well validated in pediatric patients, and adult AF guidance generally does not treat female sex alone as a sufficient indication for anticoagulation. The rationale for antiplatelet therapy should be clearly explained and supported by appropriate pediatric or congenital/electrophysiology references. If this decision was individualized, please state so.

8. ICD decision-making should be expanded.
Given the malignant arrhythmic potential of SQTS, the discussion of ICD therapy is important. Please clarify whether ICD implantation was considered in this patient, and if not, why not. The authors should describe risk stratification in this specific patient, including absence or presence of syncope, ventricular arrhythmias, family history of sudden death, Holter findings, and shared decision-making with the family.

9. Relationship between neurological comorbidities and KCNJ2 variant should be presented cautiously.
The patient has a complex neurological history, but the manuscript should avoid implying a causal relationship unless there is supporting evidence. Please clarify whether the neurological phenotype is considered related to KCNJ2, congenital infection/prematurity, or an independent condition. The discussion should clearly separate confirmed findings from speculative associations.

10. Follow-up duration and clinical outcome should be described in more detail.
Please specify the duration of follow-up, current rhythm status, ventricular rate, QT/QTc values, ventricular function, medication regimen, symptoms, hospitalizations, and any ventricular arrhythmias. A timeline figure or table would greatly improve the case presentation.

Minor Comments
The title may be revised to avoid overstatement. For example:
“A Novel KCNJ2 p.Glu299Ala Variant Associated with Short QT Phenotype and Persistent Atrial Fibrillation in a Child.”
If pathogenicity is well established after revision, the stronger wording may be retained.
Please use “variant” rather than “mutation” throughout, unless specifically referring to previously established pathogenic mutations.
There are formatting issues in the manuscript template, including “Life 2022, 12, x,” “FOR PEER REVIEW,” and typographical errors in author names. These should be corrected.
The ECG figure is low resolution and difficult to interpret. Please provide a clearer ECG image with calibration, lead labels, and QT measurement annotation.
The terms “persistent” and “permanent” atrial fibrillation are used inconsistently. Please define the rhythm status according to standard terminology.
Please ensure consistency in spelling, for example “pediatric” vs. “paediatric” and “behavioral” vs. “behavioural.”
The sentence “In simulations conducted by Deo et al. and later by Whittaker et al. have shown…” is grammatically incorrect and should be revised.
Please add a CARE-compliant timeline table summarizing key clinical events, ECG findings, genetic testing, treatments, echocardiographic changes, and follow-up.
Please include statements on informed consent from the patient’s legal guardian, ethics approval if required, and data availability.

Author Response

Dear Madam/Sir,

We would like to express our sincere gratitude to the reviewer for their thorough evaluation and constructive feedback.

Sincerely,

The authors.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

 

In the index report, the authors explore an interesting case in cardiology research by discussing the case of Short QT Syndrome type 3 due to a novel KCNJ2 mutation in a child with persistent atrial fibrillation. The abstract is well written and adequality captures the salient takeaways from their research. Overall, the paper is well written but grammatical errors are plenty. Besides, there are major potential weaknesses and areas for further exploration, which limit the impact of this report:-

• While the clinical narrative is compelling, the manuscript requires further technical detail to meet the standards of the journal. First, the authors must provide more granular detail regarding the neurological background mentioned in the abstract. Given that KCNJ2 mutations are also implicated in Andersen-Tawil Syndrome, which features periodic paralysis and dysmorphic features, the authors should explicitly state whether these were screened for and ruled out.
• Secondly, the ECG analysis would be strengthened by including a more detailed measurement of the Tpeak-Tend interval, which is often a critical marker of arrhythmogenic risk in SQTS.
• Furthermore, the discussion of the therapeutic approach is somewhat limited. The decision to use amiodarone is noted, but the manuscript would benefit from a more critical appraisal of why specific IKr blockers (like quinidine) were or were not considered, as quinidine is currently the only pharmacological agent shown to effectively prolong the QT interval in SQTS type 1 and potentially type 3.
• I recommend consolidating the literature findings into a more structured table that compares this novel mutation with previously reported KCNJ2 variants, specifically highlighting differences in age of onset, presence of AF, and QTc values. This would allow for a clearer visual comparison of clinical severity.
• Additionally, the Discussion section should be expanded to address the long-term management of persistent AF in a 14-year-old with a short QT. Is catheter ablation a viable option in this genetic context, or is the risk of procedure-induced ventricular arrhythmias too high?
• The authors should also ensure that the high-resolution ECG tracings and genetic sequencing results are clearly labeled and referenced in the text.

Author Response

Dear Madam/Sir,

We would like to express our sincere gratitude to the reviewer for their thorough evaluation and constructive feedback.

Sincerely,

The authors.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have satisfactorily responded to the concerns raised during the prior review.