**2. Methods**

#### *2.1. Study Population*

Adult patients (>21 years old) with LVNC diagnosis were recruited consecutively from a tertiary hospital from Spain, referral for cardiogenetics. Due to the controversy about the diagnostic criteria of LVNC, only patients diagnosed with LVNC, either by Petersen CMRI criteria, or Burke APE criteria, were included. Reports from 824 CMRI (from 2007 to 2015) and 89 transplanted hearts (from 2009 to 2015) were reviewed. At this step, LVNC was considered irrespective of its co-occurrence with other primary cardiomyopathies.

According to these criteria, 43 consecutive patients with LVNC diagnosis, either from CMRI criteria (from 2007 to 2015), or form APE criteria (from 2009 to 2015) were identified. Next-generation sequencing was performed in all patients who met the inclusion criteria (excluding significant CHD) and were still alive at the time this study was performed. Three patients could not be included in the clinical study due to decease without genetic testing available. Two patients with LVNC associated

with significant CHD (that could induce significant hemodynamic changes) were excluded. Therefore, clinical and genetic study was available for the remaining 38 alive patients with LVNC.

Apart from that, histopathological exam was performed in all available LVNC hearts, including those patients who had died without the possibility of a genetic test.
