The goal of this case study is to show you how to perform research to support a disorder diagnosis and to identify information suitable for optimizing a specific patient's case mangement based on the results of their genetic test results.

Approach/Workflow

• • • MedGen:  the best information is only on subtypes!  
      • Learn more about Ehlers-Danlos syndrome - a condition - in MedGen
      • Find information about rationale for genetic testing rationale (Practice Guidelines, GeneReviews/ACMG report) - 
    • GTR:  Identify a Genetic Test for Ehlers Danlos syndrome
    • Examine a faux Genetic Test Result Report  (NM_000093.5(COL5A1):c.196C>T (p.Arg66Ter) , NM_000093.5(COL5A1):c.5473C>T (p.Gln1825Ter) - VUS)
    • ClinVar:  Learn more about the Patient's variant for diagnosis validation in ClinVar - FDA Recognized, but VUS
    • MedGen:  Understand impact on case management (Clinical Practice Guideline) & possible extra-clinical impact 

 

Welcome to Your Patient!

Kristin, 22 year old female, was referred to you.... Symptoms:  joint hypermobility, joint dislocation, bruising susceptibility Kristin has always seemed healthy and physically fit.  Unfortunately, she’s had to give up softball due to repeated severe bruising and ah hertory of both a knee and shoulder dislocation. A reflection on her medical history has caused her to realize she’s always been extremely flexible, almost to the point of "grossing out" her friends and relatives with her “Elastigirl” circus tricks. Recently, she has experienced issues with tying her shoe laces due to finger joint flexibility.

(P.S. Although her condition has progressed and is under regular monitoring, she has learned critical coping skills and has joined in patient advocacy and support groups - with speaking engagements to share what she has learned.)

Learn more about Kristin's proposed diagnosis

1. To learn more about the proposed diagnosis of Ehlers Danlos syndrome, search MedGen (https://www.ncbi.nlm.nih.gov/medgen/) with: 

If you need it, you can click here to get to a link for the Medgen recordS page.

Try this (Ehlers Danlos syndrome)!

How does this information seem to fit with Kristin's history?

2. There are several subtypes of “Ehlers Danlos syndrome”. In the "Term Hierarchy" section, click the names of the subtypes to open the MedGen records and read about each sub-type.

3. Let's focus on the preliminary diagnosis of Ehlers Danlos syndrome, Classic type 1. To learn more about this disorder, in the "Disease Characteristics" section scan the summary "Excerpted from the GeneReview" and consider accessing and reading the whole article. 

• • Note: GeneReviews® is a project run by the University of Washington producing expert-authored, point-of-care information with clinically relevant and medically actionable information for inherited conditions.  It is an incredible review article-type of resource, and is thus featured in it's own section on relevant MedGen records - as an abstract with links to key sections.

1.  
2.  
   • To begin your case work-up, note the links to specific GeneReview sections below and click on the link "Differential Diagnosis"

• • To learn about which test(s) could be ordered to diagnose this condition, click the link to the "Diagnosis" section.
    • • • (Discuss invasiveness/burden, cost, insurance coverage)

• • GeneReview articles contain information on genetic testing when relevant for that disorder or condition. Continue reading the "Diagnosis" section through the "Establishing the Diagnosis" sub-section.

For this disorder, is a genetic test(s) recommended for validation?  

What to take into consideration for ordering a Genetic Test.

• • • • Pros
        • Genetic tests are decreasing in cost & are not particularly invasive.
        • A well-known genetic lesion can sometimes help in diagnosis and/or drug/therapy selection.
        • A finding may predict disorders before symptoms begin for proactive & preventative care.
      • Cons
        • We are early in our understanding of genes, gene variants and disease:  Failure to detect a pathogenic variant does not rule out the diagnosis.
        • Prediction isn’t guaranteed as pathogenic variants sometimes do not cause the same issue in all patients (penetrance, severity, multi-genic & environmental influences).
        • Lack of coverage by some insurance companies…
  •  

4. To assist you further in learning about this disorder and for preparation for discussions with your patient, there are links to:
   • many relevant publications available in PubMed - you can look on this record for these as well as on other closely-related disorder records that you saw linked in the "Term Hierarchy" section
   • Clinical Trials in ClinicalTrials.gov , when available, linked in the "Clinical Resources" section on the right-hand side of the page.

Find a genetic test to order and examine the results

5. From the MedGen record, you can quickly link (on the right-hand side of the page) to relevant Genetic Tests that are available for this disorder or condition.   

If you need it, you can click here to get to a link for the Medgen record page.

Try this!

• • • which disorders (indications) and genes are in scope
    • what biological samples are required
    • what test methods are employed
    • how the laboratory interprets their results
    • and who to contact with ways to reach them!

 

Now that you are a-ground....What to consider when discussing the results of a Genetic Test.

• • • • Clinically, what do you do with this information?
        • Hopefully, you already knew what to do with the information (potential impact of a genetic variant on the patient’s physiology and phenotype and how this relates to your choice of case management) – before the test was ordered.
        • A patient may ask: “What is wrong with me and how can we fix it?"    A great reason to consult with a Genetic Counselor!
      • Outside of this planned clinical event:  A patient may ask: “What do I (we) do now?”
        • Implications for the patient - beyond this particular surgery:  Consider having them discuss this with their primary care physician, dentist, and any other clinical professionals who may need to know for their care.
        • Implications for the patient’s family members: Should they tell others?

 

Validate the genetic test result assertion and find more information about a genetic variant

6. To validate what is asserted by this clinical testing laboratory, search NCBI’s ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/) with:  COL5A1?

If you need it, you can click here to get to a link for the ClinVar record page.

Try this!   

What does the ClinVar record indicate in the “Interpretation” field for this gene and variation?

  

Based on the information listed there, what do you think might be the status of this variant?  Why do you think ClinVar has not upgraded the "Interpretation" on this record?

 

 

Find a practice guideline to identify actionable recommendations

6. To find recommendations for a shift in case management due to the presence of this variant, go back to the MedGen page and look for Practice Guidelines.

If you need it, you can click here to get to a link for the Medgen record page.

Try this!

• •  

Find Patient Education materials to share with the patient and her family

6. To assist you further in your communications with Kristin and her family about this disorder, there are links to some helpful documents on the MedGen page. 

• • Professional literature such as a GeneReviews chapter, OMIM or one of recent Reviews in PubMed.
  • For a more lay audience, you could find information in MedlinePlus (such as) or MedlinePlus Genetics 

MH-susceptible patients MAY HAVE ISSUES WITH  ...............

You discuss the results of the genetic test and diagnosis with Kristin and write a report for her primary care physician. In addition, you hand Kristin some Patient Education materials and ask her about any questions she may have or things she would like to chat about. She is concerned about the implications of this genetic condition for her self and for a couple of other members of her family that seem to be very flexible too. She would like to know if there are specific things they should be concerned about or avoid and if this condition has ramifications for other potential long-term health-related issues.

 

Review/Recap

Specifically, genetic testing for identifying key disorders that might impact care.  More generally, genetic testing for diagnosis of a disorder with an example of how the diagnosis might impact the case management plan.

FIND RELEVANT ONES FOR Ehlers Danlos syndrome

ACMG (Secondary Findings) ACT Sheet:  https://www.acmg.net/PDFLibrary/Malignant-Hyperthermia.pdf 
ClinGen:  https://www.clinicalgenome.org/affiliation/50038/  |  https://cspec.genome.network/cspec/ui/svi/doc/GN012 | https://erepo.genome.network/evrepo/ui/classifications?matchMode=exact&expertpanel=Malignant%20Hyperthermia%20Susceptibility%20VCEP  |  https://pubmed.ncbi.nlm.nih.gov/35849058/ 
OrphaNet:  https://www.orpha.net/data/patho/Pro/en/Emergency_MalignantHyperthermia-enPro649.pdf 

National Coordinating Center for the Regional Genetics Networks (NCC):  https://geneticspolicy.nccrcg.org/   

Take-away Message!

Think about what you would expect for this with regard to:

• Case management for the disorder - why would understanding the genetic etiology help in understanding the patient's condition and also in developing your therapeutic approach?

• Communications with the patient's family - why would understanding the genetic-based molecular mechanism help in answering questions and explaining "why and how"? How would knowing about this potentially impact the patient and her family in the future?   

Ehlers Danlos syndrome support groups.....