Introducing an interactive, searchable database of LC-FAOD gene variants, genotypes and phenotypes.
Biochemical/Metabolic and Therapeutics
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Introduction:
Long-chain fatty acid oxidation disorders (LC-FAOD) are rare, life-threatening, treatable conditions detected through acylcarnitine profile analysis, performed through newborn screening (NBS) or clinical presentation when NBS is not available or missed. Confirming a LC-FAOD diagnosis with genetic testing is complicated by the rarity of the disorders, genetic and phenotypic heterogeneity, and high frequency of variants of uncertain significance (VUS). A centralized repository of LC-FAOD gene variant data aims to improve access to information needed for variant classification and clinical diagnosis.
Methods:
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 NBS results, biochemical and phenotype data, to support accurate and timely diagnosis of LC-FAOD.
Results:
Conclusion:
In rare diseases, variant-associated clinical information is scarce and VUS are frequent. Locus-specific databases such as this one provide the opportunity to compile molecular and clinical data for patients around the world into a unified and continually growing/improving resource that can aid in VUS resolution, improve overall disease understanding, and inform newborn screening. The LC-FAOD genes database is the first comprehensive database of variants, genotypes and phenotypes associated with this important sub-group of Fatty Acid Oxidation Disorders and will be a valuable resource to the broader medical and research community.
Long-chain fatty acid oxidation disorders (LC-FAOD) are rare, life-threatening, treatable conditions detected through acylcarnitine profile analysis, performed through newborn screening (NBS) or clinical presentation when NBS is not available or missed. Confirming a LC-FAOD diagnosis with genetic testing is complicated by the rarity of the disorders, genetic and phenotypic heterogeneity, and high frequency of variants of uncertain significance (VUS). A centralized repository of LC-FAOD gene variant data aims to improve access to information needed for variant classification and clinical diagnosis.
Methods:
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 NBS results, biochemical and phenotype data, to support accurate and timely diagnosis of LC-FAOD.
Results:
The database presently reports 5595 variants from 3397 individuals with 1 or more P/LP/VUS in an LC-FOAD gene. Associated phenotypes are reported for 1210 individuals, newborn screening results for 2114 individuals, and enzyme activity assays for 439 individuals.
This interactive, online database is open to the greater scientific and LC-FAOD communities through a public website, https://www.rarediseasegenes.com/lc-faod/. The database features a variant-level table for each of the 6 genes associated with LC-FAOD, a genotype-phenotype table, interactive summary analyses, and a variant submission process to contribute variant data.
The variant tables provide each variant reported in Human Genome Variation Society (HGVS) nomenclature, predicted impact, reported and/or predicted variant classification, times observed, associated phenotypes and publications reported with the variant. The variant tables are searchable for custom queries, interactive to reflect the variant position relative to the gene structure, and dynamic to filter for variants located in a selected gene region of interest.
The variant tables provide each variant reported in Human Genome Variation Society (HGVS) nomenclature, predicted impact, reported and/or predicted variant classification, times observed, associated phenotypes and publications reported with the variant. The variant tables are searchable for custom queries, interactive to reflect the variant position relative to the gene structure, and dynamic to filter for variants located in a selected gene region of interest.
The genotype-phenotype table displays biallelic genotypes with times observed, associated phenotypes and publications reported with the genotype. The genotype table is also searchable for custom queries and dynamically links to the variant details. Summary analyses show the aggregate variant metrics, geographic location, as well as interactive graphs of genotype-phenotype and variant-phenotype associations. Genotypes are interactively displayed with associated enzyme activity and results of newborn screening.
Conclusion:
In rare diseases, variant-associated clinical information is scarce and VUS are frequent. Locus-specific databases such as this one provide the opportunity to compile molecular and clinical data for patients around the world into a unified and continually growing/improving resource that can aid in VUS resolution, improve overall disease understanding, and inform newborn screening. The LC-FAOD genes database is the first comprehensive database of variants, genotypes and phenotypes associated with this important sub-group of Fatty Acid Oxidation Disorders and will be a valuable resource to the broader medical and research community.