TY  - JOUR
A1  - Kolokotronis, Konstantinos
A1  - Pluta, Natalie
A1  - Klopocki, Eva
A1  - Kunstmann, Erdmute
A1  - Messroghli, Daniel
A1  - Maack, Christoph
A1  - Tejman-Yarden, Shai
A1  - Arad, Michael
A1  - Rost, Simone
A1  - Gerull, Brenda
T1  - New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis
JF  - Journal of Clinical Medicine
N2  - Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype–genotype correlations, as well as the identification of novel candidate genes.
KW  - cardiomyopathy
KW  - cardiogenetics
KW  - whole exome sequencing
KW  - targeted gene panel
KW  - candidate genes
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236094
VL  - 9
IS  - 7
ER  - 
TY  - JOUR
A1  - Shemer, Yuval
A1  - Mekies, Lucy N.
A1  - Ben Jehuda, Ronen
A1  - Baskin, Polina
A1  - Shulman, Rita
A1  - Eisen, Binyamin
A1  - Regev, Danielle
A1  - Arbustini, Eloisa
A1  - Gerull, Brenda
A1  - Gherghiceanu, Mihaela
A1  - Gottlieb, Eyal
A1  - Arad, Michael
A1  - Binah, Ofer
T1  - Investigating LMNA-related dilated cardiomyopathy using human induced Pluripotent Stem Cell-derived cardiomyocytes
JF  - International Journal of Molecular Sciences
N2  - LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA-mutated patients' induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (I\(_f\)) density; (2) prolonged action potential duration and increased L-type Ca\(^{2+}\) current (I\(_{Ca,L}\)) density; (3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability; (4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, LMNA-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na\(^+\)/Ca\(^{2+}\) exchanger, blocked the DADs in LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy.
KW  - LMNA
KW  - dilated cardiomyopathy
KW  - iPSC-CMs
KW  - electrophysiology
KW  - arrhythmia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285673
SN  - 1422-0067
VL  - 22
IS  - 15
ER  -