Clinical filtering for trios

Find candidate diagnostic variants in affected children that might contribute to their disorder. We load VCF files (either named on the command line, or listed in a PED file) for members of a family, filter for rare, functionally disruptive variants, and assess whether each variant might affect the child's disorder. We take into account the parents genotypes (if available) and whether the parents are also affected with a (the?) disorder. For variants in known disease causative genes we check whether the inheritance patterns matches one expected for the inheritance models of the gene.

VCF requirements

The code expects VCFs as version 4.2. Many INFO entries need to take multiple alleles, and/or multiple genes into account. Multi-allelic variants expect comma-separated entries for many fields, such as in the HGNC field e.g 'GENE1,GENE1' for a multi-allelic variant where both alleles affect the gene 'GENE1'. Multi-genic variants similarly expect '|' separated entries for the multiple genes e.g. 'GENE1|GENE2' for a variant that occurs in both 'GENE1' and 'GENE2'.

Consequence strings come from VEP, and are expected in the CQ entry in the INFO. De novo mutations need a PP_DNM (posterior probability of de novo mutation, estimated by denovogear) entry in the FORMAT. By default, we screen for de novos with PP_DNM > 0.9.

Install

pip install git+git://github.com/jeremymcrae/clinical-filter.git --user

# Alternatively:
git clone https://github.com/jeremymcrae/clinical-filter.git
cd clinical-filter
python setup.py install --user

Usage

For running the filtering, the basic command is either with a ped file specified, i.e.

python clinical_filter.py \
  --ped PED_PATH

Or the individual VCF files for a trio can be specified, i.e.

python clinical_filter.py \
  --child CHILD_VCF_PATH \
  --mother MOTHER_VCF_PATH \
  --father FATHER_VCF_PATH \
  --gender M \ #M|F
  --mom-aff MOM_AFFECTED_STATUS (1=unaffected or 2=affected) \
  --dad-aff DAD_AFFECTED_STATUS (1=unaffected or 2=affected)

The ped option is the easiest if you have a large number of trios to process, so you can define all the families and their VCF paths in the ped file, and run with that.

Other options are:

• --syndrome-regions SYNDROMES_PATH # path to file listing DECIPHER regions
• --known-genes KNOWN_GENES_PATH # to specify the DDG2P database file
• --known-genes-date 2014-01-01 # to specify the version of the known genes file
• --alternate-ids ALTERNATE_IDS_PATH # path to file for mapping individuals between IDs used in the PED file, to alternate study IDs.
• --output OUTPUT_PATH # to specify that you want tab-separated output written to the given path
• --export-vcf OUTPUT_VCF_PATH # to specify you want a filtered VCF, can give a directory (when analysing multiple individuals), or give a file path
• --maf-populations POP1_AF,POP2_AF # to specify populations with MAF values within the INFO field of variants.

The output options can be omitted, or used together, whichever you need.