Elevated Levels of C14 and C14:1 Acylcarnitine via the ACADVL Gene

Newborn screening (NBS) tests are performed soon after birth with the goal of identifying individuals that may be affected by certain disorders before disease-related disability or death occurs. Appropriate medical management beginning early in life can prevent all or many symptoms in the affected individuals (Watson et al. 2006 PubMed ID: 16783161; https://www.cdc.gov/newbornscreening/). While NBS is required within all states and territories in the United States, individual state or territory public health departments determine which conditions are included on the NBS panel (https://www.babysfirsttest.org/newborn-screening/states). NBS protocols outside of the United States vary from country to country. At a minimum, all core conditions on the Recommended Uniform Screening Panel (RUSP) should be included on NBS panels within the United States. In addition, NBS testing may also include secondary conditions, which are disorders that can be detected as part of the differential diagnosis of a core condition (https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp). Following an abnormal NBS result, follow up diagnostic testing is indicated. Such testing may include biochemical methodologies (for example, urine organic acid analysis or plasma acylcarnitine analysis), enzyme assays, and/or molecular genetic testing.

This test is designed for individuals with NBS results showing elevated levels of C14 and C14:1 acylcarnitine which can indicate very long chain acyl-CoA dehydrogenase deficiency (VLCAD). VLCAD deficiency is a core condition on the RUSP.

Very long chain acyl-CoA dehydrogenase (VLCAD), encoded by the ACADVL gene, catalyzes the first step in the catabolism of fatty acids with 14-20 carbon atoms. VLCAD deficiency exhibits autosomal recessive inheritance. Hundreds of causative ACADVL variants have been reported to date. Variants are located throughout the gene and are roughly 60% missense and 40% frameshift, splicing, or nonsense. One variant, p.Val283Ala, accounts for 20% of the pathologic alleles among those identified by newborn screening. Variants which completely eliminate enzyme activity usually cause the most severe disease, while missense variants resulting in some residual enzyme activity lead to milder childhood- and adult-onset forms (Andresen et al. 1999. PubMed ID: 9973285; Gregersen et al. 2001. PubMed ID: 11524729).

Andresen et al. (1999) performed ACADVL gene sequencing on 55 VLCADD patients with demonstrated enzyme deficiency and found two likely causative variants in 47 patients (85%) and one likely causative variant in the remaining 8 patients. Boneh et al. (2006) found two causative variants in 6 of 6 patients identified through neonatal screening. Analytical sensitivity should be high because nearly 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 ACADVL 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).