At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance is not uncommon indeed, there are many known examples of ‘disease-causing mutations’ that fail to cause disease in at least a proportion of the individuals who carry them. Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as ‘reduced (or incomplete) penetrance’.
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