Variant Interpretation Pipeline - Inheritance Matcher

annotates VCF samples with denovo and possible compound flags and matching inheritance modes and genes.

Requirements

• Java 21

Input VCF file should contain single ALT alleles per line and be annotated VEP. Input should be annotated with VIP inheritance VEP plugin For full functionality.

Installation

Generate a personal access token in GitHub with at least the scope "read:packages".

Then add a settings.xml to your Maven .m2 folder, or edit it if you already have one. It should contain the following:

<?xml version="1.0"?>

<settings xsi:schemaLocation="http://maven.apache.org/SETTINGS/1.0.0 http://maven.apache.org/xsd/settings-1.0.0.xsd" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns="http://maven.apache.org/SETTINGS/1.0.0">
  <activeProfiles>
    <activeProfile>github</activeProfile>
  </activeProfiles>
  <profiles>
    <profile>
      <id>github</id>
      <repositories>
        <repository>
          <id>central</id>
          <url>https://repo1.maven.org/maven2</url>
          </repository>
          <repository>
            <id>github</id>
            <url>https://maven.pkg.github.com/molgenis/vip-utils</url>
            <snapshots>
              <enabled>true</enabled>
            </snapshots>
        </repository>
      </repositories>
    </profile>
  </profiles>

  <servers>
    <server>
      <id>github</id>
      <username>[YOUR VIP USERNAME]</username>
      <password>[YOUR PERSONAL ACCESS TOKEN]</password>
    </server>
   </servers>
</settings>

Added Sample information

##FORMAT=<ID=VI,Number=.,Type=String,Description="An enumeration of possible inheritance modes.">
##FORMAT=<ID=VIC,Number=1,Type=String,Description="List of possible compound hetrozygote variants.">
##FORMAT=<ID=VID,Number=1,Type=Integer,Description="Inheritance Denovo status.">
##FORMAT=<ID=VIG,Number=.,Type=String,Description="Genes with an inheritance match.">
##FORMAT=<ID=VIM,Number=1,Type=Integer,Description="Inheritance Match status.">
##FORMAT=<ID=VIS,Number=.,Type=String,Description="An enumeration of possible sub inheritance modes like e.g. compound, non penetrance.">

Usage

usage: java -jar vcf-inheritance-matcher.jar -i <arg> [-o <arg>] [-pd
       <arg>] [-pb <arg>] [-np <arg>] [-c] [-f] [-d]
 -i,--input <arg>            Input VCF file (.vcf or .vcf.gz).
 -o,--output <arg>           Output VCF file (.vcf or .vcf.gz).
 -pd,--pedigree <arg>        Comma-separated list of pedigree files
                             (.ped).
 -pb,--probands <arg>        Comma-separated list of proband individual
                             identifiers.
 -c,--classes <arg>   	     Comma-separated list of values in the INFO/CSQ VIPC subfield 
                             to be used in inheritance calculation. 
                             By default inheritance is calculated for all records.
 -f,--force                  Override the output file if it already
                             exists.
 -d,--debug                  Enable debug mode (additional logging).

Inheritance patterns

• AR: Autosomal recessive
• AD: Autosomal dominant
• XLR: X-linked recessive
• XLD: X-linked dominant
• YL: Y-linked
• MT: Mitochondrial
• AR_C: Autosomal recessive compound hetrozygote
• AD_IP: Autosomal dominant incomplete penetrance

Inheritance pattern rules

General rules

For inheritance matching all the members in a family are considered. This also means that all members in one family are assumed to be blood relatives to the proband(s). If a pedigree contains one or more members with an unknown affected status, then:

• Inheritance match becomes potential if it would be a match based on members with a known affected status
• The match stays false if it is false based on members with a known affected status For all patterns applies that a homozygote reference call for an affected family member means the pattern does not match. The list of supported contigs to determine if a variant is on X,Y,MT or an autosome can be found here

Autosomal Dominant

1. The variant is not on chromosome X,Y or MT.
2. Affected members need to have at least one alternative allele.
3. Unaffected members cannot have an alternative allele that was also the single alternative allele for any affected member

- Missing/partial genotypes:

4. If based on other members the pattern does not match the pattern match will stay false.
5. If based on other members the pattern does match:
   • If affected members have one missing allele and one alternative allele, the inheritance match will still be true.
   • If affected members have one missing allele and one reference allele, or both alleles are missing values, the inheritance match will be "potential".
   • If unaffected members have one missing allele and one alternative allele, the inheritance match will be false if so based on rule 3, and potential if rule 3 would lead to a match.
   • If unaffected members have one missing allele and one reference allele, or both alleles are missing values, the inheritance match will be "potential".

Autosomal Dominant incomplete penetrance

1. The variant is not on chromosome X,Y or MT.
2. Affected members need to have at least one alternative allele.
3. Unaffected members can have any genotype

- Missing/partial genotypes:

4. If based on other members the pattern does not match the pattern match will stay false.
5. If based on other members the pattern does match:
   • If affected members have one missing allele and one alternative allele, the inheritance match will still be true.
   • If affected members have one missing allele and one reference allele, or both alleles are missing values, the inheritance match will be "potential".

Autosomal Recessive

1. The variant is not on chromosome X,Y or MT.
2. Affected members need to have at least two alternative alleles.
3. Unaffected members cannot have a genotype of which both alleles are present in a affected member.

- Missing/partial genotypes:

4. If based on other members the pattern does not match the pattern match will stay false.
5. If based on other members the pattern does match:
   • If affected members have one missing allele and one alternative allele, or both alleles are missing values, the inheritance match will be potential.
   • If affected members have one missing allele and one reference allele, the inheritance match will be false.
   • If unaffected members have one missing allele and one alternative allele, or both alleles are missing values, the inheritance match will be potential.
   • If unaffected members have one missing allele and one reference allele, the inheritance match will be true.

Compound Autosomal Recessive

1. Two variant are present in the same gene for all affected members.
2. Both those variants are not matching the AR inheritance pattern.
3. The variants are not on chromosome X,Y or MT.
4. Affected members need to have at least one alternative allele in for both variants.
5. Unaffected members cannot have the same alternative alleles as an affected member for both variants, they can have the same alternative allele for one of the variants.

- Missing/partial genotypes:

6. If based on other members the pattern does not match the pattern match will stay false.
7. If based on other members the pattern does match:
   • If affected members have one missing allele or both alleles missing for one or both of the variants the pattern is a potential match.
   • If unaffected members have missing alleles in combination with an alternative allele, that has also been seen as a single alternative allele in genotypes of affected members, for both variants that this pattern does not match.
   • Other combinations of genotypes with missing alleles will lead to a "potential" match.

X-linked Dominant

1. The variant is on chromosome X.
2. Affected members need to have at least one alternative allele.
3. Unaffected members can only have an alternative allele that was also the single alternative allele for any affected member if the genotype is diploid (female), this is possible due to x inactivation.

- Missing/partial genotypes:

4. If based on other members the pattern does not match the pattern match will stay false.
5. If based on other members the pattern does match:
   • If affected members have one missing allele and one alternative allele, the pattern match will still be true.
   • If affected members have one missing allele and one reference allele, or the genotype (either haploid or diploid) is missing, the inheritance match will be "potential".
   • If unaffected members have one missing allele or the genotype (either haploid or diploid) is missing, the inheritance match will be "potential".

X-linked Recessive

1. The variant is on chromosome X.
2. Affected members cannot have a reference allele.
3. Unaffected members cannot have a genotype of which all alleles are present in a affected member.

- Missing/partial genotypes:

4. If based on other members the pattern does not match the pattern match will stay false.
5. If based on other members the pattern does match:
   • If affected members have one missing allele and one alternative allele, or the entire genotype is missing, the inheritance match will be potential.
   • If affected members have one missing allele and one reference allele, the pattern match will be false.
   • If unaffected members have one missing allele and one alternative allele, or the genotype (either haploid or diploid) is missing, the inheritance match will be potential.
   • If unaffected members have one missing allele and one reference allele, the pattern match will be true.

Y-linked

1. The variant is on chromosome Y.
2. Only genotypes of male family members are taken into account.
3. Affected members need to have an alternative allele.
4. Unaffected members cannot have an alternative allele that was also the alternative allele for any affected member.

- Missing/partial genotypes:

5. If based on other members the pattern does not match the result will stay false.
6. If based on other members the pattern does match:
   • If any members have a missing genotype the pattern match will be 'potential'.

Mitochondrial

1. The variant is on chromosome Y.
2. Affected members need to have an alternative allele.
3. Unaffected members cannot have an alternative allele that was also the alternative allele for any affected member.

- Missing/partial genotypes:

4. If based on other members the pattern does not match the result will stay false.
5. If based on other members the pattern does match:
   • If any members have a missing genotype the pattern match will be 'potential'.

Running without pedigree file

If the tool runs without a ped file, all probands are assumed to be affected. For variants on the X chromosome deploid genotypes are assumed to be female, single alleles are assumed to be male.

Running without VEP inheritance mode annotations

If the VEP inheritance mode annotation is missing the tool still calculates all possible inheritance modes. However, the actual matching on genes will obviously never yield a result.

Compatible Inheritance modes

The VIP inheritance plugin adds a whole range of inheritance modes, however for matching purposes we can only use a subset: AD,AR,XL,XLD,XLR.

Supported

OMIM Inheritance*	Annotation
X-LINKED DOMINANT	XD
X-LINKED RECESSIVE	XR
X-LINKED*	XL
AUTOSOMAL RECESSIVE	AR
AUTOSOMAL DOMINANT	AD
Y-LINKED	YL
MITOCHONDRIAL	MT
*: Please note that XL is matched by both XD and XR.

Unsupported

OMIM Inheritance*	Annotation
PSEUDOAUTOSOMAL RECESSIVE	PR
PSEUDOAUTOSOMAL DOMINANT	PD
ISOLATED CASES	IC
DIGENIC	DG
DIGENIC RECESSIVE	DGR
DIGENIC DOMINANT	DGD
MULTIFACTORIAL	MF
SOMATIC MUTATION	SM
SOMATIC MOSAICISM	SMM
INHERITED CHROMOSOMAL IMBALANCE	ICI