Management of Mitochondrial Trifunctional Protein Variant of Uncertain Significance
A VUS in mitochondrial trifunctional protein genes (HADHA/HADHB) should NOT be used to guide clinical management or dietary interventions, and the patient should be managed based on their clinical phenotype and family history alone, not the genetic finding. 1
Core Management Principle
- VUS results, by definition, represent indeterminate findings with insufficient evidence for pathogenicity and must not direct clinical decisions. 1
- The patient should be counseled that most VUS are eventually reclassified as benign (97% of reclassified VUS are downgraded to benign), making premature intervention potentially harmful. 1, 2
Clinical Assessment Independent of VUS
Base all management decisions on clinical presentation, not the genetic variant:
If the patient is symptomatic (recurrent rhabdomyolysis, cardiomyopathy, hepatic dysfunction, peripheral neuropathy, exercise intolerance): Proceed with functional testing including acylcarnitine profile, enzymatic analysis in cultured skin fibroblasts, and fatty acid oxidation flux studies to establish a biochemical diagnosis. 3, 4, 5
If the patient is asymptomatic: No dietary restrictions, exercise limitations, or L-carnitine supplementation should be implemented based solely on a VUS. 4
Variant Reclassification Strategy
Pursue active reclassification efforts rather than treating based on uncertainty:
Refer the patient to research studies and variant reclassification programs (ClinVar, ClinGen, or disease-specific consortia) to help resolve the variant's significance. 1
If affected family members exist with confirmed mitochondrial trifunctional protein deficiency, test them first to determine if the VUS segregates with disease—this is the most clinically useful approach. 1
Request functional studies from the testing laboratory, including enzymatic assays targeting long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and long-chain 3-oxoacyl-CoA thiolase activities. 6
Monitoring and Follow-Up
Establish a recontact system with the genetics laboratory every 1-2 years for variant reclassification updates, as laboratories may issue amended reports. 1
Document clearly in the medical record that clinical decisions should not be based on the VUS to prevent mismanagement by other providers. 1
Provide genetic counseling emphasizing that VUS should not be used for predictive testing of family members. 1
Critical Pitfalls to Avoid
Do not implement dietary modifications (frequent feeding, avoidance of fasting, medium-chain triglyceride supplementation) based on a VUS alone, as this imposes unnecessary burden on asymptomatic individuals. 4
Do not restrict exercise in asymptomatic VUS carriers, as this is only indicated for confirmed pathogenic variants with documented metabolic dysfunction. 4
Avoid cascade testing of family members until the variant is reclassified as pathogenic or likely pathogenic. 1
Be aware that direct-to-consumer or broad panel testing increases VUS detection rates, particularly in genes like HADHA/HADHB where missense variants predominate and functional significance is unclear. 1
If Biochemical Testing Confirms Disease Despite VUS
If acylcarnitine profile shows elevated long-chain and 3-hydroxy long-chain species AND enzymatic analysis confirms trifunctional protein deficiency, treat the biochemical disease regardless of VUS status. 3, 5
In this scenario, the VUS may represent a novel pathogenic variant requiring functional validation, but clinical management proceeds based on the confirmed metabolic defect. 3