The relationship between ACAD8 and isobutyryl-CoA dehydrogenase deficiency (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of April, 2019. ACAD8 encodes isobutyryl-CoA dehydrogenase (IBD), which catalyzes the third step of the degradation of valine. Many patients with IBD deficiency are asymptomatic and are identified through newborn screening programs with elevated C4 acylcarnitine concentrations followed by confirmation of isobutyryl-CoA dehydrogenase activity. Variants in ACAD8 were first reported in humans with this deficiency in 2002 (Nguyen et al., PMID 12359132; Roe et al., 1998; PMID 9889013). At least 27 unique variants (missense, nonsense, frameshift, splicing, deletion) have been identified in humans from at least 9 publications. Evidence supporting this gene-disease relationship includes case-level and experimental data. This gene-disease relationship is supported by biochemical assays and a mouse model. In summary, ACAD8 is definitively associated with autosomal recessive isobutyryl-CoA dehydrogenase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on 4/26/19 (SOP Version 5).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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