Newborn screening and genetic characteristics of patients with short- and very long-chain acyl-CoA dehydrogenase deficiencies

Background and aims: Acyl-CoA dehydrogenase deficiencies are a group of mitochondrial fatty-acid oxidation disorders rarely reported in mainland China. We assessed the biochemical and genetic characteristics of patients with short- and very-long-chain-acyl-CoA dehydrogenase deficiencies (SCADD/VLCADD) discovered through newborn screening.

Materials and methods: We investigated the effects of genetic variations on protein function using in silico prediction and structural modelling.

Results: Of 364,545 screened newborns, four were diagnosed with SCADD and four with VLCADD. SCADD and VLCADD incidences in our population were 1:91,136. All patients exhibited elevated C4 or C14:1 levels. Three SCADD patients had increased urinary ethylmalonic acid concentrations. Six ACADS and eight ACADVL variants were identified, with no hotspot variants, and five were unreported, including four missense variants and one splice site variant. ACADVL c.1434 + 2 T > C is a splice site variant that could affect splicing, leading to exon 14 skipping. In silico tools predicted the missense variants as pathogenic. Structural modelling confirmed that the missense variants may affect quaternary structures, causing protein instability.

Conclusions: Our findings expanded the ACADS and ACADVL mutational spectra. The combination of in silico prediction and structural modelling can improve our understanding of the pathogenicity of unreported genetic variants, providing an explanation for variant assessment.