505 A NEW NEXN GENE VARIANT LEADING TO FOETAL ONSET MIXED PHENOTYPE CARDIOMYOPATHY WITH UNKNOWN PROGNOSIS


 
 
 Idiopathic dilated cardiomyopathy (DCM) is a common cardiac disease phenotype known to result from many different triggers. Among possible etiologies, genetically determined forms have been more and more acknowledged: recent investigations made possible the identification of risk alleles and disease-causing variants encoding for structural components of the cardiac muscle. The NEXN gene encodes the protein nexilin, an essential protein for Z-disk stability. Homozygous NEXN variants are rare and associated with poor prognosis: fetal and perinatal death or severe DCM in infants.
 
 
 
 we present the case of a male infant, born at term, with prenatal diagnosis of cardiomyopathy. Postnatally, DCM with severely reduced systolic function was confirmed (LVEDd 19 mm, +2 z-scores; LVEF 25%), along with biventricular hypertrophy. The infant required medical treatment for heart failure; atrial tachyarrhythmia responsive to amiodarone was associated. Family history oriented for a genetic and familiar form of DCM (consanguinity and sudden death at a young age on both sides). Whole Exome Sequencing revealed in the proband the homozygous variant c.1156dup (p.Met386fs) in the NEXN gene (NM_144573.4), and both parents were confirmed to be carrier of the same variant at the heterozygous state. This NEXN variant has not been described previously. Complete cardiac evaluation was performed in first-degree relatives, including echocardiography and Cardiac Magnetic Resonance; the mother shows early signs of CMP, such as LBBB with mildly reduced LVEF (53%), while the only remarkable finding for the father is mild left ventricular hypertrophy.
 
 
 
 genetic DCM can have different clinical courses. It is important to reach the diagnosis: family history is essential in raising suspicion, while infectious causes and inborn error of metabolism must be ruled out. Only a few cases of NEXN-related CMP are described in literature; surprisingly, and unlike what was previously described, we observed in our patient a favorable clinical course during time, suggesting a different severity compared to so far known NEXN variants.
 
 
 
 This case helps to broaden present knowledge about NEXN variants and their clinical expression in humans, supporting the inclusion of the NEXN gene in the investigation of patients with DCM, in order to understand phenotypes, guide therapy, and provide proper genetic advice.
