954 DILATED CARDIOMYOPATHY AND ATRIOVENTRICULAR BLOCK RELATED TO THE MUTATION IN THE LMNE GENE: DESCRIPTION OF A FAMILY


 The proband was patient A2, suffering by severe left ventricular dysfunction (EF 20%) and II degree Mobitz type 1 atrioventricular block, requiring dual chamber ICD implantation, and retinitis pigmentosa. He had three brothers A1, A4, A5 suffering also by dilated cardiomyopathy and ICD/CRTD recipients. His sister A3, his daughter B1 and the firstborn brother A1 were also affected by retinitis pigmentosa. Genetic analysis was performed in A2 by NGS of a panel of genes related to heart disease and retinitis pigmentosa. It documented the presence of a missense pathogenetic variant (class 4) of the LMNA gene in heterozygosis (c.949G>A). This variant has been described in several scientific papers as associated with cardiac impairment in patients suffering from atrioventricular block and dilated cardiomyopathy.
 Laminin A/C is a fundamental protein of the nuclear envelope of the cell. Germline mutations in the LMNA gene, present on chromosome 22 (1q22), encoding the A/C lamina, have been causally linked to four different diseases with 42 reported mutations: Dilated cardiomyopathy (DCM) with disease of the conduction system; Limb girdle muscular dystrophy (LGMD); Autosomal dominant variant of Emery-Dreifuss muscular dystrophy (EDMD); Autosomal dominant partial lipodystrophy.
 LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and/or reduced systolic function frequently preceded or accompanied by significant conduction system disease. Family studies suggest that conduction system disease commonly precedes the development of DCM by a few years to a decade or more. Conduction system involvement usually starts with disease of the sinus node and/or atrioventricular node that can manifest as sinus bradycardia, sinus node arrest with junctional rhythms, or heart block (commonly first-degree heart block that progresses to second- and third-degree block). The following are also common: symptomatic bradyarrhythmias requiring cardiac pacemakers, supraventricular arrhythmias including atrial flutter, atrial fibrillation, supraventricular tachycardia, and the sick sinus syndrome (i.e., tachycardia-bradycardia syndrome), ventricular arrhythmias including frequent premature ventricular contractions and ventricular tachycardia
 Sudden cardiac death may occur with progressive disease. Although more malignant, life-threatening arrhythmias may occur with longstanding and usually previously symptomatic DCM, sudden cardiac death can also be the presenting manifestation of LMNA-related DCM, with minimal or no left ventricular dysfunction. In the cardiological setting, the AVB associated with DCM is a reliable marker for LMNA gene molecular screening.
 Regarding retinitis pigmentosa, the variant in heterozygosis c538C>G was found in the RHO gene in the proband, classifiable as pathogenetic. This gene encodes a protein necessary for the function of retinal photoreceptors and pathogenic mutations have been found in 30-40% of hereditary forms of retinitis pigmentosa. In conclusion, we believe that the tests carried out confirmed the hypothesis of a hereditary form of cardiomyopathy and retinitis pigmentosa, which seem to segregate independently in the family. Both mutations can be transmitted in 50% of cases, regardless of sex. For this reason we recommended to extend genetic analysis to all the first-degree relatives (siblings and children).