Segregation with disease¶
Segregation filters¶
In order to pass this filter, a variant or group of variants must pass at least one of the segregation filters considered. The segregation filters that are considered and their groupings into modes of inheritance are listed below:
| Mode of inheritance | Segregation Filter |
|---|---|
| biallelic | SimpleRecessive CompoundHeterozygous UniparentalIsodisomy |
| monoallelic_not_imprinted | InheritedAutosomalDominant de novo |
| monoallelic_paternally_imprinted | InheritedAutosomalDominantPaternallyImprinted |
| monoallelic_maternally_imprinted | InheritedAutosomalDominantMaternallyImprinted |
| xlinked_biallelic | XLinkedSimpleRecessive XLinkedCompoundHeterozygous |
| xlinked_monoallelic | XLinkedMonoallelic de novo |
| mitochondrial | MitochondrialGenome |
All segregation filters are considered, i.e., there is no attempt to exclude any mode of inheritance based on the pattern of disease that is observed in the family’s pedigree.
In practice, for a gene with an autosomal recessive mode of inheritance, this means that where only one variant in a gene passes the tiering filters, the variant will not be tiered as it is not consistent with the mode of inheritance.
The segregation filters are described in greater detail below.
Intersection with high evidence gene on specified gene panel and matching curated mode of inheritance¶
In order to be prioritised as Tier 1, a variant must be located in a gene whose association with the disorder being considered has been curated as high evidence (‘green’ or diagnostic grade) in the PanelApp panel applied.
The variant must also pass a segregation filter that is consistent with the curated mode of inheritance in PanelApp for that gene-disease association.
The nomenclature for modes of inheritance differs between PanelApp and tiering. The table below details which Tiering mode of inheritance would be considered appropriate for the different PanelApp modes of inheritances.
| Tiering mode of inheritance | PanelApp modes of inheritance |
|---|---|
| biallelic | biallelic monoallelic_and_biallelic monoallelic_and_more_severe_biallelic not_provided unknown |
| monoallelic_not_imprinted | monoallelic_not_imprinted monoallelic monoallelic_and_biallelic monoallelic_and_more_severe_biallelic xlinked_biallelic xlinked_monoallelic mitochondrial not_provided unknown |
| monoallelic_paternally_imprinted | monoallelic_paternally_imprinted not_provided unknown |
| monoallelic_maternally_imprinted | monoallelic_maternally_imprinted not_provided unknown |
| xlinked_biallelic | xlinked_biallelic not_provided unknown |
| xlinked_monoallelic | xlinked_monoallelic not_provided unknown |
| mitochondrial | mitochondrial not_provided unknown |
| de novo | monoallelic_not_imprinted monoallelic monoallelic_and_biallelic monoallelic_and_more_severe_biallelic monoallelic_paternally_imprinted monoallelic_maternally_imprinted xlinked_biallelic xlinked_monoallelic mitochondrial not_provided unknown |
In PanelApp some panels are “superpanels”. This means that they contain a list of “subpanels” and they inherit all the gene-disease associations from all the panels in this list. In this situation it is possible that different subpanels may list the same gene with different modes of inheritance. In this situation, all applicable modes of inheritance are considered.
Segregation filters in action¶
To illustrate the principals of the segregation filters, an illustrative example is described below for a simple trio in a full penetrance analysis.
For each segregation filter, a number of individual filters are applied; variants are only tiered when all of these filters in each family member pass.
SimpleRecessive¶
| Single sample filters | Single sample selection | Family filter |
|---|---|---|
| Affected samples are not 'reference_homozygous' or 'heterozygous' NonAffected samples are not 'alternate_homozygous’ |
At least one affected sample is 'alternate_homozygous' | Father and mother cannot be 'reference_homozygous' |
UniparentalIsodisomy¶
| Single sample filters | Single sample selection | Family filter |
|---|---|---|
| Affected samples are not 'reference_homozygous' or 'heterozygous' NonAffected samples are not 'alternate_homozygous’ |
At least one affected sample is 'alternate_homozygous' | Father or mother (and only one of them) is 'reference_homozygous' |
CompoundHeterozygote¶
Info
This filter is not applied when Tiering is performed with the incomplete penetrance mode. Each pair of variants in the gene are taken together for the family filter
| Single sample filters | Single sample selection | Family filter1 | Special Filter |
|---|---|---|---|
| Affected samples are not 'reference_homozygous' NonAffected samples are not 'alternate_homozygous’ |
At least one affected is 'heterozygous', 'alternate_hemizygous' or 'alternate_homozygous' | Father and mother are not both reference homozygous for the same variant in the pair. | None of the NonAffected members of the family have the same combination of heterozygous or alternate homozygous variants for both variants included in the pair. |
XLinkedSimpleRecessive¶
| Single sample filters | Single sample selection | Family filter |
|---|---|---|
| Affected males are not 'reference_homozygous' or 'heterozygous' NonAffected females are not 'alternate_homozygous’ |
At least one affected sample is 'alternate_homozygous' | Mother must be 'heterozygous' (if mother is present), Father cannot be affected |
XLinkedCompoundHeterozygote¶
Info
This filter is not applied when Tiering is performed with the incomplete penetrance mode. Each pair of variants in the gene are taken together for the family filter.
| Single sample filters | Single sample selection | Family filter1 | Special Filter |
|---|---|---|---|
| Affected samples are not 'reference_homozygous' NonAffected samples are not 'alternate_homozygous’ |
At least one affected female 'heterozygous' or 'alternate_homozygous' | Father and mother are not both reference homozygous for the same variant in the pair. No parent is reference_homozygous for both variants in the pair. | None of the unaffected members of the family have the same combination of heterozygous or alternate homozygous variants for both variants included in the pair. |
Monoallelic segregation filters¶
InheritedAutosomalDominant¶
| Single sample filters | Single sample selection | Family filter |
|---|---|---|
| Affected samples are not 'reference_homozygous' NonAffected samples are not 'heterozygous' or 'alternate_homozygous’ |
At least one affected sample is 'alternate_homozygous' or 'heterozygous' | Father and mother cannot be 'reference_homozygous' |
InheritedAutosomalDominantPaternallyImprinted¶
Info
Variants on the X chromosome and the mitochondrial genome are not considered under this mode of inheritance.
| Single sample filters | Single sample selection | Family filter |
|---|---|---|
| Affected samples are not 'reference_homozygous' | At least one affected is 'alternate_homozygous' or 'heterozygous' | Father is not ‘alternate_homozygous', 'heterozygous', if both parents unaffected Father is not ‘alternate_homozygous', 'heterozygous’, if father affected Mother of unaffected participant (being unaffected 'heterozygous' or 'alternate_homozygous') is not 'alternate_homozygous', 'heterozygous', if both parents unaffected Mother of unaffected participant (being unaffected 'heterozygous' or 'alternate_homozygous’) is not 'alternate_homozygous', 'heterozygous', if mother is affected |
InheritedAutosomalDominantMaternallyImprinted¶
Info
Variants on the X chromosome and the mitochondrial genome are not considered under this mode of inheritance.
| Single sample filters | Single sample selection | Family filter |
|---|---|---|
| Affected samples are not 'reference_homozygous' | At least one affected is 'alternate_homozygous' or 'heterozygous' | Mother is not ‘alternate_homozygous', 'heterozygous', if both parents unaffected Mother is not ‘alternate_homozygous', 'heterozygous’, if mother affected Father of unaffected participant (being unaffected 'heterozygous' or 'alternate_homozygous') is not 'alternate_homozygous', 'heterozygous', if both parents unaffected Father of unaffected participant (being unaffected 'heterozygous' or 'alternate_homozygous’) is not 'alternate_homozygous', 'heterozygous', if father is affected |
XLinkedMonoallelicNotImprinted¶
| Single sample filters | Single sample selection | Family filter |
|---|---|---|
| Affected samples are not 'reference_homozygous' NonAffected females are not 'alternate_homozygous' NonAffected males are not 'alternate_homozygous' or 'heterozygous |
At least one affected sample is 'alternate_homozygous' or ‘heterozygous' | Both parents are not 'reference_homozygous' |
MitochondrialGenome¶
Info
The MitochondrialGenome Segregation Filter is only considered for variants in the mitochondrial genome.
| Single sample filters | Single sample selection |
|---|---|
| Affected samples are not 'reference_homozygous' | Allele fraction ≥0.05 in affected individuals |
deNovo¶
Info
The DeNovo Segregation Filter is considered independently of other segregation filers.
| SNVs | Indels |
|---|---|
| DQ value ≥0.0013 | DQ value ≥0.02 |
Note
Only de novo variants with quality (DQ) scores as indicated in the table above will be considered during the Genomics England variant tiering approach and displayed to users in the Interpretation Portal for further consideration. The DQ scores are not included in the displayed information to the user, but are present in the VCF file available for download.