Invitae Elevated C5-OH Panel


Test description

The Invitae Elevated C5-OH Panel analyzes nine genes that are associated with elevations of C5-OH 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.

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Primary panel (9 genes)


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. It can be ordered at no additional cost.

2-methyl-3-hydroxybutyric aciduria, 3-hydroxy-3-methylglutaryl-CoA lyase (3HMG) deficiency, 3-methylcrotonyl-CoA carboxylase (3MCC) deficiency, 3-methylglutaconic aciduria type I, beta-ketothiolase deficiency, Barth syndrome, biotinidase deficiency, holocarboxylase synthetase deficiency

Elevated C5-OH acylcarnitine may be detected during NBS or plasma acylcarnitine analysis due to multiple inherited disorders. One group of disorders leads to defects in the metabolism of leucine or isoleucine—two of the branched-chain amino acids. Another group of disorders results from deficiency of the cofactor biotin, which is necessary for the proper function of the biotin-dependent carboxylases. Most of the biotin-dependent carboxylases are also involved in branched-chain amino acid metabolism. Barth syndrome can also lead to elevations of branched-chain amino acid intermediates, resulting in elevated C5-OH on NBS or plasma acylcarnitine analysis. Some healthy neonates may have abnormal elevation of C5-OH on NBS due to 3MCC deficiency in the mother.

Patients with elevated C5-OH may present with a wide range of symptoms that depend on the underlying genetic cause. Some disorders, such a 3HMG deficiency, can cause a very severe presentation within the first days of life. In contrast, most patients with 3MCC deficiency typically remain asymptomatic despite the presence of the biochemical abnormalities. Many of these disorders have some treatment, such as dietary therapy. Early diagnosis is critical in determining the severity of the underlying disorder to avoid irreversible damage and improve long-term outcomes.

This panel covers the vast majority of genetic conditions that can cause elevated C5-OH on newborn screening or acylcarnitine analysis. The rare conditions, however, which include 3-methylglutaconic aciduria type V (DNAJC19), Costeff syndrome (OPA3), and MEGDEL syndrome (SERAC1), are not included in this panel.

Most genetic causes of elevated C5-OH are inherited in an autosomal recessive manner. Barth syndrome and 2-methyl-3-hydroxybutyric aciduria are inherited in an X-linked manner.

The prevalence of elevated C5-OH is dependent on laboratory cutoffs and ethnicity. Limited data exist on the rates of false-positive elevations of C5-OH in the NBS setting. The prevalence of confirmed genetic causes of elevated C5-OH has been reported as high as 1 in 3,300 in some ethnic groups.

This panel may be appropriate for:

  • infants with elevated C5-OH on NBS or confirmatory plasma acylcarnitine analysis
  • patients with elevated C5-OH on plasma acylcarnitine analysis with unclear or unavailable urine organic acid results

This test is not appropriate for:

  • individuals of Iraqi Jewish descent due to the high prevalence of Costeff syndrome (a.k.a. 3-methylgutaconic aciduria type III) in this population
  • individuals of Canadian Hutterite descent due to the higher prevalence of 3-methylglutaconic aciduria type V in this population

For considerations for testing please refer to:

  1. American College of Medical Genetics. NBS ACT Sheet. Organic Acidemias. Accessed February 2016.
  2. Baby's first test. Newborn screening. Accessed February 2016.
  3. Baumgartner MR, Suormala T. Inborn metabolic diseases: diagnosis and treatment. 5th ed. Heidelberg: Springer; 2012. Chapter 27, Biotin-responsive disorders; p. 375–384.
  4. Ferreira, C, et al. Barth Syndrome. 2014 Oct 09. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 25299040
  5. Feuchtbaum, L, et al. Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet. Med. 2012; 14(11):937-45. PMID: 22766612
  6. Lamari F, Sedel F, Saudubray J-M.Inborn metabolic diseases: diagnosis and treatment. 5th ed Heidelberg: Springer; 2012. Chapter 35, Disorders of Phospholipid and Glycosphingolipid Synthesis; p. 485–495.
  7. Ogier de Baulny H, Dionisi-Vici C, Wendel U. Inborn metabolic diseases: diagnosis and treatment. 5th ed. Heidelberg: Springer; 2012. Chapter 19, Branched-chain organic acidurias/acidaemias; p. 277–296.
  8. Seashore, MR. The Organic Acidemias: An Overview. 2001 Jun 27. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301313
  9. 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.
  10. Wolf, B. Biotinidase Deficiency. 2000 Mar 24. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301497

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, 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.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ACAT1 NM_000019.3
AUH NM_001698.2
BTD NM_000060.3
HLCS NM_000411.6
HMGCL NM_000191.2
HSD17B10 NM_004493.2
MCCC1 NM_020166.4
MCCC2 NM_022132.4
TAZ NM_000116.4