The effect of ascertainment on penetrance estimates for rare variants: Implications for establishing pathogenicity and for genetic counselling.
Next-generation sequencing has led to an explosion of genetic findings for many rare diseases. However, most of the variants identified are very rare and were also identified in small pedigrees, which creates challenges in terms of penetrance estimation and translation into genetic counselling in th...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0290336 |
| _version_ | 1797671862217474048 |
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| author | Andrew D Paterson Sang-Cheol Seok Veronica J Vieland |
| author_facet | Andrew D Paterson Sang-Cheol Seok Veronica J Vieland |
| author_sort | Andrew D Paterson |
| collection | DOAJ |
| description | Next-generation sequencing has led to an explosion of genetic findings for many rare diseases. However, most of the variants identified are very rare and were also identified in small pedigrees, which creates challenges in terms of penetrance estimation and translation into genetic counselling in the setting of cascade testing. We use simulations to show that for a rare (dominant) disorder where a variant is identified in a small number of small pedigrees, the penetrance estimate can both have large uncertainty and be drastically inflated, due to underlying ascertainment bias. We have developed PenEst, an app that allows users to investigate the phenomenon across ranges of parameter settings. We also illustrate robust ascertainment corrections via the LOD (logarithm of the odds) score, and recommend a LOD-based approach to assessing pathogenicity of rare variants in the presence of reduced penetrance. |
| first_indexed | 2024-03-11T21:21:40Z |
| format | Article |
| id | doaj.art-2348f9b2c38e4a64896f537e35a8eb4d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-03-11T21:21:40Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-2348f9b2c38e4a64896f537e35a8eb4d2023-09-28T05:31:16ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01189e029033610.1371/journal.pone.0290336The effect of ascertainment on penetrance estimates for rare variants: Implications for establishing pathogenicity and for genetic counselling.Andrew D PatersonSang-Cheol SeokVeronica J VielandNext-generation sequencing has led to an explosion of genetic findings for many rare diseases. However, most of the variants identified are very rare and were also identified in small pedigrees, which creates challenges in terms of penetrance estimation and translation into genetic counselling in the setting of cascade testing. We use simulations to show that for a rare (dominant) disorder where a variant is identified in a small number of small pedigrees, the penetrance estimate can both have large uncertainty and be drastically inflated, due to underlying ascertainment bias. We have developed PenEst, an app that allows users to investigate the phenomenon across ranges of parameter settings. We also illustrate robust ascertainment corrections via the LOD (logarithm of the odds) score, and recommend a LOD-based approach to assessing pathogenicity of rare variants in the presence of reduced penetrance.https://doi.org/10.1371/journal.pone.0290336 |
| spellingShingle | Andrew D Paterson Sang-Cheol Seok Veronica J Vieland The effect of ascertainment on penetrance estimates for rare variants: Implications for establishing pathogenicity and for genetic counselling. PLoS ONE |
| title | The effect of ascertainment on penetrance estimates for rare variants: Implications for establishing pathogenicity and for genetic counselling. |
| title_full | The effect of ascertainment on penetrance estimates for rare variants: Implications for establishing pathogenicity and for genetic counselling. |
| title_fullStr | The effect of ascertainment on penetrance estimates for rare variants: Implications for establishing pathogenicity and for genetic counselling. |
| title_full_unstemmed | The effect of ascertainment on penetrance estimates for rare variants: Implications for establishing pathogenicity and for genetic counselling. |
| title_short | The effect of ascertainment on penetrance estimates for rare variants: Implications for establishing pathogenicity and for genetic counselling. |
| title_sort | effect of ascertainment on penetrance estimates for rare variants implications for establishing pathogenicity and for genetic counselling |
| url | https://doi.org/10.1371/journal.pone.0290336 |
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