!
Use Case Scenario
Using Mastermind to Find Related Variants
in a Gene
© 2017
GENOMENON®
[email protected]
https://www.genomenon.com
Using Mastermind to find related variants in a gene
In some instances, a variant of unknown significance (VUS) may be correlated with a specific
genetic disease, but the VUS is not yet described in the literature. Mastermind can be used as a
gateway to reveal the known variants and their biological impact in a specific gene-disease
correlation, yielding information which can be extrapolated to the VUS as a guide for clinical
interpretation.
To d e m o n s t r a t e t h i s , s t a r t f r o m t h e M a s t e r m i n d h o m e p a g e a t h t t p s : / /
mastermind.genomenon.com. we will search for variants in the myeloproliferative leukemia protein
(MPL) gene and their role in myelodysplastic syndromes. From the Mastermind home page enter
the Disease search term “myelodysplastic syndromes” and MPL for Gene (or choose the terms from
In the mutation plot, you will see all of the known published variants in the MPL gene. Each blue
vertical bar in the diagram represents a single, documented mutation and the number of
published articles associated with each. The total height of all bars combined at each a single
genomic position is indicative of a mutational hotspot.
At position 515 in the MPL protein, there are 4 documented variants. To see them, use the “FILTER BY
MUTATION” feature in the mutation plot. Enter “515” into the search box and press Return. The
coding variants at this position are W515L, W515K, W515S and W515X. The W515L variant is the most
widely-documented variant. To see a list of publications that cite the W515L variant in the full-text
or in the title/abstract, click on the number in the corresponding column.
!©2017 GENOMENON®
www.genomenon.com!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!32!
By default, the publications are ordered by their association strength, a relative measure of how
frequently the selected search terms are mentioned in the text of the article, how close together
they appear and where they appear in the article. This ranking is also depicted in the impact plot,
where the size of each circle represents the relevance of the article to the selected key terms-the
larger the circle, the greater the relevance.
!©2017 GENOMENON®
www.genomenon.com!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!33!
The list of articles can be also be sorted by publication date, journal name and impact factor. A list
containing the PubMed identifier, article name and journal can be downloaded by clicking on the
folder icon.
Further characterization of a VUS relies on the integration of data from multiple sources, for
example, family history, functional assays, diagnostics, and treatment outcomes. Mastermind
categorizes publications by content (e.g, diagnostic, prognostic, treatments, function, inheritance,
and mechanisms) so that the clinician can quickly navigate to content-specific material. This is
useful when additional lines of evidence underlying the biological significance of a VUS needs to
be obtained.
The content-specific categories (Dx, Px, Rx, Fx, Lx, Mx, SNP, GM, CR and CM) can be found at the
top of the Mastermind search results page for any gene-disease-variant query. The Mastermind
content categories are defined as: Diagnosis (Dx); Prognosis (Px); Treatment (Rx); Function (Fx);
Inheritance (Ix); Mechanism (Mx); SNP or variation (SNP); Goldmine (GM); Case Report (CR);
Custom Match (CM). Each of these categories allows the user to display only those articles that
contain content that is relevant to each individual category based on the appearance of any of
the given category’s key terms. Case Reports identify articles that are case reports as defined in
PubMed. Goldmine articles include those articles that describe large-scale studies of cohorts
where sequencing was performed (e.g. exome sequencing).
In studies of VUS, it is valuable to have family history information to understand the inheritance
mechanism of the observed trait. The “Ix”, or Inheritance category in Mastermind be used to
identify publications which describe the heritability of the W515L mutation. This information can
help guide the clinician when no family history is available. To see any subset of papers under the
Ix category click on the “DISABLE ALL” link then click on any sub-category term to load the list of
articles in Mastermind. For this Use Case scenario, click on “SOMATIC” after disabling all links.
One paper, “Somatic mutations identify a subgroup of aplastic anemia patients who progress to
myelodysplastic syndrome” [Kulasekararaj, AG et al., 2017. Blood 124 (17)] is one example of a
publication which can be used to inform and guide the clinical interpretation of a new VUS in the
MPL gene. If you have a personal or institutional subscription to the journal, then clicking on the
“Load PDF” link will load the publication in Mastermind. The toolbar at the top of the article view
will allow you to interact with the article and download it to your local computer.
!©2017 GENOMENON®
www.genomenon.com!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!34!
The “SENTENCES” section of the Mastermind report will also show you the article sentence
fragments containing your search terms of interest. The “Find” function of the PDF viewer toolbar
can be used to view the full-context of these sentence fragments.
In summary, by starting with a gene-disease query, Mastermind can be used to identify known
mutational hot spots and meta-data to find publications that can help guide and inform the
clinical interpretation of VUS.
!©2017 GENOMENON®
www.genomenon.com!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!35!