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 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.

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Copyright: © 2023 Paterson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Salary support to VJV and SCS came via a subcontract to Mathematical Medicine from the NIH grant (NS085238). This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.