Incorrect genomic co-ordinates for TAF1

[SamBryen]

Hi STRchive team,

The genomic co-ordinates for the TAF1 SVA insertion are incorrectly listed in STRchive and in PMID:38876750 where I assume they were copied from. We have found the SVA to be inserted at hg38 X:71440493 or hg19 X:70660343.

Ideally, I'd provide you with a reference validating those co-ordinates, however I have struggled to find a paper clearly defining this locus in hg38 or hg19. What we were originally after were the co-ordinates for the disease-specific sequence changes (DSC) described in multiple papers so we could screen for these variants in our rare disease cohort. We managed to find these co-ordinates by blasting the sequences in figure 2 of this publication. That gives us the following SNVs (hg38):

DSC1: X-71513660-T-A
DSC2: X-71531433-G-A
DSC3: X-71529785-C-T
DSC10: X-71441489-C-T
DSC12: X-71391195-T-G

We then searched our cohort for these SNVs and found one sample with the SVA insertion at hg38 X:71440493. This is roughly the expected distance from DSC10 when comparing these co-ordinates to figure 1 of PMID:29229810.

If you could fix up the co-ordinates in STRchive that would be much appreciated. I think it would also be useful to list the co-ordinates of the DSC for others who might want to do the same thing and screen their cohorts for this SVA insertion. Thank you!

[hdashnow]

Hi @SamBryen, thanks for sharing this!
@Macayla-weiner @laurelhiatt I'd love your thoughts on this.

[laurelhiatt]

@hdashnow and I discussed briefly at ASHG and I'm commenting here for reference/documentation: this is a super useful suggestion because the accuracy of the coordinates is so important for all downstream applications. There are some challenges as noted by @SamBryen : we try to base all information on STRchive on publications/resources, and so the fact the locus is not broadly documented is a real pain. We are meeting as a group tomorrow to discuss other STR-related decision making, and hopefully we can reach some kind of solution or approach from that. thanks again @SamBryen for your work in clarifying this!

[Macayla-weiner]

Hi again @SamBryen, after some discussion it seems that we are defining coordinates as different things! Correct me if we misunderstood, but the coordinate you gave is for the exact place in which the base shows a variant while we are defining the coordinates as the entire tandem repeat (hench why it's a range rather than a single coordinate). The way we thought to address this would be to add information about your work into the allele details.

[SamBryen]

Hi @Macayla-weiner, that definition of coordinates makes sense for the vast majority of disease-causing STR loci catalogued in STRchive. This one is different in that there is no STR in the reference that is being expanded. In that sense, it's not really an STR expansion disorder as all individuals that have the SVA retrotransposon insertion have the disease but it's the repeat expansion within the insertion that modifies the disease severity/age of onset, not an expansion of the reference.

Yes, the current co-ordinates in STRchive and PMID:38876750 do outline the same repeat motif that is in the SVA but these co-ordinates don't match up with the co-ordinates in figure 1 of PMID:29229810, so I don't think this range is related to the disease at all. Unfortunately, the authors don't seem to have added the exact co-ordinates of the insertion in this paper (unless I've missed it somewhere). Maybe it's worth reaching out to the authors to verify the coordinates of the insertion and the DSC I have listed above? I agree adding the DSC to the allele description would be really useful!

Thank you for looking into this!