Three novel ACAD8 variants in newborn-screening-positive Chinese individuals with suspected isobutyryl-CoA dehydrogenase deficiency: six genetically characterized cases and one biochemically suspected case

Abstract

Abstract Background Isobutyryl-CoA dehydrogenase deficiency (IBDD) is a rare autosomal recessive organic acidemia. Here, we present the clinical, biochemical, and molecular findings from seven newborn-screening-positive individuals, of whom six were found to harbor biallelic ACAD8 variants with biochemical findings consistent with IBDD (two molecularly confirmed and four molecularly supported because they carried at least one variant of uncertain significance), and one remained biochemically suspected without molecular confirmation. Methods We analyzed blood acylcarnitine profiles using tandem mass spectrometry (MS/MS) and urinary organic acids via gas chromatography-mass spectrometry (GC/MS). Genetic testing was performed using high-throughput sequencing, and the pathogenicity of novel variants was predicted using bioinformatics tools (SIFT, PolyPhen-2, Mutation Taster). Structural impacts of ACAD8 variants were modeled with Swiss-pdb Viewer. Results All seven individuals (four males, three females) showed elevated blood butyrylcarnitine (C4) levels. Of these seven, six underwent genetic testing, and we identified seven ACAD8 missense variants c.236G > A (p.R79Q), c.286G > A (p.G96S), c.473 A > G (p.Y158C), c.719 C > T (p.S240F), c.965T > C (p.M322T), c.1000 C > T (p.R334C), c.1015G > A (p.A339T) in six individuals. All six genetically tested individuals carried compound heterozygous variants. The case3 did not undergo genetic testing and was classified as biochemically suspected IBDD. Three novel variants (c.719 C > T, c.965T > C, c.1015G > A) were identified and classified as variants of uncertain significance (VUS) according to ACMG guidelines. In silico analyses predicted that these missense variants may have a deleterious effect and may disrupt protein tertiary structure or side-chain conformation; however, their clinical pathogenicity remains to be established. Conclusions Our findings expand the variant spectrum of ACAD8 -associated IBDD and underscore the value of genetic testing for diagnostic support/confirmation and genetic counseling of this disorder.

The authors' abstract, as published at the source. Orphanet Journal of Rare Diseases, 2026 · DOI ↗