PRNP Octapeptide repeat insertions

What should be established about the test?

The repeat count, and the method used to establish it. Published series report insertions by the number of repeats added, commonly written as 5-OPRI or 6-OPRI, and the count carries most of the prognostic information available. A report naming an insertion without the repeat number is incomplete for counselling.

Laboratories list repeat analysis separately from PRNP coding-region sequencing in their test menus, which is a reason to ask explicitly what was ordered. Where a GSS-like or CJD-like illness runs in a family and sequencing has been reported as negative, the question for the laboratory is whether repeat insertions were specifically assessed and by what method. This site has not been able to open a laboratory test page to confirm the methods currently offered, so that question belongs to the reporting laboratory rather than to a published list.

How does repeat number relate to the illness?

Both the phenotype and the tempo track with repeat number, imperfectly.

Insertions sit mostly in the region corresponding to the copper-binding domain of PrP, and the 2017 review states that they can manifest as either a genetic CJD or a GSS phenotype. On tempo, that review classifies octapeptide repeat deletions and insertions of fewer than four repeats as fast-progressing, defining the fast group as rapid decline with total disease duration usually less than three years, while most insertions of five to seven repeats, and especially those of eight or more, are classed as slow.

The correlation is not exact. The same review notes that insertions of the same size can progress at different speeds, possibly because the repeat patterns themselves differ, so two families with the same repeat count can have different courses. Reported series are small for every individual repeat number, which is why statements in this literature are directional rather than quantitative.

What are the reported ages and durations?

From the UCSF centre’s series, 12 symptomatic patients with octapeptide repeat insertions were referred and 4 were evaluated there. Mean age at onset was 44 years with a standard deviation of 14 and a range of 18 to 70. Mean disease duration among those who had died was 27.2 months with a standard deviation of 25.8 and a range of 5 to 69 months, in 5 patients.

Three things stand out. Onset is earlier on average than in E200K, where the literature average is around 60. The spread is extreme, from 18 to 70 years at onset and from 5 to 69 months in duration. And both figures come from fewer than 15 patients, so they describe the range of what has been reported rather than a central tendency anyone should rely on.

What is known about penetrance?

Less than for the common substitutions. The 2016 population-control analysis quantified penetrance for substitutions by comparing allele frequencies in 16,025 cases against 60,706 ExAC exomes and 531,575 genotyped individuals; it did not produce an equivalent figure for repeat insertions, and its stated limitation that very rare variants in both cases and controls could not be reclassified applies here.

The 2017 review gives penetrance estimates for V210I and M232R and none for insertions. It does report that a two-octapeptide deletion leads to a genetic CJD phenotype, and it groups deletions with the fast-progressing variants. The honest position for a family is that penetrance for their specific repeat count has not been quantified.

Interpretation of a particular report belongs with the issuing laboratory and a genetic counsellor; genetic counselling comes first sets out the sequence, and declining a predictive test is a recognised choice.

How do the diagnostic tests behave?

Well, relative to the other inherited forms. In the 2026 Canadian comparison of 116 diagnostic CSF samples, the inherited group included 4 cases with octapeptide repeat insertions, and all 4 were positive on all three assays: the modified deer mouse end-point assay, the standard hamster end-point assay and second-generation IQ-CSF RT-QuIC.

That is a meaningful contrast with the same study’s fatal familial insomnia results, where IQ-CSF detected none of 13. Four cases is a small number, but CSF seeding assays appear not to have the substrate-dependence problem here that they have in D178N and GSS. How prion disease is diagnosed covers the panel, and rapidly progressive dementia and CJD: more detail the assay comparison in full.

What does this mean for counselling a family?

Four points are specific to this group.

The method question comes first: establish how the insertion was detected and that the repeat count is documented, because the count carries most of the prognostic information available.

The tempo is unpredictable within a repeat count, so a family whose relative declined over 18 months and a family whose relative declined over five years can carry the same change.

Earlier average onset means the reproductive and work-related conversations often arise earlier than in the late-onset variants. Family planning options covers the published routes, and whether any of them can be applied to a repeat insertion is a question for a clinical genetics service, since the laboratory method has to be able to resolve repeat number in the sample available.

And the phenotype may not look like CJD. A slowly progressive ataxic or dementing illness over years, in a family with a prion variant, is consistent with a higher repeat count rather than evidence against the diagnosis.

Where next?

PRNP variants is the overview, P102L the classical GSS variant, M232R the contested low-risk end, and octapeptide repeat insertions for researchers the scientific page.

This page summarises published literature and a laboratory test listing, and it is not clinical or genetic advice. No figure here describes the position of any particular person, and the interpretation of a specific report belongs with the laboratory that issued it.