The Invitae Elevated C5-DC Test analyzes the GCDH gene, which is associated with elevations of C5-DC acylcarnitine on newborn screening (NBS) or on plasma or urine acylcarnitine analysis. Genetic testing of this gene 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 glutarylcarnitine (C5-DC) acylcarnitine may be detected during newborn screening (NBS) or acylcarnitine analysis due to glutaric acidemia type I (GA1). GA1 typically presents within the first few months of life with an acute encephalopathic crisis during a time of increased catabolic demand such as intercurrent illness or immunization. This crisis causes irreversible neurological sequelae, particularly acute bilateral striatal injury, which can lead to dystonia, axial hypotonia, rigidity, and spasms and cause increased morbidity and mortality. Some patients may have an “insidious onset” (onset of clinical symptoms without a precipitating encephalopathic crisis). Macrocephaly is a common finding in GA1, and some patients can have subdural and retinal hemorrhages. Although the majority of patients present with severe disease in the infantile period, later-onset childhood forms and rare, milder adult-onset forms have been reported.
GA1 is caused by a defect of the glutaryl-CoA dehydrogenase enzyme, which is involved in the metabolism of lysine, hydroxylysine, and tryptophan. In these patients, intermediates of this pathway (C5-DC, 3-hydroxyglutaric acid, glutaric acid, and, less frequently, glutaconic acid) accumulate in the body, which can be detected by plasma or urine acylcarnitine analysis and urine organic acid analysis. Of note, some patients with GA1 have normal or near-normal biochemical studies, despite having clinical disease. Molecular testing may therefore be warranted in patients with clinical suspicion of GA1 but normal biochemical studies.
A low lysine diet with carnitine supplementation and emergency diet during intercurrent illness has been shown to effectively treat patients, provided treatment is started before the onset of symptoms. Outcome remains poor in patients who are diagnosed after the onset of neurological damage, even with treatment. Early diagnosis and detection are therefore critical to improving the long-term outcome of these patients.
For patients with biochemical features consistent with glutaric aciduria type I (elevated C5-DC on acylcarnitines and elevated urine 3-hydroxyglutaric acid), >99% will have two pathogenic variants in GCDH.
GA1 is inherited in an autosomal recessive manner.
The incidence of elevated C5DC is dependent on laboratory cutoffs and ethnicity. The overall incidence of confirmed GA1 cases has been estimated at 1 in 72,000–100,000 live births, though the incidence may be much higher in certain populations. The incidence rate has been estimated at 1 in 29,000 Vietnamese Americans. Prevalence for GA1 is much higher in the Old Order Amish, Canadian Indian natives, Irish travellers, and Lumbee Native Americans in North Carolina.
This test may be appropriate for patients:
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 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|