Indication for Testing Statement
Functional metabolomic assessment to evaluate biochemical consequences of heterozygous likely pathogenic variants in SLC25A13 (citrin deficiency-related) and CYP4F3 (eicosanoid metabolism) identified by prior whole genome sequencing.
Rationale for Global MAPS Testing
This patient carries two distinct heterozygous variants with high pathogenicity scores that affect different metabolic pathways. While whole genome sequencing has identified the genetic variants, Global MAPS metabolomic screening will measure the actual downstream biochemical consequences of these variants, providing functional evidence of metabolic dysfunction that cannot be determined by DNA sequencing alone 1.
SLC25A13 Variant Assessment
The SLC25A13 variant (rs754054414, REVEL 0.944) affects citrin, the mitochondrial aspartate-glutamate transporter critical for:
- Malate-aspartate shuttle function
- Hepatic energy metabolism
- Urea cycle regulation
- Cellular redox balance
Global MAPS comprehensively evaluates amino acid metabolism, TCA cycle intermediates, and nitrogen metabolism pathways 1. This testing can detect:
- Altered citrulline, arginine, ornithine, glutamate, and aspartate levels
- Disrupted mitochondrial energy metabolism patterns
- Abnormal metabolic flux consistent with citrin dysfunction
Multiple studies confirm that SLC25A13 variants demonstrate significant allelic heterogeneity and variable expressivity 2, 3, 4, 5. Heterozygous carriers may exhibit subclinical metabolic alterations not apparent through standard laboratory testing but detectable through comprehensive metabolomic profiling.
CYP4F3 Variant Assessment
The CYP4F3 variant (rs149124841, REVEL 0.778) affects a cytochrome P450 enzyme responsible for inactivating leukotriene B4 (LTB4), a potent inflammatory mediator. Published case evidence demonstrates that heterozygous CYP4F3 missense variants can impair LTB4 metabolism, resulting in elevated circulating LTB4 levels that may warrant targeted anti-inflammatory therapy.
Global MAPS evaluates eicosanoid metabolism and can identify:
- Elevated LTB4 levels
- Altered LTB4-to-20-hydroxy-LTB4 ratios
- Shifts in other arachidonic acid-derived eicosanoids
- Abnormal lipid metabolism patterns
Clinical Utility
Metabolomic profiling provides functional validation of genetic variants of uncertain clinical significance 6, 7. When genetic sequencing identifies likely pathogenic variants, metabolomic testing can:
- Confirm biochemical pathway disruption
- Guide clinical management decisions
- Establish baseline metabolic patterns for longitudinal monitoring
- Identify therapeutic targets (e.g., zileuton for elevated LTB4)
This approach aligns with current genomic medicine implementation strategies that emphasize integrating multiple data types—genetic, biochemical, and clinical—to optimize diagnostic accuracy and therapeutic decision-making 1, 7.
Testing Justification
Standard clinical laboratory testing cannot adequately assess the >700 small-molecule metabolites across multiple interconnected pathways evaluated by Global MAPS. The pattern-based analysis of related metabolites provides superior functional insight compared to isolated biomarker measurements, particularly for identifying enzymatic bottlenecks and altered pathway regulation that may result from heterozygous variants with incomplete penetrance 8.