Diverse and unselected adults with clinically relevant ACADS variants lack evidence of metabolic disease

The clinical significance of Short-chain acyl CoA dehydrogenase deficiency (SCADD), caused by biallelic variation in the ACADS gene, is contested. Clinically ascertained individuals have a range of reported metabolic and physical symptoms. Conversely, individuals identified through newborn screening remain overwhelmingly asymptomatic. Two common ACADS variants, c.511C > T (p.Arg171Trp) and c.625G > A (p.Gly209Ser) are known to reduce enzymatic activity with undetermined clinical correlate. We applied a genome-first approach to evaluate the prevalence and clinical consequences of ACADS variants in an ancestrally diverse and unselected patient population.

We used exome sequence data linked to electronic health records (EHRs) to identify clinically relevant ACADS variants, and estimate their prevalence and clinical implications in 27,447 ancestrally diverse and unrelated adults from the BioMe Biobank in New York, NY. We extracted International Classification of Diseases, ninth (ICD-9) and tenth (ICD-10) revision codes corresponding to eight SCADD-associated phenotypes relevant to adults from participants' EHRs. Phenotypes included intellectual disability, behavioral disorders with onset in childhood, epilepsy or seizure disorders, hypoglycemia, muscle weakness, metabolic acidosis, fatty liver, and a diagnosis of SCADD or disorder of fatty acid oxidation. We performed manual chart reviews for individuals homozygous for rare pathogenic variants. Multivariate logistic regression was used to determine the association between clinically relevant ACADS variants and phenotypes of interest.

1 in 10,000 BioMe participants were homozygous for rare pathogenic variants (PVs) in ACADS, 1 in 20 were homozygous or presumed compound heterozygous for common variants (CVs), and 1 in 300 harbored both a PV and a CV. Of the 2035 variant positive individuals, none had a documented diagnosis of SCADD. We identified five PV/PV positive individuals, none of whom had evidence of symptomatic SCADD on manual chart review. CV/CV positive and CV/PV positive individuals did not have increased odds of any of the eight ACADS phenotypes evaluated compared to variant negative individuals (OR for CV/CV 0.99, 95% CI 0.86-1.1, p = .88; OR for CV/PV OR 1.49, 95% CI 0.87-2.6, p = .15).

The prevalence of clinically relevant ACADS variants in an unselected population was higher than previously reported SCADD prevalence of 1 in 35,000 in the United States. Clinically relevant variants in ACADS were not associated with evidence of metabolic disease in a large and ancestrally diverse adult population. These findings support the assertion that SCADD is more likely a biochemical entity without clinical correlate, in particular when caused by one or more common variants.