Executive Summary
As the Founder and CEO of the Limb-Girdle Muscular Dystrophy Foundation (LGMD), Dr. Lowery is committed to advancing the diagnosis and treatment of patients with LGMD 1D. His vision is to enhance patient outcomes and quality of life through improved identification, diagnosis, and management of this condition. A key component of achieving this vision involves refining the clinical interpretation and classification of genetic variants associated with this condition. This case study highlights Dr. Lowery’s strategic approach to this challenge, demonstrating how he has utilized innovative techniques and advanced technologies such as Mastermind to achieve significant progress for his patients. By focusing on improved genetic variant classification, Dr. Lowery is working towards more accurate diagnoses and more effective treatment plans, ultimately leading to better patient outcomes and an improved quality of life for those affected by LGMD.
Challenges and Approach
Limb-Girdle Muscular Dystrophy (LGMD) is a group of genetic disorders characterized by progressive weakness and wasting of muscles around the hips and shoulders. Unlike other forms of Muscular Dystrophy, LGMD can vary in its genetic issues, inheritance patterns and severity manifesting in late childhood or early adulthood.
The manifestation of LGMD symptoms can differ greatly among family members who share the same genetic variant, making definitive diagnoses particularly challenging. Utilizing Mastermind’s flexible search interface facilitates precise variant identification, thereby enhancing the understanding of these symptom variations.
Genetic testing remains another area of challenge for LGMD patients - while it can be definitive in some cases, for many testing remains inconclusive. Lack of tools to integrate all relevant genetic data and in a comprehensive manner can make it difficult for scientists and physicians. Providing quick search and cross-referencing capabilities like Mastermind does, allows researchers to effectively combine various genetic data sources and obtain meaningful insights.
Finally, a common challenge is the delay in updating literature sources. Access to the latest publications is critical for accurate variant interpretation and most solutions in the market today don’t update at a regular cadence. Users find the access to the latest genomic evidence in Mastermind together with the ability to set alerts for real-time updates extremely beneficial for variant analysis and interpretation.
Results
Mastermind’s flexible search interface allowed precise identification of genetic variants, helping Dr. Lowery understand the variability in symptoms among LGMD patients, even within the same family.
By setting up 75 gene and variant alerts in Mastermind, Dr. Lowery stayed informed of the latest research, which was critical in reclassifying two VUS variants in a patient with only VUS present, enabling effective therapy within two years.
Mastermind uncovered a pathogenic variant in a 27-year-old female initially misclassified as a carrier by lab results. The quick search, cross-referencing and frequency data provided by Mastermind confirmed the variant as causative, enhancing diagnostic accuracy.
About the LGMD 1D DNAJB6 Foundation
The LGMD 1D DNAJB6 Foundation is dedicated to supporting individuals affected by Limb-Girdle Muscular Dystrophy type 1D (LGMD1D), a rare autosomal dominant genetic disorder. One of the foundation’s key initiatives is the establishment of the Autosomal Dominant Muscular Dystrophy Registry, which includes LGMD 1D among other related conditions. This registry aims to consolidate patient data to facilitate research and enhance the understanding of these rare disorders.
The foundation offers no-cost genetic testing for muscular dystrophy, helping to identify and diagnose patients with LGMD 1D and related conditions. This initiative is crucial for early diagnosis and intervention, which can significantly improve patient outcomes. The foundation also works on political and medical advocacy, encouraging patients, caregivers, and supporters to engage in these efforts to drive policy changes and increase funding for research.
Mastermind integration: The LGMD1D DNAJB6 Foundation’s Journey with Mastermind
The LGMD 1D DNAJB6 Foundation was established to support individuals affected by Limb-Girdle Muscular Dystrophy type 1D (LGMD1D), a rare autosomal dominant genetic disorder. The foundation’s mission is to advance research, assist patients and their families, and promote awareness of LGMD 1D.
One of the initial challenges the foundation faced was the variability in symptoms among patients, even within the same family carrying the same genetic variant. This variability made definitive diagnoses challenging. Traditional genetic testing sometimes provided conclusive results, but often, the data was inconclusive, leaving patients and their families in a state of uncertainty.
To address these challenges, the foundation realized the need for a comprehensive tool that could bring all genetic pieces together and provide a clearer picture. They needed a solution that could handle the inconsistencies in genetic nomenclature and provide access to the most current genomic evidence. This is where the Mastermind platform by Genomenon came into play. The foundation decided to use a grant to purchase Mastermind Pro.
Empowering Accurate Diagnoses: The LGMD1D Foundation’s Success with Mastermind
The Mastermind solution helped Dr William Lowery and the LGMD1D DNAJB6 Foundation team understand, navigate, and reclassify variants in a series of uncommon and distinctive cases. Mastermind’s Genomic Language Processing (GLP) provided a repeatable, iterative, and standardized approach to solving their challenges.
Mastermind uncovered a pathogenic variant in a 27-year-old female who was initially misclassified as a carrier by lab results. This patient presented with progressive weakness and fasciculations, similar to her father. Using Mastermind, Dr Lowery quickly identified that the variant’s frequency was rarer than initially reported, confirming it as causative within 15 minutes. This rapid and accurate diagnosis significantly enhanced the patient’s diagnostic accuracy and clarified the condition.
"When you set up a (Mastermind) gene alert and variant alert, you are telling a patient: while you are sleeping, we are watching over literature, and sometimes all you can give them is hope.” - Dr. Lowery
By setting up 75 gene and variant alerts, Dr Lowery stayed continually updated with the latest research. This approach proved critical in reclassifying two VUS variants in a female patient. Initially, the patient had two VUS variants in 2021. Within a year, one variant was reclassified as likely pathogenic, and the following year, the second variant reached the same status, enabling effective therapy. Mastermind’s real-time updates and comprehensive literature search capabilities were essential in this reclassification process, demonstrating the importance of staying current with genetic research.
Mastermind’s flexible search interface allowed for the precise identification of genetic variants, crucial in understanding the symptom variability among LGMD patients. Even within the same family, symptoms can vary significantly, complicating definitive diagnoses. Mastermind helped Dr Lowery navigate these complexities by providing a comprehensive approach to variant identification, enhancing the understanding of the genetic landscape and symptom variability.
“Mastermind is the most efficient tool with real-time clinical application “- Dr. Lowery
