Discussion

The prevalence of Wolff–Parkinson–White varies from 3 to 11% in patients with left ventricular non-compaction,^{Reference Howard, Valdes and Hope3,Reference Tian, Yang and Zhou9,Reference Paszkowska, Mirecka-Rola and Piekutowska-Abramczuk10,Reference Sevinc Sengul, Ergul and Ayyildiz11} which is much higher than the estimated 0.1–0.3% prevalence reported in the general population.^{Reference Cohen, Triedman and Cannon12} It is hypothesised that primitive AV connections can persist in patients with left ventricular non-compaction due to an arrest in cardiac development, resulting in direct continuity between the atrial and ventricular myocardium across the fibrous annulus.^{Reference Ichida13} More importantly, in a large cohort of patients with left ventricular non-compaction, 84% of patients with Wolff–Parkinson–White pattern were reported to have cardiac dysfunction compared to 52% of those without Wolff–Parkinson–White pattern suggesting that ventricular pre-excitation could be associated with a risk of cardiac decompensation in patients with left ventricular non-compaction.^{Reference Howard, Valdes and Hope3}

The familial form constitutes approximately 20–40% of all patients with left ventricular non-compaction.^{Reference Ichida14} The first genetic mutation reported in children with left ventricular non-compaction involved the TAFAZZIN gene in patients with Barth syndrome.^{Reference Bleyl, Mumford and Thompson15} However, accumulating genetic data indicates that left ventricular non-compaction is genetically heterogeneous^{Reference Finsterer and Stöllberger16} with mutations in MYH7, TTN, and MYBPC3 being the most common.^{Reference Towbin, Lorts and Jefferies17} Wolff–Parkinson–White syndrome is mostly sporadic with rare reports of genetic associations.^{Reference Gollob, Green, Tang and Roberts6,Reference Coban-Akdemir, Charng and Azamian8} The gain-of-function mutation in PRKAG2, which encodes the gamma-2 regulatory subunit of adenosine monophosphate activated protein kinase, is most commonly implicated in familial Wolff–Parkinson–White syndrome. Hypertrophic cardiomyopathy is often an associated finding in these patients.^{Reference Wolf, Arad and Ahmad18} In addition, variants in genes associated with hypertrophic cardiomyopathy such as MYH6 (c.5653G > A; pGlu1885Lys) and MYH7 have also been associated with Wolff–Parkinson–White syndrome.^{Reference Bowles, Jou and Arrington19,Reference Bobkowski, Sobieszczańska and Turska-Kmieć20}

PRDM16 (positive regulatory domain 16) functions as a compact myocardium-enriched transcription factor and is involved in the activation of genes required for compact myocardium growth and in the repression of genes associated with trabeculae formation. In PRDM16 knockout mice, the development of left ventricular non-compaction likely results from a shift in the transcriptional profile of compact cardiomyocytes.^{Reference Wu, Liang and Zhang21} Consistent with data from PRDM16 knockout mice, PRDM16 mutations have been associated with non-syndromic forms of left ventricular non-compaction in humans.^{Reference Arndt, Schafer and Drenckhahn22} In particular, truncating variants in PRDM16 have been associated with severe left ventricular non-compaction.^{Reference Mazzarotto, Hawley and Beltrami23} The frequency of PRDM16 variants in patients with left ventricular non-compaction has been estimated at 0.5 to 4%.^{Reference Dong, Fan and Tian24,Reference Peña-Peña, Trujillo-Quintero, García-Medina, Cantero-Pérez, De Uña-Iglesias and Monserrat25}

Besides association with left ventricular non-compaction, patients with PRDM16 mutation have been noted to have Wolff–Parkinson–White pattern and supraventricular tachycardia.^{Reference Coban-Akdemir, Charng and Azamian8} The first reported patient was Caucasian who carried a de novo missense mutation [c.2666C > T, p. (Pro889Leu)], which is identical to the mutation carried by our patient. The second reported patient was Hispanic and had an inherited missense mutation [c.2855C > T, p. (Thr952Met)]. He also had atrial septal defect, ventricular septal defect, and hypothyroidism. They both, however, did not have any evidence of cardiomyopathy. There are two other submissions in ClinVar of PRDM16 mutations in patients with Wolff–Parkinson–White syndrome including [c.1642C > A (p.Pro548Thr)] and [c.706G > A (p.Asp236Asn)]. The second patient also had left ventricular non-compaction. Thus, there is accumulating evidence that genetic mutations in PRDM16 can be associated with both Wolff–Parkinson–White syndrome and left ventricular non-compaction. This, however, is the first detailed report where a genetic mutation in PRDM16 resulted in a combined phenotype of both Wolff–Parkinson–White syndrome and left ventricular non-compaction.

Less than 100 patients with Wolff–Parkinson–White and left ventricular non-compaction have been reported till date. Characteristics of these patients with both Wolff–Parkinson–White syndrome and left ventricular non-compaction are summarised in Table 1. It is noteworthy that despite left ventricular non-compaction being left-sided disease, the accessory pathways in patients with left ventricular non-compaction can either be left or right sided. Brescia et al and Paszkowska et al each described a patient each with Wolff–Parkinson–White pattern within their left ventricular non-compaction cohorts, but no accessory pathway was identified on the electrophysiology study suggesting that the patients had pseudo pre-excitation.^{Reference Paszkowska, Mirecka-Rola and Piekutowska-Abramczuk10,Reference Brescia, Rossano and Pignatelli46} Howard et al reported that 12 out of their cohort of 38 patients with Wolff–Parkinson–White syndrome and left ventricular non-compaction underwent an ablation procedure with a reported acute success rate of 83%. Four patients with cardiac dysfunction were successfully ablated, with 3 showing improvement in cardiac function.^{Reference Howard, Valdes and Hope3} The authors concluded that the presence of an accessory pathway in left ventricular non-compaction contributed to left ventricular dyssynchrony and eventually systolic dysfunction, which could increase the risk of arrhythmias and sudden cardiac death. They emphasised that ablation could improve left ventricular ejection fraction in these patients, implicating Wolff–Parkinson–White pattern as a bad prognostic indicator in patients with left ventricular non-compaction.^{Reference Howard, Valdes and Hope3}

Table 1. Characteristics of patients with WPW and LVNC

WPW = Wolff–Parkinson–White; LVNC = Left ventricular non-compaction; M = Male; F = Female; A = Asian, AA = African; C = Caucasian; H = Hispanic; SVT = Supraventricular tachycardia; VE = Ventricular ectopy; NSVT = Non-sustained ventricular tachycardia; VF = Ventricular fibrillation; AF = Atrial fibrillation; EF = Ejection fraction; N = Normal; PHTN = Pulmonary hypertension; CXR = Chest X-ray; VUR = Vesicoureteral reflux; AS = Anteroseptal; APERP = Accessory pathway effective refractory period; ORT = Orthodromic reentrant tachycardia; RF = Radiofrequency; LVH = Left ventricular hypertrophy; HCM = Hypertrophic cardiomyopathy; BAV = Bicuspid aortic valve; LV = Left ventricle; ICD = Implantable cardioverter defibrillator; LHON = Leber’s hereditary optic neuropathy.

Electrophysiologic characteristics of PRDM16-associated accessory pathways have not been well characterised. Our patient had a broad and likely epicardial pathway that could not be completely ablated despite two attempted ablations by experienced operators suggesting that accessory pathway ablation in patients with PRDM16 mutation associated with Wolff–Parkinson–White syndrome, and left ventricular non-compaction may be challenging due to complex pathway characteristics. These findings inform the need for systematic evaluation of association between PRDM16 mutation, left ventricular non-compaction, and Wolff–Parkinson–White pattern.