**1. Introduction**

Left ventricular (LV) non-compaction (LVNC) is characterized by prominent myocardial trabeculations in a thick, non-compacted layer adjacent to a thin compacted layer. LVNC is the most recently categorized cardiomyopathy, and probably the most controversial one, without available clinical guidelines. The American Heart Association classified LVNC as a distinct primary cardiomyopathy with a genetic aetiology [1]. However, it is considered an unclassified cardiomyopathy according to the European Society of Cardiology (ESC) [2] or the World Health Organization [3].

LVNC had historically been categorized as congenital condition, secondary to a failure of the compaction process during embryonic cardiac development [4–8]. However, recent data proposed additional etiopathogenic mechanisms, including acquired forms of LVNC secondary to overloading conditions [4,9–11]. Therefore, there has been a classical division between isolated LVNC [12,13] and LVNC associated with significant congenital heart defects (CHD) [14–16]. In fact, according to Jenni et al. [17], the absence of coexisting cardiac anomalies was mandatory to diagnose LVNC [17]. Nevertheless, it was also suggested that both could actually be co-occurring [18].

Agreement between the three most commonly cited transthoracic echocardiogram (TTE) diagnostic criteria, described by Chin et al. [19], Jenni et al. [17], and Stöllberger et al. [20] is known to be poor [21]. Moreover, there is a raising concern about sensitivity and specificity of TTE criteria, and whether, in fact, LVNC may be overdiagnosed [22,23]. In this scenario, cardiac MRI (CMRI) offers a high spatial resolution, and is becoming more and more used in LVNC evaluation, displacing TTE [24]. However, CMRI also raises concerns about overdiagnosis [25–27]. According to diagnostic criteria by Petersen et al., LVNC can be diagnosed if the ratio of non-compacted to compacted myocardium is >2.3 at end-diastole. [28]. Thus, LVNC is commonly associated with other overlapping cardiomyopathies phenotypes. In fact, intrafamilial phenotypic variability, including LVNC, hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), may suggest that these cardiomyopathies could be part of a broader cardiomyopathy spectrum [29–31]. In this context, genetics play an important role. From 17% to up to a 50% of patients with LVNC have a relative with another primary cardiomyopathy [32–34]. However, due to all the controversy around LVNC and the limitations in assigning its clinical diagnosis based on imaging criteria, strong genetic causal relationships have been harder to establish compared to those in HCM [31,35]. Nowadays, achieving a reliable genetic variants interpretation remains a real challenge and it is likely that some previously interpreted as pathogenic variants [36] in LVNC would need to be reclassified, based on current evidence and new criteria [18,37–39].

Moreover, the yield of genetic testing in LVNC varies from 9% to 41%, depending on patient selection and the number of genes screened [18,29,40,41]. Due to small cohort sizes, little is known about LVNC genotype-phenotype correlations. What is more, contrary to HCM guidelines [42], some authors did not support general genetic screening in all patients with LVNC [35].

On the other hand, although a gold-standard diagnostic technique for LVNC is missing [43], anatomopathological examination (APE) could be considered as such. In fact, only three APE cases were enough to support Chin TTE diagnostic criteria [19] and seven for Jenni´s criteria [17]. However, again contrary to HCM, LVNC histopathological characteristics are poorly known. Burke et al. [4,44] established the anatomopathological LVNC criteria based on 14 cases, and only a few more case-series have been published ever since, mostly focusing on compaction/non-compaction ratio and not going deeper into histopathological features.

The aim of the current investigation was to provide a comprehensive clinical view of LVNC based on genetic and anatomopathological information.
