Penetrance modes

By default, Tiering is performed assuming complete penetrance and therefore any genotypes that are present in unaffected individuals would be excluded from Tiering.

Where incomplete penetrance analysis is selected, Tiering is performed first using the complete penetrance settings and then again under incomplete penetrance. If a tiered variant is annotated with a tier under the complete penetrance segregation filter, it will not also be tiered under an incomplete penetrance segregation filter.

In the incomplete penetrance analysis, genotypes must be present in all affected individuals but are not excluded if they are also present in unaffected individuals. Genotypes in unaffected individuals may still be used to check that genotype patterns are consistent with inheritance, e.g., for phasing of compound heterozygous variants.

Incomplete penetrance analysis does not currently consider the pattern of disease in the family’s pedigree. If a disease skips generations in the pedigree, then it may be possible to deduce that particular unaffected family members should have the disease genotype. The Tiering process does not currently perform this deduction.