An analysis of mitochondrial variation in cardiomyopathy patients from the 100,000 genomes cohort: m.4300A>G as a cause of genetically elusive hypertrophic cardiomyopathy
Abstract Background A significant proportion of cardiomyopathy patients remain genetically unsolved. Our aim was to use the large genomes cohort of the 100,000 genomes project (100KGP) to explore the proportion of potentially causal mitochondrial (mtDNA) variants in cardiomyopathy patients, particul...
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2024-12-01
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| Online Access: | https://doi.org/10.1186/s40246-024-00702-9 |
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| author | Luis R. Lopes William L. Macken Seth Du Preez Huafrin Kotwal Konstantinos Savvatis Neha Sekhri Saidi A. Mohiddin Renata Kabiljo Robert D. S. Pitceathly |
| author_facet | Luis R. Lopes William L. Macken Seth Du Preez Huafrin Kotwal Konstantinos Savvatis Neha Sekhri Saidi A. Mohiddin Renata Kabiljo Robert D. S. Pitceathly |
| author_sort | Luis R. Lopes |
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| description | Abstract Background A significant proportion of cardiomyopathy patients remain genetically unsolved. Our aim was to use the large genomes cohort of the 100,000 genomes project (100KGP) to explore the proportion of potentially causal mitochondrial (mtDNA) variants in cardiomyopathy patients, particularly in genotype-elusive participants. The homoplasmic MT-TI 4300A>G is unusual in that it typically presents with a cardiac-only phenotype, but MT-TI is currently not part of the genes analysed for non-syndromic cardiomyopathies. Results We analysed 1363 cardiomyopathy genomes from the 100KGP project (of which only 172 had been previously solved) to detect disease causing mtDNA variants. MitoHPC was used to call variants. For controls, 1329 random subjects not recruited for a cardiomyopathy diagnosis and not related to any participant in the cardiomyopathy cohort were selected. We have additionally compared the frequency of detected variants with published UK Biobank data. Pathogenicity annotations were assigned based on MitoMap. Four patients, all with a diagnosis of hypertrophic cardiomyopathy (HCM) and without a previously identified genetic cause from the 100KGP clinical-standard analysis, were found to harbour the pathogenic MT-TI m.4300A>G variant (0.6% of HCM cases without a diagnosis). Conclusion These data support the inclusion of MT-TI in the initial genetic testing panel for (non-syndromic) HCM. |
| format | Article |
| id | doaj-art-2b61615b836e47ab8a0aa206e4bab0d6 |
| institution | Kabale University |
| issn | 1479-7364 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
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| series | Human Genomics |
| spelling | doaj-art-2b61615b836e47ab8a0aa206e4bab0d62024-12-08T12:37:30ZengBMCHuman Genomics1479-73642024-12-011811410.1186/s40246-024-00702-9An analysis of mitochondrial variation in cardiomyopathy patients from the 100,000 genomes cohort: m.4300A>G as a cause of genetically elusive hypertrophic cardiomyopathyLuis R. Lopes0William L. Macken1Seth Du Preez2Huafrin Kotwal3Konstantinos Savvatis4Neha Sekhri5Saidi A. Mohiddin6Renata Kabiljo7Robert D. S. Pitceathly8Institute of Cardiovascular Science, University College LondonDepartment of Neuromuscular Diseases, University College London Queen Square Institute of NeurologyNHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and NeurosurgerySt. Bartholomew’s Hospital, Barts Heart CentreInstitute of Cardiovascular Science, University College LondonSt. Bartholomew’s Hospital, Barts Heart CentreSt. Bartholomew’s Hospital, Barts Heart CentreDepartment of Neuromuscular Diseases, University College London Queen Square Institute of NeurologyDepartment of Neuromuscular Diseases, University College London Queen Square Institute of NeurologyAbstract Background A significant proportion of cardiomyopathy patients remain genetically unsolved. Our aim was to use the large genomes cohort of the 100,000 genomes project (100KGP) to explore the proportion of potentially causal mitochondrial (mtDNA) variants in cardiomyopathy patients, particularly in genotype-elusive participants. The homoplasmic MT-TI 4300A>G is unusual in that it typically presents with a cardiac-only phenotype, but MT-TI is currently not part of the genes analysed for non-syndromic cardiomyopathies. Results We analysed 1363 cardiomyopathy genomes from the 100KGP project (of which only 172 had been previously solved) to detect disease causing mtDNA variants. MitoHPC was used to call variants. For controls, 1329 random subjects not recruited for a cardiomyopathy diagnosis and not related to any participant in the cardiomyopathy cohort were selected. We have additionally compared the frequency of detected variants with published UK Biobank data. Pathogenicity annotations were assigned based on MitoMap. Four patients, all with a diagnosis of hypertrophic cardiomyopathy (HCM) and without a previously identified genetic cause from the 100KGP clinical-standard analysis, were found to harbour the pathogenic MT-TI m.4300A>G variant (0.6% of HCM cases without a diagnosis). Conclusion These data support the inclusion of MT-TI in the initial genetic testing panel for (non-syndromic) HCM.https://doi.org/10.1186/s40246-024-00702-9Mitochondrial DNAm.4300A>GHypertrophic cardiomyopathyWhole Genome Sequencing |
| spellingShingle | Luis R. Lopes William L. Macken Seth Du Preez Huafrin Kotwal Konstantinos Savvatis Neha Sekhri Saidi A. Mohiddin Renata Kabiljo Robert D. S. Pitceathly An analysis of mitochondrial variation in cardiomyopathy patients from the 100,000 genomes cohort: m.4300A>G as a cause of genetically elusive hypertrophic cardiomyopathy Human Genomics Mitochondrial DNA m.4300A>G Hypertrophic cardiomyopathy Whole Genome Sequencing |
| title | An analysis of mitochondrial variation in cardiomyopathy patients from the 100,000 genomes cohort: m.4300A>G as a cause of genetically elusive hypertrophic cardiomyopathy |
| title_full | An analysis of mitochondrial variation in cardiomyopathy patients from the 100,000 genomes cohort: m.4300A>G as a cause of genetically elusive hypertrophic cardiomyopathy |
| title_fullStr | An analysis of mitochondrial variation in cardiomyopathy patients from the 100,000 genomes cohort: m.4300A>G as a cause of genetically elusive hypertrophic cardiomyopathy |
| title_full_unstemmed | An analysis of mitochondrial variation in cardiomyopathy patients from the 100,000 genomes cohort: m.4300A>G as a cause of genetically elusive hypertrophic cardiomyopathy |
| title_short | An analysis of mitochondrial variation in cardiomyopathy patients from the 100,000 genomes cohort: m.4300A>G as a cause of genetically elusive hypertrophic cardiomyopathy |
| title_sort | analysis of mitochondrial variation in cardiomyopathy patients from the 100 000 genomes cohort m 4300a g as a cause of genetically elusive hypertrophic cardiomyopathy |
| topic | Mitochondrial DNA m.4300A>G Hypertrophic cardiomyopathy Whole Genome Sequencing |
| url | https://doi.org/10.1186/s40246-024-00702-9 |
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