Documentation / Family Analysis / Segregation Analysis

Segregation Analysis and LOD Scores in Clinical Trios

Segregation analysis asks whether a variant is transmitted through a family in the pattern expected for the stated inheritance hypothesis. Folklore computes this signal separately for each proband variant.

The result is a numerical LOD score, an evidence band, and a consistency flag. These outputs describe the observed trio pattern. They do not independently establish pathogenicity or determine final PP1 or BS4 use.

Inheritance Hypothesis Is Required

When the inheritance hypothesis is missing, unknown, or unsupported, Folklore skips segregation scoring. Proband variants receive a not-applicable state rather than a zero score. This distinguishes an analysis that was not performed from one that was performed and found no supporting segregation.

Per-Variant LOD Calculation

Each informative parent-to-proband transmission contributes log10(2), approximately 0.301, when it matches the selected inheritance model. An uninformative transmission contributes zero. Some model violations can reduce the score.

A complete trio contains at most two parent-to-proband meioses. The maximum raw score produced by two fully informative transmissions is therefore approximately 0.602 before phenotype specificity is applied.

Phenotype Specificity Multiplier

Phenotype State	Multiplier	Maximum Adjusted Trio LOD
Specific	1.0	Approximately 0.602
Broad	0.5	Approximately 0.301
Unspecified	0.25	Approximately 0.151

The multiplier is applied to the computed LOD score before evidence-band assignment. Under the default unspecified state, even a fully informative trio remains below the Supporting threshold.

Evidence Bands

LOD Range	Band	Points	Interpretation
0.0 to <0.5	Indeterminate	0	Positive or neutral segregation signal below the Supporting threshold.
0.5 to <2.0	Supporting	1	Configured PP1 Supporting-equivalent band.
2.0 to <3.0	Moderate	2	Requires more informative meioses than a complete trio normally provides.
3.0 to <5.0	Strong	4	Extended-pedigree territory under the current scoring model.
>=5.0	Very Strong	8	Requires substantial segregation evidence beyond trio-only analysis.

Supported Inheritance Models

Autosomal recessive compound heterozygous.

Autosomal recessive homozygous.

X-linked recessive.

X-linked dominant.

Mitochondrial inheritance.

Uniparental disomy, using the current recessive-like scoring approximation.

Autosomal dominant de novo cases return zero segregation LOD in the current scorer because de novo evidence is handled through the separate de novo workflow rather than PP1-style familial segregation.

Consistency Flag and Drill-Down Results

The segregation-consistent flag is true for any adjusted LOD above zero, including scores that remain in the Indeterminate band. It therefore means that the observed transmission contributes some positive support, not that PP1 Supporting has been reached.

The drill-down view can include positive but indeterminate variants because the read path selects segregation-consistent rows as well as rows in a non-indeterminate evidence band. Results are ordered by LOD score and genomic position.

PP1 and BS4 Boundary

A numerical band is an input to clinical review. PP1 application depends on the gene-disease relationship, penetrance, phenocopies, pedigree structure, and whether the meioses are genuinely informative for the variant under review.

The current scorer maps negative values back to the Indeterminate band. It does not automatically assign BS4. Evidence against segregation requires separate clinical assessment of phenotype, penetrance, and possible locus or allelic heterogeneity.

Current Pedigree Limit

The implementation currently receives a complete trio. Moderate, Strong, and Very Strong segregation bands require additional informative relatives and are not normally reachable from trio-only data. Extended-pedigree processing remains outside the present production scope.