Compound Het Detection

A compound heterozygous polymorphism refers to a child that has inherited two different heterozygous polymorphisms within the same gene, one from each parent. This could result in both copies of the gene being potentially affected.

This type of polymorphism should also alter the amino acid sequence, or be classified as a non-synonymous variant.

Note

This algorithm runs on the variants in the selected Filter Chain and not all variants originally imported.

Requirements

This algorithm requires first annotating and classifying variants using a gene annotation source.

After clicking OK you will be prompted to select a Gene Names field to group variants into genes for the Compound Heterozygous analysis.

Optionally, you may select an Allele Frequency Field to allow one variant to reach 5% frequency while the other is strictly less than 1%. This option requires first annotating against a variant frequency database. If you do not want to include an allele frequency requirement, click Skip, otherwise, select the field and click OK.

Finally you have the choice of changing the default Advanced Parameters, which include:

  • Allow de Novo het mutations to be considered: When a gene contains at least one inherited het as well as a de Novo mutation, it will be considered a compound het gene.
  • Allow duos (one missing parent): If a proband is het and only has one parent specified, this option assumes the missing parents genotype is either reference or het, to be opposite the non-missing parent. While this includes sites where both parents may be heterozygous, it provides useful candidate compound het genes.

Output in the Variant Table

There are several groups of output fields created by this algorithm.

Group by Genes

Grouping of unique values from the selected Gene Names field from the specified annotation source.

Fields include:

  • Gene Names: The set of unique gene names seen in all overlapping transcripts.

Compound Het Variants for Proband

Per-variant compound heterozygous algorithm analysis.

Fields include:

  • Compound Het?: Whether or not this variant one of the two or more heterozygous genotypes in a gene following the Compound Heterozygous inheritance model.
  • Inherited From: Whether the variant was inherited from the Father or Mother, or de Novo (if the advanced option to consider de Novo was selected).

Compound Het Genes for Proband

Per-gene compound heterozygous algorithm analysis.

Fields include:

  • Has Compound Het?: Whether or not this gene has two or more heterozygous genotypes following the Compound Heterozygous inheritance model.
  • Inherited from Father: Number of heterozygous genotypes unambiguously inherited from the father.
  • Inherited from Mother: Number of heterozygous genotypes unambiguously inherited from the mother.
  • Inherited Total: Number of heterozygous genotypes unambiguously inherited from either the mother or father.
  • Hets in Both Parents: Number of heterozygous genotypes in the affected child and both parents. These are not counted toward a Compound Heterozygous model for a gene, but may be useful to rule out genes with a high level of background variation.
  • de Novo: Number of de Novo genotypes where both parents are reference. This field is only present if the option to consider de Novo mutations was selected.
  • Second Smallest Freq: If a frequency threshold was set to allow one of the two necessary compound heterozygous genotypes to be up to a more lenient threshold, this value is set to the larger of the two rarest variants that construct a compound heterozygous gene.

Output in the Gene Table

The Compound Heterozygous algorithm also creates a split table view with a gene table on the left and a corresponding variant table on the right. The fields in the gene table include:

Group by Genes

See Group by Genes.

Compound Het Genes for Proband

Clicking on a row in the Gene table will bring up a list of variants in the right variant table. The fields displayed in this table will be the same fields that are visible in the main Variant table.

See Compound Het Genes for Proband for information on the fields.

Output in the Filter Chain

A filter card is automatically created after the algorithm finishes running. This card is placed at the bottom of the filter chain, but can be moved by clicking and dragging the card to the desired location.

If moving the Compound Het card changes the input it will be necessary to rerun the algorithm. This will be indicated by an information icon on the filter card.