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.
Under complete penetrance, a variant is only tiered if it is present in all affected individuals and absent in any unaffected individuals. The Rare Disease pipeline does not currently support gene or allele heterogeneity. A pedigree with multiple affected individuals can have a dramatically reduced number of tiered variants. If parents and proband have a similar phenotype, but it is uncertain if there is a shared genetic cause, we recommend setting the parental status in the test order form to ‘uncertain’ and running the case with incomplete penetrance. HPO terms do not need to be altered for individuals set to ‘uncertain’ affection status.
Note
A variant can be prioritised with both complete and incomplete penetrance with different segregation filters.
A pair of variants that are heterozygous in both parents and homozygous in the proband will pass the SimpleRecessive
segregation filter with complete Penetrance and will pass theCompoundHeterozygote segregation filter with incomplete
penetrance. (see Segregation with disease)
Example scenarios¶
The scenarios below consider variant(s) that are:
- Below the monoallelic allele frequency threshold
- In a gene that is green in the applied panel
- In a gene that is assigned as ‘BOTH, monoallelic and biallelic’
Scenario 1: incomplete penetrance¶
In this scenario both parents are assigned as either unaffected or uncertain when the test is ordered and the case is run with 'incomplete penetrance'.
| Proband (affected) | Mother (unaffected/uncertain) | Father (unaffected/uncertain) | Report events |
|---|---|---|---|
| 1/1 | 0/1 | 0/1 | biallelic: complete penetrance monoallelic: incomplete penetrance |
When a case is run with 'incomplete penetrance', both 'complete penetrance' and 'incomplete penetrance' are considered. The variant, which is homozygous in the proband, will have a report event with a monoallelic mode of inheritance under complete penetrance and a report event with a biallelic mode of inheritance under incomplete penetrance.
The logic underlying this is explained below.
Complete penetrance¶
Monoallelic report event¶
This variant will not have a report event with a monoallelic mode of inheritance under complete penetrance as the variant is present in individuals with unaffected/uncertain status.
Biallelic report event¶
This variant will have a report event with a biallelic mode of inheritance under complete penetrance as the variant is heterozygous in each uncertain/unaffected parent and homozygous in the affected proband.
Incomplete penetrance¶
Monoallelic report event¶
This variant will have a report event with a monoallelic mode of inheritance under incomplete penetrance as the variant is not absent in any affected individuals.
Biallelic report event¶
This variant will not have a report event with a biallelic mode of inheritance under incomplete penetrance as it has already been tiered under complete penetrance and is therefore not considered under an incomplete penetrance segregation filter.
Scenario 2: complete penetrance¶
In this scenario a parent is given an 'affected' status and the case is run with complete penetrance.
| Proband (affected) | Mother (unaffected/uncertain) | Father (affected) | Report events |
|---|---|---|---|
| 1/1 | 0/1 | 0/1 | none |
Under complete penetrance a variant is only tiered if all affected individuals have the same genotype, this variant will therefore not be tiered.
Complete penetrance¶
Monoallelic report event¶
This variant will not have a report event with a monoallelic mode of inheritance under complete penetrance as the variant is present in individuals with unaffected/uncertain status.
Biallelic report event¶
This variant will not have a report event with a biallelic mode of inheritance under complete penetrance as the variant is not homozygous in all affected individuals.
Scenario 3: compound heterozygous¶
This scenario considers a compound heterozygous variant pair, where individual variants are present in one parent, but not both.
| Proband (affected) | Mother (unaffected/uncertain) | Father (unaffected/uncertain) | Report events |
|---|---|---|---|
| 0/1 (variant 1) 0/1 (variant 2) |
0/1 (variant 1) 0/0 (variant 2) |
0/0 (variant 1) 0/1 (variant 2) |
biallelic, complete penetrance (var 1 & var 2) monoallelic, incomplete penetrance (var 1 & var2) |
Both variants will be tiered as a compound heterozygous pair under complete penetrance. As with scenario 1 above, each variant will also be individually tiered with a monoallelic mode of inheritance with incomplete penetrance.