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Inheritance Pattern Analysis

Variant-Linker provides powerful inheritance pattern analysis capabilities, helping researchers identify variants that follow expected inheritance patterns in family studies.

Overview​

The inheritance analysis module automatically examines genotype data and family relationships to deduce potential inheritance patterns for variants. This feature is essential for:

  • Clinical Genetics: Identifying causative variants in family studies
  • Research: Filtering variants based on inheritance expectations
  • Variant Prioritization: Ranking variants by inheritance pattern compatibility
  • Quality Control: Validating family relationships and genotype data

Supported Inheritance Patterns​

De Novo Variants​

Variants present in the child but absent in both parents:

  • Indicates potential new mutations
  • High priority for disease causation studies
  • Requires trio or extended family data

Autosomal Dominant (AD)​

Heterozygous variants that segregate with affected status:

  • One copy of variant causes phenotype
  • Affected individuals typically have one affected parent
  • 50% transmission rate to offspring

Autosomal Recessive (AR)​

Homozygous variants in affected individuals with carrier parents:

  • Two copies required for phenotype
  • Parents typically unaffected carriers
  • 25% transmission rate for affected offspring from carrier parents

X-linked Dominant (XLD)​

Variants on X chromosome following dominant inheritance:

  • Affects both males and females
  • Affected males pass trait to all daughters
  • Affected females have 50% transmission rate

X-linked Recessive (XLR)​

Variants on X chromosome following recessive inheritance:

  • Primarily affects males
  • Carrier mothers transmit to 50% of sons
  • Affected fathers pass carrier status to all daughters

Compound Heterozygous​

Two different variants in the same gene that together cause recessive phenotype:

  • Each variant inherited from different parents
  • Gene-level analysis required
  • Both variants must affect gene function

Analysis Modes​

Single Sample Mode​

When only one sample is present in the VCF file:

  • Limited inheritance pattern analysis
  • Focuses on variant annotation and basic pattern possibilities
  • Cannot determine de novo status or segregation

Trio Mode​

When parent-child trio is available:

  • Full de novo analysis
  • Basic dominant/recessive pattern assessment
  • Optimal for most clinical applications

Trio specification methods:

# Using PED file
variant-linker --vcf-input trio.vcf --ped trio.ped --calculate-inheritance

# Manual specification (Index, Mother, Father)
variant-linker --vcf-input trio.vcf --sample-map "PROBAND,MOTHER,FATHER" --calculate-inheritance

Extended Family Mode​

When comprehensive family structure is provided via PED file:

  • Multi-generational inheritance analysis
  • Complex pattern recognition
  • Compound heterozygous detection
  • Inheritance pattern validation across generations
# Extended family analysis
variant-linker --vcf-input extended_family.vcf --ped extended_family.ped --calculate-inheritance

Usage Examples​

Basic Trio Analysis​

# Simple trio analysis
variant-linker \
  --vcf-input family_trio.vcf \
  --ped trio.ped \
  --calculate-inheritance \
  --output JSON \
  --save trio_results.json

Extended Family Study​

# Multi-generational family analysis
variant-linker \
  --vcf-input large_family.vcf \
  --ped large_family.ped \
  --calculate-inheritance \
  --output VCF \
  --save annotated_with_inheritance.vcf

Compound Heterozygous Analysis​

# Gene-level compound heterozygous detection
variant-linker \
  --vcf-input family.vcf \
  --ped family.ped \
  --calculate-inheritance \
  --vep_params "CADD=1,SIFT=1,PolyPhen=1" \
  --output CSV \
  --save compound_het_analysis.csv

Output Format​

Inheritance Analysis Results​

When inheritance analysis is enabled, each variant annotation includes a deducedInheritancePattern object:

{
  "deducedInheritancePattern": {
    "patterns": ["autosomal_recessive", "compound_heterozygous"],
    "confidence": "high",
    "patternDetails": {
      "segregationStatus": "consistent",
      "affectedCarriers": 2,
      "unaffectedCarriers": 0,
      "genotypeCounts": {
        "homozygous_ref": 2,
        "heterozygous": 4,
        "homozygous_alt": 1
      }
    }
  }
}

Pattern Fields​

  • patterns: Array of possible inheritance patterns
  • confidence: Confidence level (high, medium, low)
  • patternDetails: Additional analysis information
  • segregationStatus: Whether variant segregates with phenotype
  • genotypeCounts: Genotype distribution in family

Confidence Levels​

High Confidence

  • Clear segregation pattern
  • Sufficient family members
  • Consistent with single inheritance mode

Medium Confidence

  • Some evidence for pattern
  • Limited family size or incomplete data
  • Multiple possible patterns

Low Confidence

  • Insufficient data for pattern determination
  • Conflicting evidence
  • Complex inheritance not clearly resolved

Algorithm Details​

Pattern Detection Logic​

  1. Genotype Extraction: Extract genotypes for all family members
  2. Relationship Mapping: Map family relationships from PED data
  3. Segregation Analysis: Analyze variant transmission patterns
  4. Pattern Matching: Compare observed patterns to expected inheritance models
  5. Confidence Assessment: Evaluate strength of evidence for each pattern

De Novo Detection​

De novo variants are identified when:

  • Child has variant (heterozygous or homozygous)
  • Both parents lack the variant (homozygous reference)
  • High-quality genotype calls for all family members
  • No evidence of sample mix-up or technical errors

Compound Heterozygous Detection​

Compound heterozygous variants are identified by:

  1. Gene-level Analysis: Group variants by affected gene
  2. Phase Analysis: Determine if variants are on different chromosomes
  3. Parent-of-Origin: Verify variants inherited from different parents
  4. Functional Impact: Both variants must potentially affect gene function

Quality Control​

The analysis includes several quality control measures:

  • Genotype Quality Filtering: Remove low-quality genotype calls
  • Mendelian Error Detection: Identify inconsistent inheritance
  • Sample Relationship Validation: Verify expected family relationships
  • Technical Artifact Filtering: Remove likely technical errors

Limitations and Considerations​

Technical Limitations​

  • Incomplete Penetrance: Not explicitly modeled in current version
  • Genomic Imprinting: Parent-of-origin effects not fully considered
  • Structural Variants: Limited support for complex structural variations
  • Mosaic Variants: Low-level mosaicism may not be detected

Data Requirements​

  • High-Quality Genotypes: Reliable genotype calls essential
  • Complete Pedigree: Missing family members reduce analysis power
  • Accurate Phenotyping: Affected status must be correctly assigned
  • Consistent Sample Naming: Sample IDs must match between VCF and PED files

Interpretation Guidelines​

  1. Multiple Patterns: Variants may show evidence for multiple inheritance patterns
  2. Confidence Levels: Consider confidence when interpreting results
  3. Functional Validation: Inheritance pattern alone insufficient for causality
  4. Clinical Context: Integrate with clinical and functional evidence

Advanced Features​

Custom Pattern Definitions​

Future versions will support custom inheritance pattern definitions for:

  • Disease-specific inheritance models
  • Population-specific patterns
  • Complex multi-gene interactions

Integration with Functional Annotation​

Inheritance analysis integrates with functional annotation to prioritize variants:

  • Functional Impact: Consider variant consequence severity
  • Gene Constraint: Integrate gene constraint metrics
  • Pathogenicity Scores: Weight by computational pathogenicity predictions

Troubleshooting​

Common Issues​

No Inheritance Patterns Detected

  • Check sample naming consistency between VCF and PED files
  • Verify family relationships in PED file
  • Ensure genotype quality is sufficient

Inconsistent Patterns

  • Review phenotype assignments in PED file
  • Check for sample mix-ups or labeling errors
  • Consider incomplete penetrance or variable expressivity

Low Confidence Results

  • Increase family size if possible
  • Improve genotype quality through better sequencing
  • Validate relationships with independent methods

Debug Mode​

Use debug mode to troubleshoot inheritance analysis:

variant-linker \
  --vcf-input family.vcf \
  --ped family.ped \
  --calculate-inheritance \
  --debug 3 \
  --output JSON

Debug output includes:

  • Genotype extraction details
  • Family relationship parsing
  • Pattern matching logic
  • Confidence calculation steps

Best Practices​

Study Design​

  1. Family Selection: Choose informative family structures
  2. Sample Quality: Ensure high-quality DNA and sequencing
  3. Phenotype Definition: Use consistent, well-defined phenotypes
  4. Control Samples: Include unaffected family members when possible

Data Processing​

  1. Genotype Filtering: Apply appropriate quality filters
  2. Variant Normalization: Ensure consistent variant representation
  3. Reference Consistency: Use consistent reference genome versions
  4. Sample Validation: Verify sample identity and relationships

Result Interpretation​

  1. Multiple Lines of Evidence: Combine inheritance with functional data
  2. Population Frequencies: Consider variant frequencies in relevant populations
  3. Clinical Context: Integrate with clinical presentation and history
  4. Functional Validation: Confirm causality through functional studies

Next Steps​