TY  - JOUR
A1  - Brodehl, Andreas
A1  - Meshkov, Alexey
A1  - Myasnikov, Roman
A1  - Kiseleva, Anna
A1  - Kulikova, Olga
A1  - Klauke, Bärbel
A1  - Sotnikova, Evgeniia
A1  - Stanasiuk, Caroline
A1  - Divashuk, Mikhail
A1  - Pohl, Greta Marie
A1  - Kudryavtseva, Maria
A1  - Klingel, Karin
A1  - Gerull, Brenda
A1  - Zharikova, Anastasia
A1  - Gummert, Jan
A1  - Koretskiy, Sergey
A1  - Schubert, Stephan
A1  - Mershina, Elena
A1  - Gärtner, Anna
A1  - Pilus, Polina
A1  - Laser, Kai Thorsten
A1  - Sinitsyn, Valentin
A1  - Boytsov, Sergey
A1  - Drapkina, Oxana
A1  - Milting, Hendrik
T1  - Hemi- and homozygous loss-of-function mutations in DSG2 (desmoglein-2) cause recessive arrhythmogenic cardiomyopathy with an early onset
JF  - International Journal of Molecular Sciences
N2  - 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.
KW  - desmoglein-2
KW  - desmocollin-2
KW  - DSG2
KW  - DSC2
KW  - ARVC
KW  - ACM
KW  - LVNC
KW  - cardiomyopathy
KW  - desmosomes
KW  - desmin
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285279
SN  - 1422-0067
VL  - 22
IS  - 7
ER  - 
TY  - JOUR
A1  - Kühnisch, Jirko
A1  - Herbst, Christopher
A1  - Al‐Wakeel‐Marquard, Nadya
A1  - Dartsch, Josephine
A1  - Holtgrewe, Manuel
A1  - Baban, Anwar
A1  - Mearini, Giulia
A1  - Hardt, Juliane
A1  - Kolokotronis, Konstantinos
A1  - Gerull, Brenda
A1  - Carrier, Lucie
A1  - Beule, Dieter
A1  - Schubert, Stephan
A1  - Messroghli, Daniel
A1  - Degener, Franziska
A1  - Berger, Felix
A1  - Klaassen, Sabine
T1  - Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3
JF  - Clinical Genetics
N2  - 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.
KW  - cardiomyopathy
KW  - genetics
KW  - pediatrics
KW  - sarcomere
KW  - TNNI3
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213958
VL  - 96
IS  - 6
SP  - 549
EP  - 559
ER  -