oa "novel Genetic Variants May Modify The Clinical Outcome Of The Phospholamban L39x Mutation In Cardiomyopathy Patients"

Background Dilated Cardiomyopathy (DCM) is a leading cause for heart failure characterized by an enlarged ventricular cavity causing systolic dysfunction. Gene mutations are estimated to be the cause in approximately 30-50% of cases, while modifier genes are thought to influence the clinical outcome. Objectives Using a global and unbiased approach: Next Generation Sequencing (NGS), for one of the largest reported cardiac gene panels, QCRC aims at discovering novel gene variants implicated in DCM pathogenesis and/or progression. Method Through the QCRC Doha-centered intercontinental DCM patient cohort, we screened 38 DCM cases, confirmed by echocardiography, who did not have a history of alcoholism or coronary angiography findings. Patients were recruited following genetic counseling and informed consent, according to institutionally approved ethics protocols. High quality DNA was extracted from peripheral blood, 170 DCM known and candidate genes (=1.6Mbases) were sequenced using the HiSeq Illumina technology, and extensive bioinformatical analysis was pursued to depict genetic variations. Results We herein report an unusual case of a male DCM patient (LVEDD: 70mm; LVESD: 59mm; LVEF: 25%), diagnosed at age 40years, who developed sustained ventricular tachycardia (VT), was implanted an AICD at age 56years, and died age 60years. By NGS we determined that he was heterozygous for a known pathogenic nonsense mutation (c.116T>G) in the phospholamban (PLN) gene, which leads to a premature stop codon (L39X). The phenotype of L39X mutation carriers in the PLN gene has been shown to vary considerably, ranging from severe DCM, to rare reports of hypertrophic CM or normal cardiac function. However, this is the first occasion of L39X DCM patient presenting with sustained VT. Three additional, novel variants, out of the 163 variants detected in this patient, were of particular interest: i) a frameshift mutation (c.1495_1496insAGAC) in the C-terminus of CACNB2 (the beta subunit of the voltage-dependent calcium channel Ca(v)1.2). Mutations in this gene/protein region have been previously associated with Brugada syndrome with shorter than normal QT or early depolarization syndrome. ii) a non-synonymous SNP (c.9217C>T; p.L3073F) in laminin 2 (LAMA2), predicted to have a deleterious (SIFT) - possibly damaging (Polyphen2) effect. LAMA2 is a major component of striated muscle cytoarchitecture, and has been proposed, in a rare occasion, to relate to DCM with ventricular arrhythmias. iii) a non-synonymous SNP (c.6082A>G; p.T2028A) in the Alstrom Syndrome 1 (ALMS1) gene, predicted to have a deleterious (SIFT) effect. ALMS1 is implicated in the development of DCM, with rare reports of cardiac arrhythmias. Conclusion The co-presence of genetic variations in genes such as CACNB2, LAMA2 or ALMS1 may have an important modifier effect to the final clinical outcome towards DCM combined with arrhythmias.