Genetic Inheritance Patterns

Genetic Models

The following sections describe what rules that apply for the different genetic models.

By default genmod will annotate a variant that a inheritance pattern is followed if it is not contradicted in the data. So for example if a sick proband is 0/1and one healthy parent is 0/0and the other healthy parent is ./. the Autosomal Dominant inheritance pattern is followed, since there is nothing in the data that contradicts the model. There is a flag in genmod named --strict. When used each model has to be 'prooved' in the data. So in the above example the proband would not be annotated as Autosomal Dominant. More of that under each model.

Short explanation of genotype calls in VCF format##

Genetic inheritance models will only be correctly annotated for diploid (human) species, the genotypes represent what we see on both alleles in a single position. 0 represents the reference sequence, 1 is the first of the alternative alleles, 2 second alternative and so on. If no phasing has been done the genotype is an unordered pair on the form x/x, so 0/1 means that the individual is heterozygote at the given position with the reference base on one of the alleles and the first of the alternatives on the other. 2/2 means that we see the second of the alternatives on both alleles. Some chromosomes are only present in one copy in humans, here it is allowed to only use a single digit to show the genotype. A 0 would mean reference and 1 first of alternatives.

If phasing has been done the pairs are not unordered anymore and the delimiter is then changed to '|', so one can be heterozygote in two ways; 0|1 or 1|0. In this case we say that the variant is phased.

Conditions for Genetic Models

Autosomal Recessive

For this model individuals can be carriers so healthy individuals can be heterozygous. Both alleles need to have the variant for an individual to be sick so a healthy individual can not be homozygous alternative and a sick individual has to be homozygous alternative. If the pattern is followed the variant will be annotated with AR_hom. The variant will be annotated with AR_hom_dn if the pattern is followed and one of the parents are 0/0.

A variant is following the AR_hom pattern if:

• Healthy individual:

  • Can not be homozygote alternative.
  • If no call we can not exclude AR

• if --strict:

  • Have to be homozygote reference or heterozygote.
  • No call will induce that the model is not followed

• Affected individual:

  • Have to be homozygote alternative.
  • If no call we can not exclude AR

• if --strict:

  • Have to be homozygote alternative
  • No call will return false

Autosomal Dominant

If the Autosomal Dominant pattern is followed the variant will be annotated with AD.

A variant is following the dominant patttern if:

• Healthy:

  • Can not have the variant in any form.
  • If no call we can not exclude dominant.

• if --strict:

  • Have to be homozygote reference
  • No call will return false

• Affected:

  • Has to be heterozygote for this position.
  • If no call we can not exclude dominant.

• if --strict:

  • Have to be heterozygote
  • No call will return false

• No affection status:

  • We can not tell if variant follows the model or not.

Autosomal Compound Heterozygote

This model includes pairs of exonic variants that are present within the same gene. The default behaviour of genmod is to look for compounds only in exonic/canonical splice sites. The reason for this is that since some genes have huge intronic regions the data will be drowned in compound pairs. If the user wants all variants in genes checked use the flag -gene/--whole_gene. If the pattern is followed for a variant it will be annotated with AR_comp.

1. Non-phased data:

   • Affected individuals have to be het. for both variants
   • Healthy individuals can be het. for one of the variants but cannot have both variants
   • Variant is considered de novo if only one or no variant is found in the parents

2. Phased data:

   • All affected individuals have to be het. for both variants and the variants has to be on two different alleles
   • Healthy individuals can be heterozygous for one but cannot have both variants
   • If only one or no variant is found in parents it is considered de novo

X-Linked Dominant###

These traits are inherited on the x-chromosome, of which men have one allele and women have two. If the pattern is followed the variant will be annotated with XD.

A variant is following the XD pattern if:

• Healthy:

  • Can not be homozygote alternative
  • Healthy females can be heterozygotes. This is possible since there are several documented diseases where only one allele at a time is expressed during development.
  • If no call we can not exclude XR -if strict:
  • Have to be homozygote reference (or heterozygote womens).
  • No call will return False

• Affected:

  • Have to be heterozygote.
  • If no call we can not exclude AR

• if strict:

  • Have to be heterozygote or homozygote(for males)
  • No call will return false

• No affection status:

  • We can not tell if variant follows the model or not.

X Linked Recessive

If the pattern is followed the variant will be annotated with XR.

A variant is following the XR pattern if:

• Healthy:

  • Can not be homozygote alternative
  • If no call we can not exclude XR
  • Males can not have variant at all. This is added since sometimes males get called as heterozygotes even though they only have one copy of the X chromosome.

• if strict:

  • Have to be homozygote reference(if male) or heterozygote(if female).
  • No call will return False

• Affected:

  • Have to be homozygote alternative(or heterozygote if male).
  • If no call we can not exclude AR

• if strict:

  • Have to be homozygote alternative(or heterozygote if male)
  • No call will return false

• No affection status:

  • We can not tell if variant follows the model or not.