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 or HOM call, and
    • no unaffected person has a HET or HOM call.

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 or HET call.
    • The unaffected parents of affected persons must not be REF or HOM.
    • There is no unaffected person that has a HOM call.

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 or NOCALL,
      • the person has no father or the father has calls HET or NOCALL,
      • the person has no mother or the mother has calls REF or NOCALL.

    • A variant is compatible regarding the maternal side if:

      • the person has calls HET or NOCALL,
      • the person has no mother or the mother has calls HET or NOCALL,
      • the person has no father or the father has calls REF or NOCALL.

    • 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 or HOM.
      • If the paternal list is not empty then the genotype of the person in the maternal list must not be REF or HOM.
      • 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 or HOM.
      • 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 or HOM.
      • 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.

  • 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 and mp and the second two genotypes be pm and mm.
      • In the case of pp == HET and mp == REF and pm == REF and mm == HET and the case of pp == REF and mp == HET and pm == HET and mm == REF, the candidate pairs incompatible and compatible otherwise.

Autosomal 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 a HET or a HOM 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 or HOM call or a affected female a HET call for this variant, * no affected person has a REF call, * no a affected female has a HOM call, and * no unaffected person has a HET or HOM call.

Autosomal 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 a 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 male has a HET or HOM call or a affected female a HOM call for this variant,

    • no affected person has a REF or no affected female person has a HET call.

    • For the parents of affected femals
      • the father must be affected and
      • the mother cannot have it REF or HOM
    • For the parents of affected males * the unaffected father cannot have the variant HET or HOM * the mother cannot be HOM
    • There is no unaffected person that has a HOM call.
    • There is no unaffected male person that has a HET call.

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 female HOM,
      • the person has no father or the father has calls HET, HOM, or NOCALL,
      • the person has no mother or the mother has calls REF or NOCALL.

    • A variant is compatible regarding the maternal side if:

      • the person has calls HET, NOCALL, or if not female HOM,
      • the person has no mother or the mother has calls HET or NOCALL, and
      • no restrcition to the father because he must be affected. See ckecks later.

    • 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 or HOM.
      • 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 female HOM.
      • 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 or HOM.
      • 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.

  • 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 a HET 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.