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  • Test code: 06107
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Elevated C4 Panel

Test description

The Invitae Elevated C4 Panel analyzes up to four genes that are associated with elevations of C4 acylcarnitine on newborn screening (NBS) or plasma acylcarnitines. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions.

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Primary panel (3 genes)
Add-on Limited Evidence Gene (1 gene)

NBS labs that use a butylation derivatization method may have trouble distinguishing elevations of formiminoglutamic acid (FIGLU) from butyryl/isobutyryl-acylcarnitine (C4-acylcarnitine). Given the potential biochemical overlap during NBS of patients with glutamate formiminotransferase deficiency and other causes of elevated C4, analyzing the FTCD gene may be appropriate. This gene can be included at no additional charge.

FTCD

Alternative tests to consider

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. They can be ordered at no additional cost.

  • ethylmalonic encephalopathy
  • isobutyryl-CoA dehydrogenase deficiency
  • short chain acyl-CoA dehydrogenase (SCAD) deficiency

Elevated C4 acylcarnitine may be detected during newborn screening due to isobutyric aciduria, short chain acyl-CoA dehydrogenase (SCAD) deficiency, or ethylmalonic encephalopathy. Most patients with isobutyryl-CoA dehydrogenase deficiency and SCAD deficiency are asymptomatic. Recent studies have even suggested that alternative causes may be responsible for clinical presentations originally ascribed to SCAD deficiency. Infants with ethylmalonic encephalopathy (EE), however, typically have more severe clinical manifestations. EE patients often have acrocyanosis, petechiae, chronic diarrhea, hypotonia, seizures, and abnormal movements.

This panel covers all known genetic conditions that can cause elevated C4 on newborn screening or acylcarnitine analysis.

All causes of elevated C4 are inherited in an autosomal recessive manner.

The prevalence of elevated C4 is dependent on laboratory cutoffs and ethnicity. Limited data exist on the rates of false-positive elevations of C4. The prevalence of confirmed genetic causes of elevated C4 has been reported as high as 1 in 8,400 in some ethnic groups.

This panel may be appropriate for:

  • infants with elevated C4 on NBS or confirmatory plasma acylcarnitine analysis
  • patients with elevated C4 on plasma acylcarnitine analysis with unclear or unavailable urine organic acid results

For considerations for testing please refer to:

  1. Feuchtbaum, L, et al. Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet. Med. 2012; 14(11):937-45. PMID: 22766612
  2. van, Maldegem, BT, et al. Clinical aspects of short-chain acyl-CoA dehydrogenase deficiency. J. Inherit. Metab. Dis. 2010; 33(5):507-11. PMID: 20429031
  3. Waisbren, SE, et al. Short-chain acyl-CoA dehydrogenase (SCAD) deficiency: an examination of the medical and neurodevelopmental characteristics of 14 cases identified through newborn screening or clinical symptoms. Mol. Genet. Metab. 2008; 95(1-2):39-45. PMID: 18676165
  4. Gallant, NM, et al. Biochemical, molecular, and clinical characteristics of children with short chain acyl-CoA dehydrogenase deficiency detected by newborn screening in California. Mol. Genet. Metab. 2012; 106(1):55-61. PMID: 22424739
  5. Pena, L, et al. Follow-up of patients with short-chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies identified through newborn screening: one center's experience. Genet. Med. 2012; 14(3):342-7. PMID: 22241096
  6. Papetti, L, et al. Severe early onset ethylmalonic encephalopathy with West syndrome. Metab Brain Dis. 2015; :None. PMID: 26194623
  7. Dweikat, I, et al. Ethylmalonic encephalopathy associated with crescentic glomerulonephritis. Metab Brain Dis. 2012; 27(4):613-6. PMID: 22584649
  8. Wolfe, L, et al. Short-Chain Acyl-CoA Dehydrogenase Deficiency. 2011 Sep 22. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 21938826
  9. Baby's first test. Newborn screening. http://www.babysfirsttest.org/ Accessed February 2016.
  10. Wilcken B, Rinaldo P, Matern D. Inborn metabolic diseases: diagnosis and treatment. 5th ed. Heidelberg: Springer; 2012. Chapter 3, Newborn screening for inborn errors of metabolism; p. 75–86.
  11. American College of Medical Genetics. NBS ACT Sheet. Short-Chain Acyl-CoA Dehydrogenase (SCAD) Deficiency. https://www.acmg.net/StaticContent/ACT/C4.pdf Accessed September 2018.
  12. Majumdar, R, et al. Allelic spectrum of formiminotransferase-cyclodeaminase gene variants in individuals with formiminoglutamic aciduria. Mol Genet Genomic Med. 2017; 5(6):795-799. PMID: 29178637

Assay and technical information

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
ACAD8 NM_014384.2
ACADS NM_000017.3
ETHE1 NM_014297.3
FTCD NM_006657.2