Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy
Abstract Objective Molecular genetic etiologies in epilepsy have become better understood in recent years, creating important opportunities for precision medicine. Building on these advances, detailed studies of the complexities and outcomes of genetic testing for epilepsy can provide useful insight...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-09-01
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| Series: | Epilepsia Open |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/epi4.12348 |
| _version_ | 1798043763186073600 |
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| author | Rebecca Truty Nila Patil Raman Sankar Joseph Sullivan John Millichap Gemma Carvill Ali Entezam Edward D. Esplin Amy Fuller Michelle Hogue Britt Johnson Amirah Khouzam Yuya Kobayashi Rachel Lewis Keith Nykamp Darlene Riethmaier Jody Westbrook Michelle Zeman Robert L. Nussbaum Swaroop Aradhya |
| author_facet | Rebecca Truty Nila Patil Raman Sankar Joseph Sullivan John Millichap Gemma Carvill Ali Entezam Edward D. Esplin Amy Fuller Michelle Hogue Britt Johnson Amirah Khouzam Yuya Kobayashi Rachel Lewis Keith Nykamp Darlene Riethmaier Jody Westbrook Michelle Zeman Robert L. Nussbaum Swaroop Aradhya |
| author_sort | Rebecca Truty |
| collection | DOAJ |
| description | Abstract Objective Molecular genetic etiologies in epilepsy have become better understood in recent years, creating important opportunities for precision medicine. Building on these advances, detailed studies of the complexities and outcomes of genetic testing for epilepsy can provide useful insights that inform and refine diagnostic approaches and illuminate the potential for precision medicine in epilepsy. Methods We used a multi‐gene next‐generation sequencing (NGS) panel with simultaneous sequence and exonic copy number variant detection to investigate up to 183 epilepsy‐related genes in 9769 individuals. Clinical variant interpretation was performed using a semi‐quantitative scoring system based on existing professional practice guidelines. Results Molecular genetic testing provided a diagnosis in 14.9%‐24.4% of individuals with epilepsy, depending on the NGS panel used. More than half of these diagnoses were in children younger than 5 years. Notably, the testing had possible precision medicine implications in 33% of individuals who received definitive diagnostic results. Only 30 genes provided 80% of molecular diagnoses. While most clinically significant findings were single‐nucleotide variants, ~15% were other types that are often challenging to detect with traditional methods. In addition to clinically significant variants, there were many others that initially had uncertain significance; reclassification of 1612 such variants with parental testing or other evidence contributed to 18.5% of diagnostic results overall and 6.1% of results with precision medicine implications. Significance Using an NGS gene panel with key high‐yield genes and robust analytic sensitivity as a first‐tier test early in the diagnostic process, especially for children younger than 5 years, can possibly enable precision medicine approaches in a significant number of individuals with epilepsy. |
| first_indexed | 2024-04-11T22:53:37Z |
| format | Article |
| id | doaj.art-63da92c7102c47088be6ed489b30083b |
| institution | Directory Open Access Journal |
| issn | 2470-9239 |
| language | English |
| last_indexed | 2024-04-11T22:53:37Z |
| publishDate | 2019-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Epilepsia Open |
| spelling | doaj.art-63da92c7102c47088be6ed489b30083b2022-12-22T03:58:30ZengWileyEpilepsia Open2470-92392019-09-014339740810.1002/epi4.12348Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsyRebecca Truty0Nila Patil1Raman Sankar2Joseph Sullivan3John Millichap4Gemma Carvill5Ali Entezam6Edward D. Esplin7Amy Fuller8Michelle Hogue9Britt Johnson10Amirah Khouzam11Yuya Kobayashi12Rachel Lewis13Keith Nykamp14Darlene Riethmaier15Jody Westbrook16Michelle Zeman17Robert L. Nussbaum18Swaroop Aradhya19Invitae San Francisco CaliforniaDepartments of Pediatrics and Neurology University of California Los Angeles Los Angeles CaliforniaDepartments of Pediatrics and Neurology University of California Los Angeles Los Angeles CaliforniaPediatric Epilepsy Center University of California San Francisco San Francisco CaliforniaLurie Children's Hospital and Northwestern University Chicago IllinoisKen and Ruth Davee Department of Neurology Northwestern University Chicago IllinoisInvitae San Francisco CaliforniaInvitae San Francisco CaliforniaInvitae San Francisco CaliforniaInvitae San Francisco CaliforniaInvitae San Francisco CaliforniaInvitae San Francisco CaliforniaInvitae San Francisco CaliforniaInvitae San Francisco CaliforniaInvitae San Francisco CaliforniaInvitae San Francisco CaliforniaInvitae San Francisco CaliforniaInvitae San Francisco CaliforniaInvitae San Francisco CaliforniaInvitae San Francisco CaliforniaAbstract Objective Molecular genetic etiologies in epilepsy have become better understood in recent years, creating important opportunities for precision medicine. Building on these advances, detailed studies of the complexities and outcomes of genetic testing for epilepsy can provide useful insights that inform and refine diagnostic approaches and illuminate the potential for precision medicine in epilepsy. Methods We used a multi‐gene next‐generation sequencing (NGS) panel with simultaneous sequence and exonic copy number variant detection to investigate up to 183 epilepsy‐related genes in 9769 individuals. Clinical variant interpretation was performed using a semi‐quantitative scoring system based on existing professional practice guidelines. Results Molecular genetic testing provided a diagnosis in 14.9%‐24.4% of individuals with epilepsy, depending on the NGS panel used. More than half of these diagnoses were in children younger than 5 years. Notably, the testing had possible precision medicine implications in 33% of individuals who received definitive diagnostic results. Only 30 genes provided 80% of molecular diagnoses. While most clinically significant findings were single‐nucleotide variants, ~15% were other types that are often challenging to detect with traditional methods. In addition to clinically significant variants, there were many others that initially had uncertain significance; reclassification of 1612 such variants with parental testing or other evidence contributed to 18.5% of diagnostic results overall and 6.1% of results with precision medicine implications. Significance Using an NGS gene panel with key high‐yield genes and robust analytic sensitivity as a first‐tier test early in the diagnostic process, especially for children younger than 5 years, can possibly enable precision medicine approaches in a significant number of individuals with epilepsy.https://doi.org/10.1002/epi4.12348diagnostic genetic testingnext‐generation sequencing panelcopy number variantprecision medicineclinical managementvariant of uncertain significance |
| spellingShingle | Rebecca Truty Nila Patil Raman Sankar Joseph Sullivan John Millichap Gemma Carvill Ali Entezam Edward D. Esplin Amy Fuller Michelle Hogue Britt Johnson Amirah Khouzam Yuya Kobayashi Rachel Lewis Keith Nykamp Darlene Riethmaier Jody Westbrook Michelle Zeman Robert L. Nussbaum Swaroop Aradhya Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy Epilepsia Open diagnostic genetic testing next‐generation sequencing panel copy number variant precision medicine clinical management variant of uncertain significance |
| title | Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy |
| title_full | Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy |
| title_fullStr | Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy |
| title_full_unstemmed | Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy |
| title_short | Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy |
| title_sort | possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy |
| topic | diagnostic genetic testing next‐generation sequencing panel copy number variant precision medicine clinical management variant of uncertain significance |
| url | https://doi.org/10.1002/epi4.12348 |
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