Inheritance Searching

seqr implements a set of standard Mendelian inheritance methods to identify variants that segregate with a phenotype in a family. These filters are described in detail below, but first a few notes about these methods.

  • These methods rely on the affected status of individuals. Individuals with an Unknown phenotype will not be taken into consideration for genotype filters. If all individuals in a family are Unknown, they will simply return all variants.

  • All methods assume complete penetrance

  • seqr assumes unphased genotypes

Homozygous Recessive

Returns variants where all affected individuals have two copies of the same alternate allele at a specific postion (Alt/Alt genotype) and all unaffected individuals have at least one reference allele at this position.

Compound Heterozygous

A compound heterozygous genotype refers to two non-reference alleles each on different copies of the same gene, thus predicted to disrupt both copies of the gene.

This method finds any pairs of heterozygous variants in the same gene that are present in all affected individuals, but not in any unaffected individuals. Additionally, no affected individuals can be homozygous alternate for either of the variants.

Note that if parents are present, this method implicitly considers phasing. If not, it searches for pairs of heterozygous variants and cannot determine if they are on different copies of the gene.

In some cases multiple pairs of variants in a gene will meet the above criteria, meaning there is a chance more than two variants in a gene would be returned.

X-Linked Recessive

Variants will pass this filter if they are on the X chromosome, are homozygous alt in affected individuals, heterozygous in unaffected mothers, and homozygous reference in unaffected fathers.

Recessive

This method returns all variants passing the Homozygous Recessive, X-Linked Recessive, and Compound Heterozygous filtration parameters. The results do not distinguish which variants are the result of which sub-method, but this can be determined by patient genotype.

Dominant / De Novo

Finds variants where all affected individuals are heterozygous (or homozygous alternate) and all unaffected individuals are homozygous reference.