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We have arrayCGH (aCGH) results for one sample. There is a 0.5 Mb terminal duplication on chromosome 19 (62995490-63407936, according to NCBI36/hg18). The duplication is rare: a literature review suggests there are only 3-4 samples with clinical information.

What are the steps to validate the results? How do we ascertain that this duplication is the cause of the clinical symptoms?

I have some ideas:

  • aCGH the parents. Not sure how this would help.
  • whole genome exome sequencing. Worried this might make it more difficult to pinpoint genetic cause.
  • whole genome sequencing?
  • other ideas?

Note: I am new to aCGH and high-throughput sequencing, any advice is welcome.

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  • $\begingroup$ Is the duplication in the telomere or before it? $\endgroup$
    – Devon Ryan
    May 31, 2017 at 21:15
  • $\begingroup$ @DevonRyan I think, it is before, on the last band of chr19. Does it matter, sorry not being ignorant, just no clue about it. $\endgroup$
    – zx8754
    May 31, 2017 at 21:25
  • $\begingroup$ Telomeric sequences are highly repetitive, so yes it matters :) $\endgroup$
    – Devon Ryan
    May 31, 2017 at 21:26
  • $\begingroup$ Telomere starts at the end of the last band, or is it part of chromosome? $\endgroup$
    – zx8754
    May 31, 2017 at 21:28
  • $\begingroup$ If you look at the UCSC genome browser, the telomere is the GGGTTA simple repeat at the end. In others it's just a stretch of NNNN in the reference (no clue how this looks in hg18). $\endgroup$
    – Devon Ryan
    May 31, 2017 at 21:43

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Why not just good old qPCR? That's (A) quick, (B) cheap and (C) easy to analyze. If you care about the exact location of the break point (I'm guessing from the context that you don't), then targeted sequencing with a custom capture kit would work.

Regarding validating the biological relevance of this, there are multiple (parallel) routes one can take. Firstly, screen unaffected family members for this same alteration. If you find this in unaffected individuals then it's obviously not the causative alteration. Ideally, one would also do either a cell-line experiment or a mouse (or other model organism) experiment to see if you can reconstitute at least some component of the clinical phenotype. This may not always be possible, of course.

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