Long-Chain Fatty Acid Oxidation Disorder Genes: A Comprehensive Genetic Database of LC-FAOD Variants, Genotypes, and Phenotypes.
PMID 42422157 | PMCID PMC13342283 | DOI 10.1155/humu/6864813 · Human mutation · 2026
Long-chain fatty acid oxidation disorders (LC-FAODs) are characterized by the inability to metabolize long-chain fatty acids. Serious clinical manifestations occur, including cardiomyopathy, hypoglycemia, rhabdomyolysis, and liver failure. Confirming a diagnosis with genetic testing is complicated by the rarity of the disorders, genetic and phenotypic heterogeneity, and the high frequency of variants of uncertain significance. A new locus-specific database for variants in the six genes associated with LC-FAOD was established to collect and disseminate information about disease-associated variants in ACADVL, CPT1A, CPT2, HADHA, HADHB, and SLC25A20. The database integrates data from a systematic literature review and a sponsored gene panel program with associated clinical and biochemical data. The database was reviewed and curated by an expert panel and stored in MongoDB and MySQL. As of March 2025 (literature review cutoff), the database reports 6947 variants from 4188 individuals with ≥ 1 variant in an LC-FAOD gene. ACADVL variants are the most common (40%), followed by HADHA (25%), CPT2 (21%), CPT1A and HADHB (5% each), and SLC25A20 (4%). Associated phenotypes are reported for 1496 individuals, newborn screening results for 2589, and enzyme activity assays for 499 individuals. Severe outcomes (cardiomyopathy < 1 year or death at any age) are reported for 219 individuals with ≥ 2 P/LP LC-FAOD gene variants, and the most common genotype among them is homozygosity for the LCHAD variant, HADHA p.Glu510Gln (n = 48/219). The LC-FAOD gene database is a comprehensive archive of variants, genotypes, and phenotypes associated with this important group of FAODs. It is open to the greater scientific and LC-FAOD communities through a public website.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | ACADVL | “A new locus-specific database for variants in the six genes associated with LC-FAOD was established to collect and disseminate information about disease-associated variants in ACADVL, CPT1A, CPT2, HADHA, HADHB, and SLC25A20.” | 0.98 | hgnc_dict_v1 |
| gene | CPT1A | “A new locus-specific database for variants in the six genes associated with LC-FAOD was established to collect and disseminate information about disease-associated variants in ACADVL, CPT1A, CPT2, HADHA, HADHB, and SLC25A20.” | 0.98 | hgnc_dict_v1 |
| gene | CPT2 | “A new locus-specific database for variants in the six genes associated with LC-FAOD was established to collect and disseminate information about disease-associated variants in ACADVL, CPT1A, CPT2, HADHA, HADHB, and SLC25A20.” | 0.98 | hgnc_dict_v1 |
| gene | HADHA | “A new locus-specific database for variants in the six genes associated with LC-FAOD was established to collect and disseminate information about disease-associated variants in ACADVL, CPT1A, CPT2, HADHA, HADHB, and SLC25A20.” | 0.98 | hgnc_dict_v1 |
| gene | HADHB | “A new locus-specific database for variants in the six genes associated with LC-FAOD was established to collect and disseminate information about disease-associated variants in ACADVL, CPT1A, CPT2, HADHA, HADHB, and SLC25A20.” | 0.98 | hgnc_dict_v1 |
| gene | SLC25A20 | “A new locus-specific database for variants in the six genes associated with LC-FAOD was established to collect and disseminate information about disease-associated variants in ACADVL, CPT1A, CPT2, HADHA, HADHB, and SLC25A20.” | 0.98 | hgnc_dict_v1 |
| phenotype | cardiomyopathy | “Serious clinical manifestations occur, including cardiomyopathy, hypoglycemia, rhabdomyolysis, and liver failure.” | 0.98 | phenotype_alias_lexicon_v2 |
| population | Population | “As of March 2025 (literature review cutoff), the database reports 6947 variants from 4188 individuals with ≥ 1 variant in an LC-FAOD gene.” | 0.80 | saudi_context_rules_v1 |
| variant | p.Glu510Gln | “Severe outcomes (cardiomyopathy < 1 year or death at any age) are reported for 219 individuals with ≥ 2 P/LP LC-FAOD gene variants, and the most common genotype among them is homozygosity for the LCHAD variant, HADHA p.Glu510Gln (n = 48/219).” | 0.95 | hgvs_regex_v1 |