The 2025 American College of Medical Genetics and Genomics (ACMG) Annual Meeting spotlighted some of the most innovative research in rare disease diagnostics and mitochondrial medicine. Among the contributions from Baylor Genetics were four compelling studies that explored the power of functional genomics, redefined diagnostic approaches, and expanded our understanding of pathogenic mechanisms in genetic disease. Here’s a closer look at the studies we presented.
Mitochondrial Electron Transport Defects associated with Low-Heteroplasmy mtDNA Deletions: Shedding Light on SLSMDSs
In a landmark study of more than 1,100 cases, researchers examined muscle samples with both mitochondrial DNA (mtDNA) sequencing and electron transport chain (ETC) functional testing to better understand single large-scale mtDNA deletion syndromes (SLSMDSs)—which include Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), and Pearson syndrome (PS).
Key Findings:
- 16 patients with the CPEO/KSS phenotype had detectable single mtDNA deletions.
- Remarkably, 7 patients (44%) showed ETC deficiencies despite low levels of heteroplasmy (<10%)—a level often dismissed as insignificant in standard diagnostics.
- Complex IV was the most affected, though the genes disrupted by the deletions do not fully correlate with the specific ETC complex involvement.
Takeaway: Even mtDNA deletions with low heteroplasmy can compromise mitochondrial function, reinforcing the importance of combining molecular testing with functional studies in muscle specimens to support a diagnosis of SLSMDSs. View the abstract here.
Reflex RNA Sequencing Enhances Variant Classification in WES/WGS Testing
Variants of unknown significance (VUS)—especially those predicted to impact splicing—can leave patients with rare diseases with inconclusive results from exome or genome sequencing. This study demonstrated how reflex RNA sequencing (RNAseq) offers critical insights that can lead to variant reclassification, confirmed diagnoses, and clinical management changes.
Key Findings:
- Of 10 cases where reflex RNAseq was performed, five variants (50%) were reclassified from VUS to likely pathogenic after RNAseq revealed aberrant splicing patterns, including exon deletion, exon skipping, and intron retention events — even in genes with low RNA expression in whole blood.
- One case involving a splicing variant in FOXP4 led to the resolution of a long diagnostic odyssey for a child with complex neurological symptoms and confirmed the patient’s eligibility for antisense oligonucleotide therapy.
Takeaway: Integrating reflex RNAseq into the clinical WES/WGS workflow provides vital functional evidence for splicing alterations, empowering clinicians to make more definitive diagnoses and improving patient outcomes. View the poster here.
A Novel MAD1L1 Variant Identified in a Case of Mosaic Variegated Aneuploidy Syndrome (MVAS)
This case study described only the second known instance of MAD1L1-related Mosaic Variegated Aneuploidy Syndrome (MVAS)—a rare condition marked by chromosomal instability that causes developmental delay, congenital malformations, and predisposition to cancer.
Key Findings:
- Whole genome sequencing and follow-up reanalysis revealed a novel homozygous missense variant of uncertain significance in MAD1L1 (p.Arg650Trp).
- The variant was reclassified to likely pathogenic after cytogenetic testing confirmed mosaic aneuploidy and bioinformatics tools supported its pathogenicity.
- The patient presented with a striking constellation of symptoms including myelodysplastic syndrome, developmental delays, and congenital anomalies explained by the variant.
Takeaway: This case underscores the critical role of reanalysis, orthogonal testing, and karyotyping in confirming ultra-rare diagnoses—and demonstrates how novel findings can expand the known phenotypic spectrum of complex syndromes like MVAS. View the poster here.
mRNA Nonstop Decay (NSD): A Hidden Pathogenic Mechanism with Major Clinical Implications
Nonstop decay (NSD) is a lesser known but essential cellular mechanism that degrades mRNA transcripts lacking stop codons. This study revealed how stop-loss variants that activate NSD are often overlooked in clinical diagnostics due to gaps in current interpretation guidelines.
Key Findings:
- A novel pipeline identified NSD susceptibility in 44 genes among 663 tested, representing a significant subset of clinically relevant genes.
- Multiple whole genome sequencing cases were highlighted where NSD-triggering variants played a clear role in disease phenotypes, such as Immunodeficiency 38 and Mitochondrial Complex I Deficiency.
- These variants would have remained VUS under current classification frameworks, highlighting the importance of recognizing NSD as a pathogenic mechanism.
Takeaway: Including NSD in variant interpretation guidelines could lead to more accurate diagnoses. This study provides compelling evidence that PVS1 criteria should be extended to stop-loss variants in NSD-susceptible genes to improve patient care. View the abstract here.
Looking Ahead: A New Era of Precision Diagnostics
Collectively, these four studies from Baylor Genetics demonstrate how combining genomic, transcriptomic, and functional data can significantly refine diagnostic accuracy for rare and mitochondrial diseases. From unmasking pathogenic low-heteroplasmy deletions to revealing the clinical impact of RNA sequencing, the research from Baylor Genetics is pushing the boundaries of what’s possible in precision medicine.
As the field continues to evolve, these studies make one thing stand out: multi-omic integration, thoughtful reanalysis, and attention to functional genomics are key drivers of improved outcomes for patients with rare genetic conditions.
Baylor Genetics
