In the present study, we studied the family in which the proband presented with the LVNC. We performed NGS on the family members and identified a missense heterozygous genetic mutation in PRKAG2 (c.905G༞A [p. R302Q]) which might to be the potentially pathogenic mutation. To our knowledge, this is the first study to describe the association of this mutation with LVNC.
LVNC, first described by Grant in 192623, is a heterogeneous myocardial disease characterized by prominent trabeculae, intratrabecular recesses, and two distinct layers of left ventricular myocardium: compaction and non-compaction24, 25. There is continuity between the left ventricular cavity and the deep intratrabecular recesses2. Assessment of imaging and pathologic changes shows that the disease is characterized by spongy left ventricular myocardium with abnormal trabeculae, usually most pronounced at the left ventricular apex26. The development of LVNC, is associated with cessation of end-stage myocardial compaction and morphogenesis2, 27–29. The American Heart Association (AHA) classifies LVNC as a separate genetic cardiomyopathy, but the European Society of Cardiology (ESC) defines it as an unclassified entity30. Currently, the incidence of LVNC is increasing, which may be due to greater awareness and more sensitive diagnostic tools such as modern ultrasound techniques and cardiac magnetic resonance (CMR) 31–34. CMR has improved cardiac imaging, which has allowed for a more detailed understanding of the disease26. More importantly, genetics and genetic analysis play an important role in the prediction and management of LVNC 35.
The PRKAG2 mutation have been already described previously in HCM and WPW syndrome4. However, our study found that the PRKAG2 mutation [c.905G༞A (p.R302Q)] was associated with LVNC. Previous studies have described a heterogeneous phenotypic presentation of LVNC26, 36, such as hypertrophic LVNC, dilated LVNC, restrictive LVNC, arrhythmogenic LVNC and benign LVNC with preserved systolic and diastolic function37. Of those, the hypertrophic subtype was characterized by left ventricular hypertrophy, usually with asymmetric septal hypertrophy, usually accompanied by diastolic or systolic dysfunction. In families expressing both HCM and LVNC phenotypes, genotypes may overlap and both diseases can occur simultaneously 6. Previous trials have collected a total of 242 children diagnosed with isolated LVNC, and 66 patients (27%) presented with hypertrophic38.
The proband and her young sister presented with LVNC combined with short PR and sinus bradycardia. Previous studies confirmed that the association of WPW syndrome with LVNC was widely recognized and has been described in 17% of pediatric patients with LVNC. Sinus bradycardia is also associated with LVNC24, 39, with a lower incidence than WPW syndrome. Previous studies have confirmed that patients misdiagnosed with HCM were definitively LVNC by autopsy, and eight of nine patients had arrhythmias, in most cases sinus bradycardia, confirming that ventricular muscle dyssynchrony was often associated with conduction defects40–42. It has been proposed that fibrosis might be a possible cause of AV in patients with LVNC43, 44and defective local myocardial angiogenesis may be a potential cause of conduction abnormalities. Patients with progressive sinus bradycardia are associated with an abnormal vascular supply near the sinus node. Our study indicated that except for one SCD victim (II-5), the most LVNC survivors were about more than 30 years old. The mechanisms of how this missense mutation interferes with the PRKAG2 function and then leads to LVNC are not clear yet. Further biochemical and cell biological studies are needed to determine the consequence of this missense mutation.
The proband’s sister and son (II-4 and III-1) manifesting with LVNC carried the mutation. The proband’s brother (II-5) died of SCD, thus we concluded that the proband’s brother may have suffered from LVNC and carried the same mutation. Our predictive genetic testing identified an asymptomatic individual (III-3) who was 6 years old and carried the disease-causing mutation, but unfortunately, he was so young that he could not cooperate to complete the CMR. His associated clinical symptoms have not yet expressed. Therefore, on the basis of our genetic diagnosis of LVNC in this family, we have been able to identify this young mutation carrier without phenotypic expression, which will facilitate better disease management and follow-up by clinicians before the appearance of symptoms. Bioinformatic prediction can provide us with some useful information about the pathogenicity of the PRKAG2 mutation [c.905G༞A (p.R302Q)]. However, our experiments do not reflect the true pathology of this mutant in cardiac myocytes. Due to the inaccessibility of human heart tissues, we were unable to obtain sufficient numbers of patient heart tissues. The creation of mutant mice using CRISPR/Cas9 gene editing methods or the use of patient-specific induced pluripotent stem cell (iPSC) derived cardiomyocytes are state-of-the-art methods to directly and reproducibly study the pathogenicity of human mutants. In the future, we will further investigate the pathogenic role of the mutation using cardiomyocytes derived from patient-specific iPSCs.