The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic
Abstract Background The diagnostic yield of genetic testing for inherited cardiac diseases is up to 40% and is primarily indicated for screening of at-risk relatives. Here, we evaluate the role of genomics in diagnosis and management among consecutive individuals attending a specialised clinic and i...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-022-01149-0 |
| _version_ | 1797973604207427584 |
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| author | Fergus Stafford Neesha Krishnan Ebony Richardson Alexandra Butters Sophie Hespe Charlotte Burns Belinda Gray Caroline Medi Natalie Nowak Julia C. Isbister Hariharan Raju David Richmond Mark P. Ryan Emma S. Singer Raymond W. Sy Laura Yeates Richard D. Bagnall Christopher Semsarian Jodie Ingles |
| author_facet | Fergus Stafford Neesha Krishnan Ebony Richardson Alexandra Butters Sophie Hespe Charlotte Burns Belinda Gray Caroline Medi Natalie Nowak Julia C. Isbister Hariharan Raju David Richmond Mark P. Ryan Emma S. Singer Raymond W. Sy Laura Yeates Richard D. Bagnall Christopher Semsarian Jodie Ingles |
| author_sort | Fergus Stafford |
| collection | DOAJ |
| description | Abstract Background The diagnostic yield of genetic testing for inherited cardiac diseases is up to 40% and is primarily indicated for screening of at-risk relatives. Here, we evaluate the role of genomics in diagnosis and management among consecutive individuals attending a specialised clinic and identify those with the highest likelihood of having a monogenic disease. Methods A retrospective audit of 1697 consecutive, unrelated probands referred to a specialised, multidisciplinary clinic between 2002 and 2020 was performed. A concordant clinical and genetic diagnosis was considered solved. Cases were classified as likely monogenic based on a score comprising a positive family history, young age at onset, and severe phenotype, whereas low-scoring cases were considered to have a likely complex aetiology. The impact of a genetic diagnosis was evaluated. Results A total of 888 probands fulfilled the inclusion criteria, and genetic testing identified likely pathogenic or pathogenic (LP/P) variants in 330 individuals (37%) and suspicious variants of uncertain significance (VUS) in 73 (8%). Research-focused efforts identified 46 (5%) variants, missed by conventional genetic testing. Where a variant was identified, this changed or clarified the final diagnosis in a clinically useful way for 51 (13%). The yield of suspicious VUS across ancestry groups ranged from 15 to 20%, compared to only 10% among Europeans. Even when the clinical diagnosis was uncertain, those with the most monogenic disease features had the greatest diagnostic yield from genetic testing. Conclusions Research-focused efforts can increase the diagnostic yield by up to 5%. Where a variant is identified, this will have clinical utility beyond family screening in 13%. We demonstrate the value of genomics in reaching an overall diagnosis and highlight inequities based on ancestry. Acknowledging our incomplete understanding of disease phenotypes, we propose a framework for prioritising likely monogenic cases to solve their underlying cause of disease. |
| first_indexed | 2024-04-11T04:06:54Z |
| format | Article |
| id | doaj.art-f184e1d0a01942f097115bc1973c0a47 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-04-11T04:06:54Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-f184e1d0a01942f097115bc1973c0a472023-01-01T12:24:01ZengBMCGenome Medicine1756-994X2022-12-0114111410.1186/s13073-022-01149-0The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinicFergus Stafford0Neesha Krishnan1Ebony Richardson2Alexandra Butters3Sophie Hespe4Charlotte Burns5Belinda Gray6Caroline Medi7Natalie Nowak8Julia C. Isbister9Hariharan Raju10David Richmond11Mark P. Ryan12Emma S. Singer13Raymond W. Sy14Laura Yeates15Richard D. Bagnall16Christopher Semsarian17Jodie Ingles18Cardio Genomics Program at Centenary Institute, The University of SydneyCardio Genomics Program at Centenary Institute, The University of SydneyCardio Genomics Program at Centenary Institute, The University of SydneyCardio Genomics Program at Centenary Institute, The University of SydneyCentre for Population Genomics, Garvan Institute of Medical Research, and UNSW SydneyFaculty of Medicine and Health, The University of SydneyFaculty of Medicine and Health, The University of SydneyDepartment of Cardiology, Royal Prince Alfred HospitalFaculty of Medicine and Health, The University of SydneyFaculty of Medicine and Health, The University of SydneyDepartment of Cardiology, Royal Prince Alfred HospitalFaculty of Medicine and Health, The University of SydneyDepartment of Cardiology, Royal Prince Alfred HospitalFaculty of Medicine and Health, The University of SydneyFaculty of Medicine and Health, The University of SydneyCardio Genomics Program at Centenary Institute, The University of SydneyFaculty of Medicine and Health, The University of SydneyFaculty of Medicine and Health, The University of SydneyCardio Genomics Program at Centenary Institute, The University of SydneyAbstract Background The diagnostic yield of genetic testing for inherited cardiac diseases is up to 40% and is primarily indicated for screening of at-risk relatives. Here, we evaluate the role of genomics in diagnosis and management among consecutive individuals attending a specialised clinic and identify those with the highest likelihood of having a monogenic disease. Methods A retrospective audit of 1697 consecutive, unrelated probands referred to a specialised, multidisciplinary clinic between 2002 and 2020 was performed. A concordant clinical and genetic diagnosis was considered solved. Cases were classified as likely monogenic based on a score comprising a positive family history, young age at onset, and severe phenotype, whereas low-scoring cases were considered to have a likely complex aetiology. The impact of a genetic diagnosis was evaluated. Results A total of 888 probands fulfilled the inclusion criteria, and genetic testing identified likely pathogenic or pathogenic (LP/P) variants in 330 individuals (37%) and suspicious variants of uncertain significance (VUS) in 73 (8%). Research-focused efforts identified 46 (5%) variants, missed by conventional genetic testing. Where a variant was identified, this changed or clarified the final diagnosis in a clinically useful way for 51 (13%). The yield of suspicious VUS across ancestry groups ranged from 15 to 20%, compared to only 10% among Europeans. Even when the clinical diagnosis was uncertain, those with the most monogenic disease features had the greatest diagnostic yield from genetic testing. Conclusions Research-focused efforts can increase the diagnostic yield by up to 5%. Where a variant is identified, this will have clinical utility beyond family screening in 13%. We demonstrate the value of genomics in reaching an overall diagnosis and highlight inequities based on ancestry. Acknowledging our incomplete understanding of disease phenotypes, we propose a framework for prioritising likely monogenic cases to solve their underlying cause of disease.https://doi.org/10.1186/s13073-022-01149-0Inherited cardiac conditionsSudden cardiac deathGenetic testing |
| spellingShingle | Fergus Stafford Neesha Krishnan Ebony Richardson Alexandra Butters Sophie Hespe Charlotte Burns Belinda Gray Caroline Medi Natalie Nowak Julia C. Isbister Hariharan Raju David Richmond Mark P. Ryan Emma S. Singer Raymond W. Sy Laura Yeates Richard D. Bagnall Christopher Semsarian Jodie Ingles The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic Genome Medicine Inherited cardiac conditions Sudden cardiac death Genetic testing |
| title | The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic |
| title_full | The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic |
| title_fullStr | The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic |
| title_full_unstemmed | The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic |
| title_short | The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic |
| title_sort | role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic |
| topic | Inherited cardiac conditions Sudden cardiac death Genetic testing |
| url | https://doi.org/10.1186/s13073-022-01149-0 |
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