CPHx: Elizabeth A Worthey, Medical College of Wisconsin – Making a Definitive Diagnosis: Successful clinical application of diagnostic whole enome sequencing

Making a Definitive Diagnosis: Successful clinical application of diagnostic whole enome sequencing
Elizabeth A Worthey, Medical College of Wisconsin


Making a Definitive Diagnosis.

Original request came 2009, young child with intractable irritable bowel disease.  No known test was diagnostic.   Primary physician went to a talk on WGS, and wanted to know if it would work on the child.

Case, poor weight gain at 15 months w perianal abscess.  symptoms consistent with sever Crones disease.  90 trips to the OR by the age of 3. Disease progressed even after severe operations.  [Some very graphic photos here.]

Time is of the essence, bottleneck was in the analysis.  Child was very ill, so had to work fast.  Expected about 15,000 variation.    Used Adobe Flex UI, java middleare layer, oracle 11g DB.

CarpeNovo.  Gives variant reports, etc. Used the tool for about 4-5 months to narrow down 16k to just 2 that were highly conserved positions, not found in additional human genome sequences.  Left only 1 variant after more analysis.

XAIP gene.  Mutation changed single amino acid.  Clinical diagnostics done to confirm sequence variant.  Also not in other family members.  Conservation of this position is extreme, including in non-mammal model organisms.

Mutation would be predicted to affect release of inflammatory molecules.  Used assays to confirm this was the case in vitro.

Diagnosis then was made, and compared to other XIAP deficiencies, such as XLP2.  Standard treatment for XLP2 is allogenic hematopoetic transplant.  After this treatment, child progressed very well, and has few recurring symptoms, etc.  Doing well!

Not the end of the story.  After this, other physicians started to request similar programs.  Did not have resources to do this for everyone who requested it.  Went to the hospital and looked for funds to continue this program with additional children.

Multi-disciplinary, multi-institutional review process.  Patents receiving care at the hospital can be nominated.  Review committee makes decisions.  This is NOT a research project – it’s focussed on treatment of patient.  Is there a likely outcome for potentially changing treatment, can it reduce the cost of diagnostic testing, etc?

Structure of review board covered.  External expert physicians, committee review and nominating physician.  It takes 8-10 hours of work per patient nominated.

Discussion of ethics of what to return.  Data observed from NGS is not added to electronic health record.

WGS done on 6 individuals since.

Case #2.

Intractable siezures, neurological symptoms.  Also: was the twin sibling at risk?

Found two mutations that cause Jubert syndrome, but presentation was not classic.  Unfortunately, no direct actions were possible.

Case #3

Full term infant born, seemed normal, but at 10 weeks rushed to the hospital.  [missed the why though]  Two mutations in twinkle gene.  Child died at 6 months of age.  Avoided major futile surgery.

Broader findings.

Have pre-authorization from insurance.  Education of providers and patients are necessary.  Large diverse teams required.  Diseases will be redefined:  known phenotype but different gene.  You don’t always have improved treatment options, and sometimes there are none.




4 thoughts on “CPHx: Elizabeth A Worthey, Medical College of Wisconsin – Making a Definitive Diagnosis: Successful clinical application of diagnostic whole enome sequencing

  1. Pingback: Copenhagenomics » Recap of Day 2 at CPHx

  2. Some of these people whose talks you are transcribing, they need blogs. I’ve never read a better example of how this sort of business works in the real world — sometimes it just tells a patient that nothing can be done, and spares them the expensive agony of futile procedures. That’s a drag but it’s a lot better than the alternative.

    The whole CPHx exercise has been a bit of a triumph for you, I think. Like AGBT but your dispatches are better :-)

    • Practice makes perfect. (=

      Actually, I could still improve my note taking somewhat, but I do feel I’m getting better at publishing instant blogs that capture the core points of a talk. There really isn’t a guide for how to do it well, so a lot of it is trial and error.

      In any case, I really agree that some of the people who gave talks could provide fantastic blogs of their own. Elizabeth Worthey’s talk is one that could really have been expanded into a book. It’s a shame that the talks all had to end so quickly.

      • Liz just (4/26/12) gave an updated version of this talk at Bio-IT World in Boston and alluded to the fact that a related paper is in prep or maybe submitted, which may help explain why no blog – her time, effort and mindshare are directed elsewhere. I looked at her online CV, which indicates that a few related papers are forthcoming or maybe already out:

        Worthey EA, Dimmock DP, and Jacob HJ. (2012). CarpeNovo; a tool for support of interpretation of Clinical Diagnostic
        Whole genome sequence data. In final preparation. 
        Worthey (2012). Next‐Generation Sequencing as a Clinical Tool: Present and Future. Molecular Diagnostics and Therapy. Review; in submission. 

        Plus an entry in Current Protocols in Human Genetics on “Clinical annotation and variant calling of Whole genome Sequence data” in final prep.

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