5. Dominant de Novo

Looking at the inheritance model container, the first filter logic is variants of Dominant de Novo inheritance. The Dominant de Novo filter logic is based on the Mendel Error, Gene Inheritance and the ACMG Auto Classification. The Mendel Error algorithm computes the Mendel Error status, i.e. Mendelian inheritance, for the child’s genotype and for this inheritance pattern, de Novo allele is selected. This filter indicates that the child’s genotype shows 152 de Novo mutations that are not present in either parent. This can also be understood by looking at the genotype zygosity for the proband, mother and father in the variant table. The proband has heterozygous calls whereas the parents are either homozygous-reference or missing.

de novo zygosity

Figure 5-1: Dominant de Novo zygosity in variant table.

The next filter card criteria is Gene Inheritance, which Dominant is selected. This filter logic is pulled from the ACMG Sample Classifier but is based on the known gene inheritance from OMIM, a licensed annotation. OMIM is an annotation that is already integrated into the project but if absent can be added by going to File>Add>Variant Annotation>Secure Annotations>OMIM. This filter results in 6 variants where the Gene Inheritance is Dominant. The last filter logic applied is the Auto Classification from the ACMG Sample Classifier, which utilizes the available variant evidence and scores it according to the ACMG guideline criteria. Together, this filter logic identified one Pathogenic de Novo mutation with a Dominant inheritance pattern.At the bottom of the Dominant de Novo filter container, clicking on the 1 in the filter logic will display the variant that has passed the filtering restrictions for this inheritance pattern in the variant table.

Dominant de novo

Figure 5-2: Inheritance filter container.

We can also visualize the genotype call in Genome Browse. To do this open the Genome Browse tab and click on the individual variant in your variant table and it will be displayed in the Genome Browse view. In Genome Browse you can see it is a heterozygous variant in the proband but missing in the mother and father.

Genome browse

Figure 5-3: Visualizing genotype calls in Genome Browse.

Next, we will take a look at the Dominant Inherited filter logic.