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Case Study

Unlocking Real-Time Precision in Variant Interpretation and Literature Discovery

Ann & Robert H. Lurie Children’s Hospital of Chicago

Executive summary

Lurie Childrens’ Vision

  1. Enhance the process of clinical interpretation and variant classification in the Lurie molecular diagnostics lab.
  2. Establish a framework for quickly and accurately finding and reviewing new publications.


  1. An increase in whole exome and whole genome sequencing requires better access to the most current genomic evidence for analysis.
  2. Common sources of curated literature may not contain the most recent papers due to lags between publication and software updates.
  3. Due to nomenclature issues, search algorithms struggle to accurately identify variants, especially for CNVs.


  1. Utilize Mastermind's search interface to achieve precise variant identification.
  2. Leverage Mastermind's extensive CNV search function, capitalizing on its adaptability to various nomenclatures.
  3. Ensure access to the latest genomic evidence by standardizing on Mastermind for up-to-date information.


  1. Mastermind correctly identified a whole gene deletion that had been misinterpreted as a translocation in other databases, which led to the correct diagnosis.
  2. Mastermind provided additional evidence not available in other databases, facilitating the reclassification of a patient's variant from VUS to pathogenic.
  3. The hospital delivered successful results for a patient by uncovering a recent paper with valuable information, integrated into Mastermind just two months after its release.

“In our experience, the usage of such a real-time search tool (Mastermind) with these variant-specific search capabilities was key, and has definitely positively impacted our diagnosis of cases that we encounter in the clinical lab.”
 –Kai Lee Yap, PhD, FACMG, Director of Molecular Diagnostics, , Ann & Robert H. Lurie Children’s Hospital of Chicago


Ann & Robert H. Lurie Children's Hospital of Chicago is dedicated to providing exceptional pediatric care in an environment that incorporates the latest advancements in medical technology, research, and family-friendly design. The Lurie Molecular Diagnostics Lab specializes in genetic testing for pediatric germline conditions and somatic malignancies.


"When we search for variants, when we're looking for relevant publications for the variants, it's just really hard to make sure that we don't miss a variant because of an error in entering the nomenclature during search, or maybe because some publications have named the genes in a slightly different way or named the variants in a slightly different way. That is, I think, especially pertinent for variants like copy number variants (CNVs), because for those variants, the breakpoints tend to be a lot more variable in terms of software.“

Mastermind accommodates various nomenclatures for variants, including CNVs. Not only does it recognize specific exon coordinates, but it also provides a comprehensive list of nearby copy number variants, detailing their occupied space and degree of overlap. Lurie Children's used these advanced search features to significantly enhance the hospital's molecular diagnosis accuracy, identifying a greater number of variants compared to their previous search system. As director of molecular diagnostics Kai Lee Yap said In our experience, the usage of such a real-time search tool with these variant-specific search capabilities was key, and has definitely positively impacted our diagnosis of cases that we encounter in the clinical lab.

Mastermind, a dynamic real-time search tool, ensures clinical diagnostic laboratories stay updated by indexing every new publication release. With the addition of up to 15,000 new genomic full-text articles weekly, Mastermind’s Genomic Language Processing identifies evidence regardless of nomenclature in even the most recent articles, enhancing their capability to provide accurate molecular diagnoses for patients.


Lurie Children’s Hospital deals with a large number of cases related to genetic testing for pediatric germline disorders and somatic malignancies. These cases are critical because common databases of curated literature used for reference may not always have the most recent papers due to a lag in updates, or it won't recognize the exact variant due to nomenclature issues.

Incorporating Mastermind into the process of recognizing and finding relevant literature was crucial in a clinical case where deletion of the CELF4 gene (whole gene deletion) was observed. Other databases did not have any relevant information. However, after searching for a deletion in Mastermind, one paper was found that indicated the presence of the deletion. Scientists later realized that this deletion was present in the Human Gene Mutation Database (HGMD), but it was annotated as a translocation. Additionally, another paper was found through Mastermind, which helped scientists to determine a strong association between the deletion and a specific disease.

A second case highlights the importance of timely identification of new publications. The patient carried 19 variants that required further analysis. One CTLA4 splice variant lacked literature and was assumed to be a VUS (variant of uncertain significance) since nothing was found in other databases. However, searching for literature through Mastermind resulted in finding multiple papers. Even though this variant was initially classified as a VUS, scientists were able to reclassify it as pathogenic and confirm it as the cause of the patient’s disease.

In a third case, a CHRNA3 2-base pair homozygous loss of function (LOF) variant was identified, but there was no literature to support it. Another institution contacted the hospital and described two individuals with the same exact variant, with one of them having the same phenotype. A paper describing that patient was published in May 2021, and scientists were waiting for it to be available in databases for further curation. However, even three months after publishing, the paper was not available in HGMD. Fortunately, the clinical team found the paper in Mastermind, and they were able to finish their curation and provide results for their patient.

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