Performing a family analysis

Comparison of genetic variation among family members is a powerful NGS filter. With Moon, you can perform family analyses on any family configuration you’d like.

1

Create new samples for each family member you want to include in the family analysis. For a trio analysis for example, you need to create three new samples (mother-father-index) and add a VCF file for each of these. Multiplex VCF files are not supported.

2

If you want to simultaneously perform SNV and SV analyses for the desired family configuration, make sure to upload SV VCF files for each of the family members you want to include. You can upload SV VCF files for existing samples, either the proband or healthy relatives, at the bottom of the corresponding Patient info screens.

3

Family information should be added to the Patient info of the index patient. This information will be taken into account for both the SNV and SV analyses.

  • Click Add Family Member
  • Enter the sample names of family members to include, or simply select the right sample from the list
  • Indicate whether the family member is affected/healthy
  • Select the family relation between the added family member and the index sample

When saving the Patient info, the patient icon on the Samples overview screen changes, to indicate that family relations were added to a specific sample.

4

Run the analysis for the index patient. For both SNVs and SVs, Moon will now take co-segregation of variants with the phenotype into account for selection of candidate variants. Moon takes into account all possible inheritance patterns:

  • Autosomal recessive (homozygous or compound heterozygous in the index patient)
  • Autosomal dominant (heterozygous in all affected members and absent from healthy members)
  • De novo (heterozygous in the index patient and absent from the healthy parents)
  • X-linked recessive (hemizygous, homozygous or compound heterozygous in the index patient)
  • X-linked dominant (hemizygous or heterozygous in index patient)

In addition to these pure Mendelian inheritance patterns, Moon also lists the most relevant candidate variants (SNVs or SVs) for the input phenotype that don't show a clearly Mendelian inheritance pattern (eg. a heterozygous variant also present in an unaffected parent). In this way, also candidate variants subject to incomplete penetrance, imprinting etc. will be identified, when performing a family analysis.

Segregation info is displayed in the variant cards for both SNVs and SVs. For variants with incomplete penetrance, additional annotation is shown in both the overview table and the variant card, indicating the lack of Mendelian co-segregation.

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