Mode Of Inheritance Filters¶
Jannovar includes functionality to filter variants for being compatible with a given pedigree and a mode of inheritance. These filters work well for single individuals and the common case of two parents and a number of children. However, there are limitations when using them for larger pedigrees. For such larger families, the filters lose specificity but not sensitivity. That is, they can fail to filter out less than theoretically possible, but they should not lose any data.
This section describes in detail the checks performed on the variant and pedigrees to give the user a clear understanding on the algorithms and limitations.
The filters are passed a pedigree and a list of VariantContext calls from the HTSJDK lib (which include Genotypes). The mode of inheritance is selected by the filter choice. Multiple modes are possible. The whole list of VariantContext calls (usually the variants falling onto one gene or transcripts) is then checked for compatibility with the given mode of inheritance(s) and pedigree.
The program rewrites the VariantContext Genotypes to own genotypes.
These own genotypes can either be NOCALL
(no genotype was determined for the person), REF
(homozygous wild-type), HET
(heterozygous alternative), or HOM
(homozygous alternative).
In general a caller calls a hemizygous mutations as homozygous. Therefore we use HOM
and for sensitivity HET
on known males as hemizygous. The persons can either be affected, unaffected, or their affection state is unknown.
Autosomal Dominant Filter¶
This filter can be used to filter for de novo mutations as well.
If the pedigree only contains one person then the variant call list must contain one
HET
call.If there is more than one person in the pedigree then there must be at least one compatible call, meaning:
- at least one affected person has a
HET
call for this variant, - no affected person has a
REF
orHOM
call, and - no unaffected person has a
HET
orHOM
call.
- at least one affected person has a
Autosomal Recessive Filter¶
The filter first checks for compatibility with autosomal recessive (AR) homozygous and then AR compound heterozygous mode of inheritance.
For AR homozygous, the following checks are performed.
If the pedigree only contains one person then the variant call list must contain one
HOM
call.If there is more than one person in the pedigree then there must be at least one compatible variant call in the list. For this, the following must be true for one variant in the list:
- at least one affected person has a
HOM
call for this variant and - no affected person has a
REF
orHET
call. - The unaffected parents of affected persons must not be
REF
orHOM
. - There is no unaffected person that has a
HOM
call.
- at least one affected person has a
For AR compound heterozygous, the following checks are performed.
If the pedigree only contains one person then there must be at least two
HET
entries in the variant list.If there is more than one person in the pedigree then the algorithm first enumerates candidate pairs of variants. The pairs are enumerated for all affected persons that have a father, a mother, or both in the pedigree.
The first entry in the pair is compatible with inheritance from the maternal side and the second entry in the pair is compatible from the paternal side.
A variant is compatible regarding the paternal side if:
- the person has calls
HET
orNOCALL
, - the person has no father or the father has calls
HET
orNOCALL
, - the person has no mother or the mother has calls
REF
orNOCALL
.
- the person has calls
A variant is compatible regarding the maternal side if:
- the person has calls
HET
orNOCALL
, - the person has no mother or the mother has calls
HET
orNOCALL
, - the person has no father or the father has calls
REF
orNOCALL
.
- the person has calls
Further, no candidate pair may contain the same call for both the maternal and the paternal side, and
there must be at least one call for the person, mother, or father that is not
NOCALL
.
Each candidate pair is then check for compatibility with affected persons. The following is performed as described below and also with a role swap of the paternal and maternal variant call list.
- For each affected person, the maternal and paternal variant call list is performed for compatibility. For this, each of the following must be checked:
- If the maternal list is not empty then the genotype of the person in the paternal list must not be
REF
orHOM
. - If the paternal list is not empty then the genotype of the person in the maternal list must not be
REF
orHOM
. - If the paternal list is not empty and the person has a father then the father’s genotype in the paternal list must not be
REF
orHOM
. - If the maternal list is not empty and the person has a mother then the mother’s genotype in the maternal list must not be
REF
orHOM
. - None of the affected person’s unaffected siblings must be both
HET
in the paternal or maternal list. - Every affected siblings of an afffected person must have
HET
in the paternal or maternal list.
- If the maternal list is not empty then the genotype of the person in the paternal list must not be
- For each affected person, the maternal and paternal variant call list is performed for compatibility. For this, each of the following must be checked:
Finally, we check every unaffected person in the pedigree.
- For each unaffected person in the pedigree, neither the maternal nor the paternal call list from the candidate can contain a
HOM
call for the unaffected person. - If the call for the unaffected persons is
HET
in both the paternal and the maternal call list. Then, the father’s and mother’s genotype are checked in the maternal call list of the candidate their genotypes in the paternal call list are considered.- Let the first two genotypes be
pp
andmp
and the second two genotypes bepm
andmm
. - In the case of
pp == HET and mp == REF and pm == REF and mm == HET
and the case ofpp == REF and mp == HET and pm == HET and mm == REF
, the candidate pairs incompatible and compatible otherwise.
- Let the first two genotypes be
- For each unaffected person in the pedigree, neither the maternal nor the paternal call list from the candidate can contain a
X-Dominant Filter¶
- First of all variants must be X-Chromosomal.
- If the pedigree only contains one person then we decide if * the person is female then the variant call list must contain one
HET
call. * else the variant call list must contain aHET
or aHOM
call.- If there is more than one person in the pedigree then there must be at least one compatible call, meaning: * at least one affected male has a
HET
orHOM
call or a affected female aHET
call for this variant, * no affected person has aREF
call, * no a affected female has aHOM
call, and * no unaffected person has aHET
orHOM
call.
X-Recessive Filter¶
The filter first checks for compatibility with X-chromosomal recessive (XR) homozygous and then XR compound heterozygous mode of inheritance. XR is different to the AR filter, because affected males are always hemizygous (homozygous for the callers). So males do not have compund heterozygous variants.
For XR homozygous, the following checks are performed.
First of all variants must be X-Chromosomal.
- If the pedigree only contains one person then we decide if
- the person is female then the variant call list must contain one
HOM
call, - else the variant call list must contain a
HET
or aHOM
call.
- the person is female then the variant call list must contain one
If there is more than one person in the pedigree then there must be at least one compatible variant call in the list. For this, the following must be true for one variant in the list:
- at least one affected male has a
HET
orHOM
call or a affected female aHOM
call for this variant, - no affected person has a
REF
or no affected female person has aHET
call. - For the parents of affected femals
- the father must be affected and
- the mother cannot have it
REF
orHOM
- For the parents of affected males
* the unaffected father cannot have the variant
HET
orHOM
* the mother cannot beHOM
- There is no unaffected person that has a
HOM
call. - There is no unaffected male person that has a
HET
call.
- at least one affected male has a
For XR compound heterozygous, the following checks are performed.
First of all variants must be X-Chromosomal.
- If the pedigree only contains one person then we decide if
- the person male we do not allow any call. Please use the XR filter.
- else we use the AR compound heterozygous filter.
If there is more than one person in the pedigree then the algorithm first enumerates candidate pairs of variants. The pairs are enumerated for all affected persons that have a father, a mother, or both in the pedigree.
The first entry in the pair is compatible with inheritance from the maternal side and the second entry in the pair is compatible from the paternal side.
A variant is compatible regarding the paternal side if:
- the person has calls
HET
,NOCALL
, or if not femaleHOM
, - the person has no father or the father has calls
HET
,HOM
, orNOCALL
, - the person has no mother or the mother has calls
REF
orNOCALL
.
- the person has calls
A variant is compatible regarding the maternal side if:
- the person has calls
HET
,NOCALL
, or if not femaleHOM
, - the person has no mother or the mother has calls
HET
orNOCALL
, and - no restrcition to the father because he must be affected. See ckecks later.
- the person has calls
Further, no candidate pair may contain the same call for both the maternal and the paternal side, and
there must be at least one call for the person, mother, or father that is not
NOCALL
.
Each candidate pair is then check for compatibility with affected persons. The following is performed as described below and also with a role swap of the paternal and maternal variant call list.
- For each affected person, the maternal and paternal variant call list is performed for compatibility. For this, each of the following must be checked:
- If the maternal list is not empty then the genotype of a female person in the paternal list must not be
REF
orHOM
. - If the paternal list is not empty then the genotype of the person in the paternal list must not be
REF
or in case of a femaleHOM
. - If the paternal list is not empty and the person has a father then the father’s genotype in the paternal list must not be
REF
. - If the maternal list is not empty and the person has a mother then the mother’s genotype in the maternal list must not be
REF
orHOM
. - None of the affected person’s unaffected siblings must be both
HET
in the paternal or maternal list. - Every affected siblings of an afffected person must have
HET
in the paternal or maternal list.
- If the maternal list is not empty then the genotype of a female person in the paternal list must not be
- For each affected person, the maternal and paternal variant call list is performed for compatibility. For this, each of the following must be checked:
Finally, we check every unaffected person in the pedigree.
- For each unaffected person in the pedigree, neither the maternal nor the paternal call list from the candidate can contain a
HOM
or for males also aHET
call for the unaffected person. - If the call for the unaffected persons is
HET
in both the paternal and the maternal call list. Then, the father’s and mother’s genotype are checked in the maternal call list of the candidate their genotypes in the paternal call list are considered.
Mitochondrial Filter
- For each unaffected person in the pedigree, neither the maternal nor the paternal call list from the candidate can contain a
Jannovar’s filter therefore uses the following rules.
- Males and females can be affected by mitochrondial mutations, and so if there is any call from a variant on the mitochondrion, a singleton sample is compatible with mitochondrial inheritance.
- For analyses of mulitple family members, Jannovar calls a variant as compatible with mitochondrial inheritance if all affecteds have the mutation and if the mutation was transmitted by the mother. If an affected person is homozygous reference, then mitochondrial inheritance is ruled out. At least one affected must be called heterozygous or homozygous ALT. Jannovar has no requirement for a certain genotype because current variant callers do not reliably report levels of heteroplasmy.