Phenotype-Driven Blood-Biomarker and Muscle Functional Genomics Significantly Increase Neuromuscular Disease Diagnosis of >400 Patients


Genetic Testing

Poster Number: 218


Samya Chakravorty, PhD, Kiera Berger, BS, Laura Rufibach, PhD, Sarah Emmons, BS, Alka Chaubey, PhD, FACMG, Matthew Wicklund, MD, Matthew Harms, MD, Tahseen Mozaffar, MD, Criss Hartzell, PhD, Dalia Arafat, MS, Greg Gibson, PhD, Madhuri Hegde, PhD, FACMG


1. Emory University, 2. Georgia Instt of Technology, 3. Jain Foundation, 4. Jain Foundation, 5. PerkinElmer Genomics, 6. University of Colorado Denver, 7. University of Columbia, 8. University of California Irvine, 9. Emory University, 10. Georgia Instt of Technology, 11. Georgia Istt of Technology, 12. PerkinElmer Genomics

Background: 50-70% of inherited neuromuscular disease (NMD) patients remain undiagnosed even after DNA testing, a barrier for clinical trial enrolment. The major hurdles are: a) lack of genotype-phenotype correlation b) high prevalence (72%) of variants of uncertain significance (VUSs), c) >30% of all patients had pathogenic variant(s) or VUSs in ≥2 genes (multi-genic), and d) the lack of less-invasive biomarker-driven approaches.
Objectives: Our objective was to functionally resolve VUSs and multi-genic cases, by combining clinical and genetic data with different functional assays using minimally-invasive biomarker approach or target muscle biopsies, to enhance diagnostic yields and for better trial-readiness of patients by resolving genotype-phenotype correlations.
Results: We show in a cohort study of 394 Dysferlinopathy-suspected genetically unconfirmed NMD patients, a significant increase in diagnostic yield from 35% to 85% by using a combinatorial blood biomarker-driven CD14+ monocyte assay and whole blood targeted RNA-seq along with clinical correlation. Importantly, this further facilitated patient stratification, and mapping DYSF variant landscape. Moreover, in clinically-suspected Pompe cases (considered a monogenic disorder), we identified a high prevalence (72 cases) of one pathogenic variant or VUS each in GAA and another LGMD recessive gene, which are being functionally resolved using blood or muscle-based enzyme assays, immunoblotting, and RNA-Seq.
Conclusions: Using clinically driven-functional omics, we are resolving VUSs, and the nature of the defect in different pathways that lead to multi-genic contribution in NMDs, pointing towards their clinical utility. Our results show the importance of using a multi-tiered diagnostic approach that includes biomarkers, omics platforms and genotype-phenotype correlations not only for precision medicine diagnostics but also for testing clinical trial efficacy.