@article{BrodehlGerull2022,
  author    = {Brodehl, Andreas and Gerull, Brenda},
  title     = {Genetic insights into primary restrictive cardiomyopathy},
  series = {Journal of Clinical Medicine},
  volume    = {11},
  journal   = {Journal of Clinical Medicine},
  number    = {8},
  issn      = {2077-0383},
  doi       = {10.3390/jcm11082094},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270621},
  year      = {2022},
  abstract  = {Restrictive cardiomyopathy is a rare cardiac disease causing severe diastolic dysfunction, ventricular stiffness and dilated atria. In consequence, it induces heart failure often with preserved ejection fraction and is associated with a high mortality. Since it is a poor clinical prognosis, patients with restrictive cardiomyopathy frequently require heart transplantation. Genetic as well as non-genetic factors contribute to restrictive cardiomyopathy and a significant portion of cases are of unknown etiology. However, the genetic forms of restrictive cardiomyopathy and the involved molecular pathomechanisms are only partially understood. In this review, we summarize the current knowledge about primary genetic restrictive cardiomyopathy and describe its genetic landscape, which might be of interest for geneticists as well as for cardiologists.},
  language  = {en}
}
@article{BrodehlMeshkovMyasnikovetal.2021,
  author    = {Brodehl, Andreas and Meshkov, Alexey and Myasnikov, Roman and Kiseleva, Anna and Kulikova, Olga and Klauke, B{\"a}rbel and Sotnikova, Evgeniia and Stanasiuk, Caroline and Divashuk, Mikhail and Pohl, Greta Marie and Kudryavtseva, Maria and Klingel, Karin and Gerull, Brenda and Zharikova, Anastasia and Gummert, Jan and Koretskiy, Sergey and Schubert, Stephan and Mershina, Elena and G{\"a}rtner, Anna and Pilus, Polina and Laser, Kai Thorsten and Sinitsyn, Valentin and Boytsov, Sergey and Drapkina, Oxana and Milting, Hendrik},
  title     = {Hemi- and homozygous loss-of-function mutations in DSG2 (desmoglein-2) cause recessive arrhythmogenic cardiomyopathy with an early onset},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {7},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22073786},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285279},
  year      = {2021},
  abstract  = {About 50\% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2-c.378+1G>T) in the first patient and a nonsense mutation (DSG2-p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.},
  language  = {en}
}
@article{KolokotronisPlutaKlopockietal.2020,
  author    = {Kolokotronis, Konstantinos and Pluta, Natalie and Klopocki, Eva and Kunstmann, Erdmute and Messroghli, Daniel and Maack, Christoph and Tejman-Yarden, Shai and Arad, Michael and Rost, Simone and Gerull, Brenda},
  title     = {New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis},
  series = {Journal of Clinical Medicine},
  volume    = {9},
  journal   = {Journal of Clinical Medicine},
  number    = {7},
  doi       = {10.3390/jcm9072168},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236094},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{BrodehlPourHakimiStanasiuketal.2019,
  author    = {Brodehl, Andreas and Pour Hakimi, Seyed Ahmad and Stanasiuk, Caroline and Ratnavadivel, Sandra and Hendig, Doris and Gaertner, Anna and Gerull, Brenda and Gummert, Jan and Paluszkiewicz, Lech and Milting, Hendrik},
  title     = {Restrictive cardiomyopathy is caused by a novel homozygous desmin (DES) mutation p.Y122H leading to a severe filament assembly defect},
  series = {Genes},
  volume    = {10},
  journal   = {Genes},
  number    = {11},
  issn      = {2073-4425},
  doi       = {10.3390/genes10110918},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193121},
  year      = {2019},
  abstract  = {Here, we present a small Iranian family, where the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block. Genetic analysis revealed a novel homozygous missense mutation in the DES gene (c.364T > C; p.Y122H), which is absent in human population databases. The mutation is localized in the highly conserved coil-1 desmin subdomain. In silico, prediction tools indicate a deleterious effect of the desmin (DES) mutation p.Y122H. Consequently, we generated an expression plasmid encoding the mutant and wildtype desmin formed, and analyzed the filament formation in vitro in cardiomyocytes derived from induced pluripotent stem cells and HT-1080 cells. Confocal microscopy revealed a severe filament assembly defect of mutant desmin supporting the pathogenicity of the DES mutation, p.Y122H, whereas the wildtype desmin formed regular intermediate filaments. According to the guidelines of the American College of Medical Genetics and Genomics, we classified this mutation, therefore, as a novel pathogenic mutation. Our report could point to a recessive inheritance of the DES mutation, p.Y122H, which is important for the genetic counseling of similar families with restrictive cardiomyopathy caused by DES mutations.},
  language  = {en}
}
@article{KuehnischHerbstAl‐Wakeel‐Marquardetal.2019,
  author    = {K{\"u}hnisch, Jirko and Herbst, Christopher and Al-Wakeel-Marquard, Nadya and Dartsch, Josephine and Holtgrewe, Manuel and Baban, Anwar and Mearini, Giulia and Hardt, Juliane and Kolokotronis, Konstantinos and Gerull, Brenda and Carrier, Lucie and Beule, Dieter and Schubert, Stephan and Messroghli, Daniel and Degener, Franziska and Berger, Felix and Klaassen, Sabine},
  title     = {Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3},
  series = {Clinical Genetics},
  volume    = {96},
  journal   = {Clinical Genetics},
  number    = {6},
  doi       = {10.1111/cge.13645},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213958},
  pages     = {549 -- 559},
  year      = {2019},
  abstract  = {The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel-based next-generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38\%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.},
  language  = {en}
}