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Article

Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

1
Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr–University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, Germany
2
National Medical Research Center for Therapy and Preventive Medicine, Petroverigsky per., 10, bld. 3, 101000 Moscow, Russia
3
Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tuebingen, Liebemeister-strasse 8, 72076 Tuebingen, Germany
4
Comprehensive Heart Failure Center (CHFC) and Department of Internal Medicine I, University Hospital Würzburg, 97080 Würzburg, Germany
5
Clinic for Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, University Hospital of the Ruhr–University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, Germany
6
Center for Congenital Heart Defects, Heart and Diabetes Center NRW, University Hospital of the Ruhr–University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, Germany
7
Medical Research and Educational Center, Lomonosov Moscow State University, Lomonosovsky Prospect 27, Building 10, 119991 Moscow, Russia
8
National Medical Research Center for Cardiology, 3–ya Cherepkovskaya Street 15A, 121552 Moscow, Russia
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors contributed as shared senior authors to this work.
Academic Editor: Hector Barajas-Martinez
Int. J. Mol. Sci. 2021, 22(7), 3786; https://doi.org/10.3390/ijms22073786
Received: 5 March 2021 / Revised: 29 March 2021 / Accepted: 31 March 2021 / Published: 6 April 2021
(This article belongs to the Special Issue Genetic Basis and Molecular Mechanisms of Heart Rhythm Disorders)
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. View Full-Text
Keywords: desmoglein-2; desmocollin-2; DSG2; DSC2; ARVC; ACM; LVNC; cardiomyopathy; desmosomes; desmin desmoglein-2; desmocollin-2; DSG2; DSC2; ARVC; ACM; LVNC; cardiomyopathy; desmosomes; desmin
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MDPI and ACS Style

Brodehl, A.; Meshkov, A.; Myasnikov, R.; Kiseleva, A.; Kulikova, O.; Klauke, B.; Sotnikova, E.; Stanasiuk, C.; Divashuk, M.; Pohl, G.M.; Kudryavtseva, M.; Klingel, K.; Gerull, B.; Zharikova, A.; Gummert, J.; Koretskiy, S.; Schubert, S.; Mershina, E.; Gärtner, A.; Pilus, P.; Laser, K.T.; Sinitsyn, V.; Boytsov, S.; Drapkina, O.; Milting, H. Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset. Int. J. Mol. Sci. 2021, 22, 3786. https://doi.org/10.3390/ijms22073786

AMA Style

Brodehl A, Meshkov A, Myasnikov R, Kiseleva A, Kulikova O, Klauke B, Sotnikova E, Stanasiuk C, Divashuk M, Pohl GM, Kudryavtseva M, Klingel K, Gerull B, Zharikova A, Gummert J, Koretskiy S, Schubert S, Mershina E, Gärtner A, Pilus P, Laser KT, Sinitsyn V, Boytsov S, Drapkina O, Milting H. Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset. International Journal of Molecular Sciences. 2021; 22(7):3786. https://doi.org/10.3390/ijms22073786

Chicago/Turabian Style

Brodehl, Andreas, Alexey Meshkov, Roman Myasnikov, Anna Kiseleva, Olga Kulikova, Bärbel Klauke, Evgeniia Sotnikova, Caroline Stanasiuk, Mikhail Divashuk, Greta M. Pohl, Maria Kudryavtseva, Karin Klingel, Brenda Gerull, Anastasia Zharikova, Jan Gummert, Sergey Koretskiy, Stephan Schubert, Elena Mershina, Anna Gärtner, Polina Pilus, Kai T. Laser, Valentin Sinitsyn, Sergey Boytsov, Oxana Drapkina, and Hendrik Milting. 2021. "Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset" International Journal of Molecular Sciences 22, no. 7: 3786. https://doi.org/10.3390/ijms22073786

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