From Genotype to Phenotype: Investigating SLC22A5 Variants and Their Significance in Carnitine Deficiency: A...

Area of Science:

• Genetics and Molecular Biology
• Biochemistry
• Clinical Medicine

Background:

• Primary carnitine deficiency (PCD) is an inherited metabolic disorder caused by mutations in the SLC22A5 gene, impacting carnitine uptake and fatty acid oxidation.
• Clinical manifestations of PCD range from fatigue to severe cardiomyopathy, with genotype-phenotype correlations often unclear.
• Over 100 mutations in SLC22A5 have been identified, necessitating a deeper understanding of their pathogenicity and clinical relevance.

Purpose of the Study:

• To systematically review the association between SLC22A5 mutations and PCD, with a specific focus on cardiomyopathy.
• To characterize the molecular and functional consequences of identified SLC22A5 variants.
• To explore the implications of these variants for improved diagnosis, treatment, and personalized care strategies in PCD.

Main Methods:

• A systematic literature search of PubMed was performed to gather genetic, clinical, and biochemical data on SLC22A5.
• Variants were classified using ACMG guidelines and CADD scores to assess pathogenicity.
• Data were synthesized using descriptive analyses to identify trends in mutation types, locations, and functional impact.

Main Results:

• Missense mutations are the most common (≈80%), followed by deletions (12.7%). Pathogenic or likely pathogenic variants constitute ≈72% of cases.
• Exons 1 and 8 show the highest mutation frequency, while Exons 5 and 6 exhibit higher pathogenicity and CADD scores.
• Nonsense and frameshift mutations, particularly severe truncating variants, are associated with the highest pathogenicity and early-onset cardiomyopathy.

Conclusions:

• Variant pathogenicity in PCD is determined by functional impact rather than mutation frequency alone.
• Understanding genotype-specific effects, especially in key exons like 5 and 6, is crucial for predicting disease severity and guiding treatment.
• This review provides a foundation for personalized medicine approaches in managing primary carnitine deficiency and its cardiac complications.