How to interpret interruptions and how strict to count?

[b8hale]

For ATXN1 the pathogenic motif is CTG and the interruption which reduces penetrance is CAT.

• How are the interruptions clinically evaluated? Do you subtract the interruptions from the pathogenic repeats number?
• Do you report only the uninterrupted expansions or the overall sum of the pathogenic motif?
• Also, trgt counts other motifs, e.g. GTG or ATG as pathogenic. Is that correct or should one be really strict about counting?

We trying trgt out and wonder about the correct usage of the results. I would be very happy for some hints or experiences regarding this.

[hdashnow]

Hi @b8hale,

According to https://pmc.ncbi.nlm.nih.gov/articles/PMC3723530/
"the age at onset inversely correlates linearly with the longer uninterrupted CAG stretch"
So, looking at the longest strictly perfect stretch is likely to be most useful for predicting the age of onset. However, it's unclear if it can also be used to assess overall pathogenicity. Tests may not include information about interruptions, so it's difficult to say how these could be interpreted clinically. Likely, both the total length and the longest uninterrupted stretch would be useful to consider.