An article published in GenomeMedicine presents a novel method for genetic penetration estimation in autosomal dominant phenotypes using population-scale data. This can facilitate the characterisation of disease risks associated with rare variants.
]. For example, ALS and frontotemporal dementia each share a genetic basis, and considering a family history of frontotemporal dementia is reasonable when assessing familiality in a person with ALS. If the extended kinship is incorporated within familial disease state definitions, then the familial rate will trend upwards and inflate penetrance estimates. Using a wider definition of being affected is acceptable, although it will yield penetrance estimates for the joint condition.
A further caveat is that the model equations assume a particular family structure. It is not feasible to include all possible family configurations for large quantities of summary data however and approximations made are sufficiently close to provide an estimate of penetrance. This method is suitable for calculating the point, rather than age-dependent, penetrance of pathogenic variants and can be applied to any germline genetic variation associated with a disease via an autosomal dominant inheritance pattern. Penetrance can be derived for an individual variant or for an aggregated set of variants, with the latter indicating an averaged burden of variants meeting the given criteria.
When samples include only people harbouring the variant, the method assumes the stability of disease states among sampled families over time. This assumption is typical in case–control research designs, which expect that members of the control sample will not later become cases. However, in traits with age-dependent penetrance, estimates would be influenced by the age at time of sampling.
Reasonable lifetime penetrance estimates can however be obtained at earlier sampling times even in circumstances of age-dependent onset when disease state rates are calculated via weighted proportions of variant frequency estimates within those states sampled.
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