Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset
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 u...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-04-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/7/3786 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Andreas Brodehl Alexey Meshkov Roman Myasnikov Anna Kiseleva Olga Kulikova Bärbel Klauke Evgeniia Sotnikova Caroline Stanasiuk Mikhail Divashuk Greta Marie Pohl Maria Kudryavtseva Karin Klingel Brenda Gerull Anastasia Zharikova Jan Gummert Sergey Koretskiy Stephan Schubert Elena Mershina Anna Gärtner Polina Pilus Kai Thorsten Laser Valentin Sinitsyn Sergey Boytsov Oxana Drapkina Hendrik Milting |
| spellingShingle |
Andreas Brodehl Alexey Meshkov Roman Myasnikov Anna Kiseleva Olga Kulikova Bärbel Klauke Evgeniia Sotnikova Caroline Stanasiuk Mikhail Divashuk Greta Marie Pohl Maria Kudryavtseva Karin Klingel Brenda Gerull Anastasia Zharikova Jan Gummert Sergey Koretskiy Stephan Schubert Elena Mershina Anna Gärtner Polina Pilus Kai Thorsten Laser Valentin Sinitsyn Sergey Boytsov Oxana Drapkina Hendrik Milting Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset International Journal of Molecular Sciences desmoglein-2 desmocollin-2 DSG2 DSC2 ARVC ACM |
| author_facet |
Andreas Brodehl Alexey Meshkov Roman Myasnikov Anna Kiseleva Olga Kulikova Bärbel Klauke Evgeniia Sotnikova Caroline Stanasiuk Mikhail Divashuk Greta Marie Pohl Maria Kudryavtseva Karin Klingel Brenda Gerull Anastasia Zharikova Jan Gummert Sergey Koretskiy Stephan Schubert Elena Mershina Anna Gärtner Polina Pilus Kai Thorsten Laser Valentin Sinitsyn Sergey Boytsov Oxana Drapkina Hendrik Milting |
| author_sort |
Andreas Brodehl |
| title |
Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset |
| title_short |
Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset |
| title_full |
Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset |
| title_fullStr |
Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset |
| title_full_unstemmed |
Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset |
| title_sort |
hemi- and homozygous loss-of-function mutations in dsg2 (desmoglein-2) cause recessive arrhythmogenic cardiomyopathy with an early onset |
| publisher |
MDPI AG |
| series |
International Journal of Molecular Sciences |
| issn |
1661-6596 1422-0067 |
| publishDate |
2021-04-01 |
| description |
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. |
| topic |
desmoglein-2 desmocollin-2 DSG2 DSC2 ARVC ACM |
| url |
https://www.mdpi.com/1422-0067/22/7/3786 |
| work_keys_str_mv |
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doaj-970dc997e2ef4c3099f68c5c23e3e5d62021-04-06T23:06:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01223786378610.3390/ijms22073786Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early OnsetAndreas Brodehl0Alexey Meshkov1Roman Myasnikov2Anna Kiseleva3Olga Kulikova4Bärbel Klauke5Evgeniia Sotnikova6Caroline Stanasiuk7Mikhail Divashuk8Greta Marie Pohl9Maria Kudryavtseva10Karin Klingel11Brenda Gerull12Anastasia Zharikova13Jan Gummert14Sergey Koretskiy15Stephan Schubert16Elena Mershina17Anna Gärtner18Polina Pilus19Kai Thorsten Laser20Valentin Sinitsyn21Sergey Boytsov22Oxana Drapkina23Hendrik Milting24Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRWNational Medical Research Center for Therapy and Preventive Medicine, Petroverigsky per., 10, bld. 3, 101000, Moscow, RussiaNational Medical Research Center for Therapy and Preventive Medicine, Petroverigsky per., 10, bld. 3, 101000, Moscow, RussiaNational Medical Research Center for Therapy and Preventive Medicine, Petroverigsky per., 10, bld. 3, 101000, Moscow, RussiaNational Medical Research Center for Therapy and Preventive Medicine, Petroverigsky per., 10, bld. 3, 101000, Moscow, RussiaErich and Hanna Klessmann Institute, Heart and Diabetes Center NRWNational Medical Research Center for Therapy and Preventive Medicine, Petroverigsky per., 10, bld. 3, 101000, Moscow, RussiaErich and Hanna Klessmann Institute, Heart and Diabetes Center NRWNational Medical Research Center for Therapy and Preventive Medicine, Petroverigsky per., 10, bld. 3, 101000, Moscow, RussiaErich and Hanna Klessmann Institute, Heart and Diabetes Center NRWNational Medical Research Center for Therapy and Preventive Medicine, Petroverigsky per., 10, bld. 3, 101000, Moscow, RussiaCardiopathology, Institute for Pathology and Neuropathology, University Hospital Tuebingen, Liebemeister-strasse 8, 72076 Tuebingen, GermanyComprehensive Heart Failure Center (CHFC) and Department of Internal Medicine I, University Hospital Würzburg, 97080 Würzburg, GermanyNational Medical Research Center for Therapy and Preventive Medicine, Petroverigsky per., 10, bld. 3, 101000, Moscow, RussiaErich and Hanna Klessmann Institute, Heart and Diabetes Center NRWNational Medical Research Center for Therapy and Preventive Medicine, Petroverigsky per., 10, bld. 3, 101000, Moscow, RussiaCenter for Congenital Heart Defects, Heart and Diabetes Center NRW, University Hospital of the Ruhr–University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, GermanyMedical Research and Educational Center, Lomonosov Moscow State University, Lomonosovsky Prospect 27, Building 10, 119991 Moscow, RussiaErich and Hanna Klessmann Institute, Heart and Diabetes Center NRWMedical Research and Educational Center, Lomonosov Moscow State University, Lomonosovsky Prospect 27, Building 10, 119991 Moscow, RussiaCenter for Congenital Heart Defects, Heart and Diabetes Center NRW, University Hospital of the Ruhr–University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, GermanyMedical Research and Educational Center, Lomonosov Moscow State University, Lomonosovsky Prospect 27, Building 10, 119991 Moscow, RussiaNational Medical Research Center for Cardiology, 3–ya Cherepkovskaya Street 15A, 121552 Moscow, RussiaNational Medical Research Center for Therapy and Preventive Medicine, Petroverigsky per., 10, bld. 3, 101000, Moscow, RussiaErich and Hanna Klessmann Institute, Heart and Diabetes Center NRWAbout 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.https://www.mdpi.com/1422-0067/22/7/3786desmoglein-2desmocollin-2DSG2DSC2ARVCACM |