Documentation / Family Analysis / Compound Heterozygous Variants

Compound Heterozygous Variant Analysis in Trios

A compound heterozygous candidate contains two heterozygous variants in the same gene. In a recessive disorder, the pair is most informative when the variants occur on different parental chromosomes, with one inherited from each parent.

Folklore identifies candidate pairs and records the available phasing evidence. A paired result does not establish that both variants are clinically significant and does not by itself establish a molecular diagnosis.

Current Production Scope

The production workflow phases variants from a complete proband-mother-father trio. Parental genotypes are read from the normalized joint call set, where each parent has an explicit genotype or no-call at every evaluated site.

Candidate Selection

The detector begins with proband variants that are heterozygous, mapped to a gene, and assigned an included molecular consequence. Intronic, upstream, downstream, and synonymous variants are excluded from the initial candidate set.

Missense variants.

Stop-gained and stop-lost variants.

Frameshift variants.

In-frame insertions and deletions.

Splice donor, splice acceptor, and splice-region variants.

Start-lost and initiator-codon variants.

Pair Formation Within Each Gene

Genes with at least two candidate variants are evaluated by pairing each retained variant with every other retained variant in that gene. The detector evaluates each unordered pair once and writes the result back symmetrically to both variants.

To keep pair growth bounded in very large genes, the workflow applies a configurable per-gene candidate limit after consequence filtering and records when that guard is used. Reviewers should consider this limit when a gene contains an unusually large number of potentially relevant variants.

Parental-Origin States

Phase State	Confidence	Meaning	Handling
Trio phased	High	One variant is inherited from the mother and the other from the father, with an explicit reference genotype on the opposite parental side for each site.	The pair is supported as being in trans and is retained for clinical review.
Cis detected	Excluded	Both variants are inherited from the same parent, or a homozygous-alternate parental state prevents a valid trans interpretation.	The pair is not treated as a compound heterozygous candidate.
Cis ambiguous	Low	The parental genotypes do not distinguish a trans configuration from a same-haplotype configuration.	The pair remains visible with unresolved phase.
Parental coverage gap	Low	At least one parental genotype required for phasing is a no-call.	The pair cannot be phased confidently from the available trio data.
Parental genotypes missing	Low	All four parental genotype observations needed for the pair are no-calls.	No parental-origin conclusion is made.

What Counts as an In-Trans Pair

A high-confidence pair requires reciprocal parental transmission. For one variant, the mother is heterozygous and the father is reference. For the partner variant, the father is heterozygous and the mother is reference, or the same pattern occurs in the opposite order.

A homozygous-alternate genotype in either parent excludes a high-confidence trans interpretation. That parent would transmit the alternate allele to every child, which does not represent the required one-allele-from-each-parent pattern.

Multiple Candidate Partners

One variant can form candidate pairs with more than one variant in the same gene. Folklore records a primary partner and separately marks that additional partners exist.

Reviewers should inspect all relevant partners when the multiple-partner flag is present rather than treating the primary partner as the only possible pair.

Clinical-Grade Reporting Subset

The reporting overlay counts a pair only when both variants are high-confidence, have a non-null partner relationship, pass the configured proband filter status, satisfy the population-frequency ceiling, and have HIGH or MODERATE impact or the configured splice-rescue signal.

The configured population ceiling is applied per allele. The reporting overlay narrows the review set; it does not modify the detector result or the stored ACMG classifications of either variant.

PM3 Evidence Boundary

A trio-phased result provides technical support that two variants are in trans. PM3 use still depends on the clinical significance of the partner allele, the gene-disease mechanism, the inheritance model, and the applicable ACMG or ClinGen specifications.

Folklore records the pair, phase source, confidence, and both proband classifications. A qualified genetics professional decides whether the evidence supports PM3 and at what strength.

Clinical Interpretation

Phase and pathogenicity are separate questions. A confirmed in-trans pair can still contain one or two benign variants, and two clinically relevant variants can remain unresolved when parental coverage is insufficient.