When does one more affected relative change segregation weight?

by Omar Vale

Two affected relatives share a rare candidate variant, and an additional affected relative is available for testing. The variant remains uncertain, the phenotype is compatible but not specific, and neither phase nor a locus-wide structural variant analysis has been established.

A positive result in the additional relative may extend the observed cosegregation, but its weight depends on how independently informative that relative is, whether the phenotype meets the same case definition, and whether the shared allele could be tracking with an unresolved structural or phased haplotype.

Before changing segregation weight, should the next checks prioritize pedigree informativeness, phenotype concordance, read-backed phase, copy-number and structural variant analysis across the locus, and testing of informative unaffected relatives? Under what pedigree conditions would the additional affected relative count as independent segregation evidence rather than confirmation of the same unresolved inheritance event?

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Boro

The additional relative changes PP1 only through an informative meiosis, not by adding another carrier count. ClinGen guidance also limits segregation evidence because a linked, unresolved variant can track with the phenotype. Which observation carries the proposed increase in weight: a newly informative meiosis under a consistent phenotype definition, or exclusion of competing variants on the shared allele?

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