The Invitae Elevated C5 Panel analyzes the two genes that are associated with elevations of C5 acylcarnitine on newborn screening (NBS) or plasma acylcarnitine analysis. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions.
The Invitae Organic Acidemias 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.
Elevated C5 acylcarnitines levels that are detected during newborn screening may have genetic and non-genetic causes. Isovaleric acidemia (IVA) and short/branched-chain acyl-CoA dehydrogenase (SBCAD) deficiency can cause elevated C5 on newborn screening or plasma acylcarnitine analysis. Pivalic acid containing antibiotics and sivelestat, as well as some cosmetics, may cause an elevated C5-related artifact on newborn screening.
Patients with IVA can range from severe clinical presentation to asymptomatic. Patients with severe disease may present in the newborn period with lethargy, vomiting, seizures, and metabolic acidosis. If untreated, affected infants can progress to coma and death. Further, these patients may have a “sweaty feet” odor, particularly in times of metabolic crisis. Late-onset intermittent forms have also been described with childhood onset; these patients are typically well and may only have metabolic acidosis during intercurrent illness, prolonged fasting, or increased protein load. In patients with severe disease, treatment by dietary restriction and acute management protocols is possible, though clinical outcome improves when the onset of treatment is prior to the onset of symptoms. Several patients with IVA and at least one copy of p.Ala282Val have also been shown to be very mild or asymptomatic despite elevated C5 and increased urine isovaleric acid and isovalerylglycine. In all cases, early molecular diagnosis may help guide management decisions; in more severely affected patients, it can also improve long-term outcomes.
Patients with SBCAD deficiency that have been diagnosed based on clinical symptoms may present with developmental delay, acute metabolic acidosis, and seizures, but since the advent of expanded newborn screening, diagnosed patients have been largely asymptomatic. Even in the absence of clinical symptoms, patients still show the hallmark elevation of C5 on plasma acylcarnitine analysis and elevation of 2-methylbutyrylglycine in urine.
For patients with elevated C5 acylcarnitine and elevations of either isovaleric acid with isovalerylglycine in urine or elevation of 2-methylbutyrylglycine in urine, >99% will have two pathogenic variants in ACADSB or IVD, respectively.
All genetic causes of elevated C5 are inherited in an autosomal recessive manner.
The prevalence of elevated C5 is dependent on laboratory cutoffs and ethnicity. Limited data exist on the rates of false-positive elevations of C5 and on the non-genetic causes of elevated C5. The prevalence of confirmed genetic causes of elevated C5 have been reported as high as 1 in 22,000 in some ethnic groups. SBCAD deficiency is especially prevalent in the Hmong population, whose recent prevalence estimates range from 1 in 45 to 1 in 125.
This panel may be appropriate for:
For considerations for testing 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 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|