In a recent webinar, Dr. Kai Lee Yap, Director of Molecular Diagnostics at Lurie Children’s Hospital, speaks with the Genomenon team about how Mastermind is streamlining the variant interpretation process within the Department of Pathology and Laboratory Medicine.

Mastermind at Lurie: Simplifying Pediatric Diagnosis

Lurie Children’s is a leading pediatric hospital named the best in Illinois for its outstanding work in clinical care and research. Over 800 professionals within six medical programs conduct their investigations at Lurie’s pediatric research center, the Manne Research Institute. Lurie is ranked amongst the top ten children’s hospitals in the nation for their achievements in neonatology and pediatric cancer, fields closely associated with rare disease. Kai Lee, a pathology and laboratory medicine specialist, has used Mastermind to further her clinical work since 2019. As her team is dedicated to the diagnosis of pediatric germline disorders, they frequently perform large-scale genetic sequencing.

Kai Lee’s team works with a variety of genetic and variant screening services throughout their pipeline. Notably, for copy number variant (CNV) diagnosis and search, the team must work with databases that are updated in real time.

“If we are really suspicious of any specific variants in our CNV interpretation workflow where all these in-pipeline annotations are not possible, we will do a search on the Mastermind Professional website, because that is a live search”

Mastermind proved critical to a clinical case involving a three megabase deletion after the Lurie team couldn’t find any relevant literature evidence using HGMD. The patient, a four year old boy presenting with global developmental delays and breath-holding episodes, exhibited a whole-gene deletion of CELF4. At the time of search, HGMD’s portrayal of the CELF4 mutation spectrum was insufficient to classify the patient’s variant as disease-causing. HGMD contained only one of the two necessary papers contributing to the final variant classification, and failed to present it upon search due to improper variant annotation.

The variant was labeled with only a truncation point 18q12.2 rather than a full-scale deletion of the CELF4 gene, as was relevant to the clinical case.

The Lurie team was able to discover both entries using Mastermind, a testament to both the breadth of a database updated in real time and Mastermind’s AI-driven search capacity. On the macro level, the vast majority of genetic search engines are “just not equipped to do variant-specific search.” PubMed and Google Scholar were deemed functional for gene search, but failed to present relevant results for variant search. Many variant search engines are also insufficient for Lurie’s work. An ostensibly promising search tool LitVar2, published by NCBI, lacks the capacity for CNV search entirely. The aforementioned clinical case proves that even services that do allow variant-specific/CNV search are subject to poorly configured search priorities. Genomenon’s sensitivity-first mindset has cultivated a search engine that actually shows users all of the relevant data available from Mastermind’s expansive collection of literature.

“What we have kind of landed on in our lab is to use Mastermind to aid in this comprehensive search for genetic variants and association with human disease.”

Why exactly did HGMD fail to present relevant information where Mastermind succeeded? Dr. Brittnee Jones, Genomenon director of customer success, speaks to several key points of the Mastermind interface and AI specific to CNV search. The first is Mastermind’s Genomic Language Processing (GLP) engine. This is the software that allows Mastermind to draw informative connections between genes, variants, copy number variants (CNVs), diseases, phenotypes, therapies, and categorical keywords. It is also what accurately identified the truncation at 18q12.2 as a three-megabase deletion in this clinical case.

Additionally, the GLP processor contributes to how Mastermind organizes all the significant information available about a variant, extracting data from both standardized search terms as well as descriptive text. This is particularly relevant to clinical teams with existing pipelines, as annotations from Mastermind can greatly enhance the supplemental data available for the pertinent variants and integrate that data into VCF files.

Brittnee also discusses a “fuzzy search” using Mastermind, in which a user searches a CNV with exact coordinates and Mastermind returns every information on the size and location of overlap of every nearby CNV in the database with the searched coordinates. Results that match the search terms exactly are shown first, and indicated with a small icon for convenience — and to avoid overwhelming the user with results from Mastermind’s 8.5+ million articles. CNV “fuzzy search” is also relevant for clinical teams collecting annotations on disease association.

Kai Lee’s team collects annotations for “every single variant… during the pipeline” using HGMD, but cannot do so for CNV analysis, as HGMD’s permissible search parameters for CNV breakpoints are extremely rigid, thus limiting search results. Mastermind users can perform the same fuzzy CNV search used for manual review in order to extract uniquely detailed supplemental data.

The pediatric research team in Kai Lee’s laboratory in the Department of Pathology and Laboratory Medicine at Ann & Robert H. Lurie Children’s Hospital.

The extraordinary work at the Lurie Children’s Hospital would not be possible without genetic search and variant
classification services. Genomenon is proud to be an integral component of the Lurie interpretation framework.

“I would say it’s a pretty frequent occurrence that we actually find more papers in Mastermind, but that’s just the difference between a curator database versus a real-time search, is that the real-time search is supposed to give you more whereas the curator database is not supposed to give you everything that is out there; it’s only supposed to be something that they’ve deemed relevant.”

Mastermind is used by over 2,000 diagnostic labs and has been integrated into 18 clinical-grade decision support platforms and reference databases across the globe. Genomenon’s partnerships with clinical and research institutes give experts the resources they need for diagnosis and treatment of rare disease, and further the ambition to eventually curate the entire human genome through Mastermind. You can sign up for a free Mastermind account here.

For a deeper dive into how Mastermind is used at Lurie Children’s, watch the complete webinar here.

About the Author
Liz Krema is a freelance editor and author studying molecular and cellular biology. She has worked with Genomenon to provide webinar transcripts since 2020.

Disclosures: Kai Lee Yap is referencing the usage of a number of academic and commercial softwares/tools, these were incorporated into the interpretation workflows we have established in our laboratory, and has no financial relationships with mentioned entities.