The Invitae Very Long Chain Acyl-CoA Dehydrogenase Deficiency Test analyzes the ACADVL gene, which is associated with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants would also guide testing and diagnosis of at-risk relatives.
The phenotypic presentation of VLCAD deficiency can range from severe to mild, depending on the amount of residual enzyme activity. On the most severe end of the spectrum is the classic presentation, with onset of symptoms typically occurring within the first few months of life. Symptoms can include cardiomyopathy, cardiac arrhythmia, hepatomegaly, hypotonia, rhabdomyolysis, and hypoketotic hypoglycemia. The childhood-onset form presents in early childhood with hypoketotic hypoglycemia, hepatomegaly, and recurrent rhabdomyolysis. The late-onset form, which is the mildest end of the spectrum, presents in later childhood or adulthood with muscle myopathy, recurrent rhabdomyolysis, muscle myalgia, and exercise intolerance. The late-onset form is the most common form of VLCAD deficiency. Symptoms may be precipitated by prolonged fasting and intercurrent illness for all subtypes of VLCAD deficiency.
In addition to elevated C14 and C14:1 on NBS, patients with VLCAD deficiency can have elevated C14 and C14:1 on plasma acylcarnitines, low free carnitine and elevated creatine kinase during attacks. It is important to note that confirmatory testing following an abnormal newborn screen may be normal in asymptomatic neonates with VLCAD deficiency. Fatty acid oxidation in vitro probe assays may show elevation of long chain acylcarnitine species; however, this assay typically requires a skin biopsy.
A low-fat, high-carbohydrate diet with medium-chain triglyceride (MCT) and avoidance of fasting has been used to treat patients with VLCAD deficiency. Emergency protocols may also be implemented during times of intercurrent illness to avoid catabolism. These therapies have been reported to successfully treat the cardiomyopathy in some patients. Early diagnosis and detection may improve the long-term outcome of these patients.
For patients with biochemical features consistent with VLCAD deficiency (elevated C14 and C14:1 on acylcarnitines), approximately >85 to 95% will have two pathogenic variants in the ACADVL gene.
VLCAD deficiency is inherited in an autosomal recessive manner.
The overall prevalence of confirmed VLCAD deficiency has been estimated at 1 in 67,000, but it can be as high as 1 in 15,000 individuals in some ethnic populations (PMID: 22766612).
This test may be appropriate for patients with elevated C14 or C14:1 acylcarnitines on newborn screening or plasma acylcarnitine analysis. On plasma acylcarnitine analysis, the patient may also have elevations of C16, C16:1, C18, or C18:1.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|