Short Chain Acyl-CoA Dehydrogenase Deficiency via the ACADS Gene

Short chain acyl-CoA dehydrogenase deficiency (SCADD, OMIM #201470) is a defect in the breakdown of fatty acids within the mitochondria that causes accumulation of butyrylcarnitine and ethylmalonic acid in the blood and urine. Currently, the majority of new patients are identified through tandem mass spectrometry in neonatal screening, and they remain asymptomatic. However, older patients identified through clinical symptoms commonly have chiefly neuromuscular symptoms including hypotonia, developmental delay, and seizures. Other reported symptoms include speech delay, feeding difficulty, vomiting, hypoglycemia, and lethargy. Further studies are needed to clarify the relationship between variants in the SCAD gene and disease, and the long term consequences of SCADD (van Maldegem et al. JAMA 296:943-952, 2006; Jethva et al. Mol Genet Metab 95:195-200, 2008; Pedersen et al. Hum Genet 124:43-56, 2008).

Short chain acyl-CoA dehydrogenase (SCAD), encoded by the ACADS gene (OMIM #606886), catalyzes one of the steps in the breakdown of fatty acids with short carbon chains, particularly butyryl-CoA. SCAD deficiency is an autosomal recessive inborn error of metabolism. Unlike most other genetic diseases causing fatty acid oxidation defects, the vast majority of variants reported to date in ACADS have been missense variants. It may well be that complete absence of short chain acyl-CoA dehydrogenase activity is lethal. Two common sequence variants in ACADS, c.511C>T (p.Arg171Trp, rs1800556; frequency of T allele ~3%) and c.625G>A (p.Gly209Ser, rs17848088; frequency of A allele ~20%), impair folding and stability. These variants are thought to modify or even cause the disorder in combination with adverse cellular conditions, especially when homozygous for the rare alleles. Genotype-phenotype correlations have not been identified at this time, though genotype correlates well with biochemical profiles (Corydon et al. Pediatr Res 49:18- 23, 2001; van Maldegem et al. 2006; Waisbren et al. Mol Genet Metab 95:39-45, 2008).

Incidence of SCADD has been estimated at 1/33,000 births, using a cut-off for butyrylcarnitine of 1.9µmol/L (Waisbren et al. Mol Genet Metab 95:39-45, 2008). Analytical sensitivity should be high because all variants reported to date are expected to be detected by sequence analysis of genomic DNA.

This test provides full coverage of all coding exons of the ACADS gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).