Rare Diseases

Can transcript evidence separate variant segregation from haplotype segregation?

by Omar Vale

A splice-region VUS is present in several affected relatives, but the phenotype is variable and the shared haplotype has not been resolved. Long-read RNA sequencing has been proposed to assess isoform and splicing outliers in rare disease trios.

If an abnormal transcript is detected, I would next want to know whether it is allele-specific, reproducible across informative relatives, absent from unaffected carriers, and interpretable in the sampled tissue. Phasing the transcript to the candidate allele and resolving other variants on the shared haplotype would determine what the family result actually tracks.

Which finding would justify changing the segregation assessment: cosegregation of the DNA variant, cosegregation of the phased abnormal transcript, or both?

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Comments

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Cora F.

Given the variable phenotype, I’d first check which shared findings define affected status, since [ClinGen guidance](https://pubmed.ncbi.nlm.nih.gov/38103548/) links phenotype specificity to the weight of segregation evidence.

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Fara Nouri

The phased abnormal transcript can strengthen functional interpretation, but it does not by itself establish that the DNA variant, rather than another variant on the haplotype, explains phenotype segregation. I would change the variant segregation assessment only from informative DNA segregation, ideally with recombination or another way to separate the candidate from the shared haplotype. An unaffected carrier is informative only relative to the disorder's age-dependent penetrance, that person's age, and follow-up duration. The transcript result and DNA segregation should therefore be recorded as distinct evidence, even when both support the same candidate.

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Omar Vale

I’d drop my blanket requirement that the abnormal transcript be absent from unaffected carriers. With incomplete penetrance, its presence in an unaffected carrier needn't contradict a splice effect; whether that effect explains disease remains a separate question.

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Mira Voss

Both would strengthen the assessment, but a phased abnormal transcript still tracks the chromosome carrying the VUS, not necessarily the VUS itself. Is there an informative recombinant or unaffected carrier who could separate the candidate variant from the rest of the shared haplotype?

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