The Invitae Elevated C14, C14:1 Test analyzes the ACADVL gene, which is associated with elevations of C14 and C14:1 acylcarnitines on newborn screening (NBS) or plasma acylcarnitine analysis. Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions.
The Invitae Fatty Acid Oxidation Defects Panel has been designed to provide a broad genetic analysis of this class of disorders. Depending on the individual’s clinical and family history, this broader panel may be appropriate. It can be ordered at no additional cost.
Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency
Elevated C14 and C14:1 acylcarnitines may be detected during newborn screening or acylcarnitine analysis due to very long chain acyl-CoA dehydrogenase (VLCAD) deficiency.
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, onset of symptoms typically occurs within the first few months of life and 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. Bouts of 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 >99% will have two pathogenic variants in the ACADVL gene.
VLCAD deficiency is inherited in an autosomal recessive manner.
The prevalence of elevated C14, C14:1 acylcarnitines is dependent on laboratory cutoffs and ethnicity. 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.
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.
For considerations for testing please refer to:
For management guidelines please refer to:
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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
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