@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}
}
@phdthesis{Kolokotronis2021,
  author    = {Kolokotronis, Konstantinos},
  title     = {Genetische Ursachen heredit{\"a}rer Herzerkrankungen},
  doi       = {10.25972/OPUS-23116},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231164},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {Heredit{\"a}re Kardiomyopathien sind durch klinische und genetische Heterogenit{\"a}t gekennzeichnet, welche die Kardiogenetik vor Herausforderungen stellt. In dieser Arbeit wurden manche dieser Herausforderungen angegangen, indem anhand einer Kohorte von 61 Patienten mit Kardiomyopathie bzw. prim{\"a}rer Arrhythmie eine Exom-Diagnostik mit anschließender stufenweiser Datenanalyse vorgenommen wurde. Ein Ziel der Arbeit war, die aktuellen diagnostischen Detektionsraten zu pr{\"u}fen sowie zu bewerten, ob eine erweiterte Exom-Diagnostik im Vergleich zur {\"u}blichen Genpanel-Analyse einen diagnostischen Zugewinn bringt. Zudem sollten potenzielle Krankheitsgene sowie komplexe Genotypen identifiziert werden. Die Ergebnisse zeigten, dass bei insgesamt 64\% der Patienten eine Variante von Interesse gefunden wurde. Hervorzuheben ist die hohe Detektionsrate in der gr{\"o}ßten Subkohorte, die aus Patienten mit dilatativer bzw. linksventrikul{\"a}rer Non-Compaction Kardiomyopathie bestand: 69\% und damit h{\"o}her im Vergleich zur in der Literatur berichteten Detektionsrate von bis zu 50\%. Im Rahmen der stufenweisen Daten-Auswertung zeigte sich zwar, dass die meisten kausalen Varianten in den ph{\"a}notypspezifischen Panels zu finden waren, die Analyse eines erweiterten Panels mit 79 Genen sowie der Gesamtexom-Daten aber zu einer zus{\"a}tzlichen Aufkl{\"a}rungsquote von 13\% bzw. 5\% f{\"u}hrte. Durch die Erweiterung der Diagnostik konnten interessante, teilweise neue Assoziationen zwischen Genotyp und Ph{\"a}notyp sowie neue Kandidatengene identifiziert werden. Das beste Beispiel daf{\"u}r ist eine trunkierende Variante im STK38-Gen, das an der Phosphorylierung eines Regulators der Expression kardialer Gene beteiligt ist. Zusammenfassend konnte gezeigt werden, dass, obwohl die Detektionsrate von Genpanels f{\"u}r die Routine-Diagnostik akzeptabel ist, die Anwendung von Exom-Diagnostik einen diagnostischen Zugewinn, die Entdeckung von interessanten Genotyp-Ph{\"a}notyp-Korrelationen sowie die Identifizierung von Kandidatengenen erm{\"o}glicht.},
  subject      = {Herzmuskelkrankheit},
  language  = {de}
}
@article{HofrichterMojaradDolletal.2018,
  author    = {Hofrichter, Michaela A. H. and Mojarad, Majid and Doll, Julia and Grimm, Clemens and Eslahi, Atiye and Hosseini, Neda Sadat and Rajati, Mohsen and M{\"u}ller, Tobias and Dittrich, Marcus and Maroofian, Reza and Haaf, Thomas and Vona, Barbara},
  title     = {The conserved p.Arg108 residue in S1PR2 (DFNB68) is fundamental for proper hearing: evidence from a consanguineous Iranian family},
  series = {BMC Medical Genetics},
  volume    = {19},
  journal   = {BMC Medical Genetics},
  number    = {81},
  doi       = {10.1186/s12881-018-0598-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175755},
  year      = {2018},
  abstract  = {Background: Genetic heterogeneity and consanguineous marriages make recessive inherited hearing loss in Iran the second most common genetic disorder. Only two reported pathogenic variants (c.323G>C, p.Arg108Pro and c.419A>G, p.Tyr140Cys) in the S1PR2 gene have previously been linked to autosomal recessive hearing loss (DFNB68) in two Pakistani families. We describe a segregating novel homozygous c.323G>A, p.Arg108Gln pathogenic variant in S1PR2 that was identified in four affected individuals from a consanguineous five generation Iranian family. Methods: Whole exome sequencing and bioinformatics analysis of 116 hearing loss-associated genes was performed in an affected individual from a five generation Iranian family. Segregation analysis and 3D protein modeling of the p.Arg108 exchange was performed. Results: The two Pakistani families previously identified with S1PR2 pathogenic variants presented profound hearing loss that is also observed in the affected Iranian individuals described in the current study. Interestingly, we confirmed mixed hearing loss in one affected individual. 3D protein modeling suggests that the p.Arg108 position plays a key role in ligand receptor interaction, which is disturbed by the p.Arg108Gln change. Conclusion: In summary, we report the third overall mutation in S1PR2 and the first report outside the Pakistani population. Furthermore, we describe a novel variant that causes an amino acid exchange (p.Arg108Gln) in the same amino acid residue as one of the previously reported Pakistani families (p.Arg108Pro). This finding emphasizes the importance of the p.Arg108 amino acid in normal hearing and confirms and consolidates the role of S1PR2 in autosomal recessive hearing loss.},
  language  = {en}
}