Penetrance modes

The penetrance mode is defined at the time of test ordering and the options of either complete or incomplete penetrance are available.

Penetrance overview

Under incomplete penetrance a variant or variant pair can still be eligible for tiering if it is present in an unaffected individual. The three tables below give a general overview of how the results from tiering may differ between complete and incomplete penetrance analysis for heterozygous variants in monoallelic genes and alternate homozygous or compound heterozygous variants in biallelic genes.

Monoallelic variants

Penetrance	Mode of inheritance	Scenario	Behaviour
Complete	Monoallelic	Heterozygous variant present in unaffected/uncertain individual	Variant not eligible for tiering
Incomplete	Monoallelic	Heterozygous variant present in unaffected/uncertain individual	Variant eligible for tiering

Alternate homozygous variants

Penetrance	Mode of inheritance	Scenario	Behaviour
Complete	Biallelic	Alternate homozygous variant present in unaffected/uncertain individual	Variant not eligible for tiering
Incomplete	Biallelic	Alternate homozygous variant present in unaffected/uncertain individual	Variant eligible for tiering

Compound heterozygous variants

Penetrance	Mode of inheritance	Scenario	Behaviour
Complete	Biallelic	Compound heterozygous variant pair present in unaffected/uncertain individual	Variant not eligible for tiering
Incomplete	Biallelic	Compound heterozygous variant pair present in unaffected/unaffected individual	Variant eligible for tiering

The details of complete and incomplete penetrance are further outlined below.

Complete penetrance

Under complete penetrance a pedigree with multiple affected individuals can have a dramatically reduced number of tiered variants. The Rare Disease pipeline does not currently support gene or allele heterogeneity. If parents or other family members, and proband have a similar phenotype, but it is uncertain if there is a shared genetic cause, we recommend setting non-proband's affection status in the test order form to ‘uncertain’ and running the case with incomplete penetrance.

Note

For individuals set to "uncertain" affection status it is preferable to add HPO terms. Although the HPO terms will not be used in tiering, the parental phenotype information helps Diagnostic Discovery and, subject to consent, research in the NGRL.

Incomplete penetrance

As described above, under incomplete penetrance, the presence of a variant or variant pair in an unaffected/uncertain individual does not exclude the variant from tiering. Genotypes in unaffected/uncertain individuals may still be used to check that genotype patterns are consistent with inheritance, e.g., for phasing of compound heterozygous variants.

Where incomplete penetrance analysis is selected, tiering is performed first using the complete penetrance settings and then again under incomplete penetrance.

Note

If a variant is tiered under complete penetrance it will not then be tiered with the exact same segregation filter under incomplete penetrance but may be tiered with incomplete penetrance under a different segregation filter - please see example scenarios below for further information.

Note

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.

Example scenarios

Four example scenarios are included below. The first scenario is included to demonstrate the interaction between penetrance and affected status in both monoallelic and biallelic scenarios. The second scenario demonstrates the reduction in tiered variants under complete penetrance when multiple individuals in the pedigree are assigned as affected. The third scenario demonstrates the behaviour of compound heterozygous variants under incomplete penetrance. The fourth scenario demonstrates that variants may be tiered with different segregation filters under different penetrance modes.

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’

Report Events are justifications (evidence) for why a variant is tiered in a particular group (e.g. Tier1/Tier2). In the scenarios included below we highlight the mode of inheritance (MOI), the penetrance and the applied segregation filter (see: Segregation filters) that is included in the Report Event.

Info

In the Rare Disease pipeline a Report Event is a justification for why a variant is tiered. Each variant may have several Report Events assigned to them. If, for example, a gene is green in multiple applied panels there will be a Report Event corresponding to each panel. If a variant is tiered under multiple segregation filters, there will be a Report Event for each segregation filter.

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	MOI: biallelic penetrance: complete segregation filter: SimpleRecessive MOI: monoallelic penetrance: incomplete segregation filter: InheritedAutosomalDominant

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 incomplete penetrance with the same SimpleRecessive segregation filter.

Scenario 2: complete penetrance

In this scenario a parent is assigned 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

The heterozygous status of the variant in the unaffected mother prevents the variant being tiered under a monoallelic mode of inheritance. The considerations for each mode of inheritance are described 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 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 (var 1) 0/1 (var 2)	0/1 (var 1) 0/0 (var 2)	0/0 (var 1) 0/1 (var 2)	MOI: biallelic penetrance: complete segregation filter: CompoundHeterozygote variants: var 1 & var 2 MOI: monoallelic penetrance: incomplete segregation filter: InheritedAutosomalDominant variants: var 1 & var 2

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.

Complete penetrance

Monoallelic Report Event

Neither variant will have a Report Event with a monoallelic mode of inheritance under complete penetrance as both variants are present in individuals with unaffected/uncertain status.

Biallelic Report Event

The variant pair will have a Report Event with a biallelic mode of inheritance under complete penetrance with a CompoundHeterozygote segregation filter as the variant pair is present in the only affected individual and the variant pair is not present in any unaffected / uncertain individual.

Incomplete penetrance

Monoallelic Report Event

Each variant will have a monoallelic Report Event under incomplete penetrance as each variant is present in all affected individuals.

Biallelic Report Event

The variant pair 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 incomplete penetrance with the same CompoundHeterozygote segregation filter.

Scenario 4: compound heterozygous and recessive

This scenario considers a compound heterozygous variant pair, where individual variants are present in both parents and are homozygous in the affected proband.

Proband (affected)	Mother (unaffected/uncertain)	Father (unaffected/uncertain)	Report Events
1/1 (var 1) 1/1 (var 2)	0/1 (var 1) 0/1 (var 2)	0/1 (var 1) 0/1 (var 2)	MOI: biallelic penetrance: complete segregation filter: SimpleRecessive variants: var 1 & var 2 MOI: biallelic penetrance: incomplete segregation filter: CompoundHeterozygote variants: var 1 & var 2 MOI: monoallelic penetrance: incomplete segregation filter: InheritedAutosomalDominant variants: var 1 & var 2

Each variant will have a biallelic Report Event under complete and incomplete penetrance and a monoallelic Report Event under incomplete penetrance. The logic underlying this is explained below.

Note

This example considers a scenario where a gene is assigned as both biallelic and monoallelic. Please note that the two biallelic Report Events would also occur if the gene was only assigned as biallelic.

Complete penetrance

Monoallelic Report Event

Neither variant will have a Report Event with a monoallelic mode of inheritance under complete penetrance as both variants are present in individuals with unaffected/uncertain status.

Biallelic Report Event

Each variant will have a Report Event with a biallelic mode of inheritance under complete penetrance with a SimpleRecessive segregation filter, as the variant is heterozygous in each uncertain/unaffected parent and homozygous in the affected proband.

Neither variant will have a Report Event with a biallelic mode of inheritance under complete penetrance with a CompoundHeterozygote segregation filter as both variant pairs are present in the uncertain/unaffected parents.

Incomplete penetrance

Monoallelic Report Event

Each 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

Each variant will have a Report Event with a biallelic mode of inheritance under incomplete penetrance with a CompoundHeterozygote segregation filter as both variant pairs are present in the uncertain/unaffected parents.

Neither variant will have a Report Event with a biallelic mode of inheritance under incomplete penetrance with a SimpleRecessive segregation filter as this has already been considered under complete penetrance.