Invitae Elevated C4-OH Test


Test description

The Invitae Elevated C4-OH Test analyzes the HADH gene, which is associated with elevations of C4-OH acylcarnitine on newborn screening (NBS) or plasma acylcarnitine analysis. Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions.

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Primary panel (1 gene)


3-hydroxyacyl-CoA dehydrogenase deficiency, also known as medium/short chain acyl-CoA dehydrogenase deficiency

Elevated C4-OH acylcarnitine may be detected during newborn screening or acylcarnitine analysis due to 3-hydroxyacyl-CoA dehydrogenase deficiency, which is also known as medium/short chain acyl-CoA dehydrogenase (M/SCHAD) deficiency. Patients with this rare disorder show phenotypic variability. Most patients present with hypoketotic hyperinsulinism due to defective allosteric regulation of glutamate dehydrogenase. Patients have also presented with fulminant feeding difficulties, lethargy, hypotonia, liver failure, hepatomegaly with coagulopathy, and even sudden infant death syndrome (SIDS). In addition to elevated C4-OH on acylcarnitine analysis, patients have been reported with various elevations on urine organic acids such as 3-hydroxyglutaric acid, glutaric acid, 4-hydroxybutyric acid, and mild dicarboxylic aciduria. In patients with higher residual enzyme activity, these biochemical abnormalities may only be present with a large protein load or while the patient is ill. Patients who are suspected of having this rare metabolic disorder need to be evaluated immediately, as periods of illness, fever, and fasting may lead to serious decompensation and sudden death. Early diagnosis and detection may improve the long-term outcome of these patients and may prevent sudden death. Patients are responsive to diazoxide therapy.

For patients with a biochemical features that are consistent with M/SCHAD deficiency (elevated C4-OH on acylcarnitines with elevated urine 3-hydroxyglutaric acid and other hydroxydicarboxylic acids), >99% will have two pathogenic variants in HADH.

M/SCHAD deficiency is inherited in an autosomal recessive manner.

The prevalence of elevated C4-OH is dependent on laboratory cutoffs and ethnicity. The overall prevalence of confirmed M/SCHAD deficiency has been estimated at 1 in 500,000.

This test may be appropriate for patients:

  • with elevated C4-OH on newborn screening or plasma acylcarnitine analysis
  • with elevated urine hydroxydicarboxylic acids

For considerations for testing please refer to:

  1. American College of Medical Genetics. NBS ACT Sheet. 3-Hydroxyacyl-Coenzyme A Dehydrogenase Deficiency Medium/Short Chain Acyl-CoA Dehydrogenase (M/SCHAD)Deficiency. Accessed February 2016.
  2. Baby's first test. Newborn screening. Accessed February 2016.
  3. Bennett, MJ, et al. Mitochondrial short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency: a new defect of fatty acid oxidation. Pediatr. Res. 1996; 39(1):185-8. PMID: 8825408
  4. Feuchtbaum, L, et al. Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet. Med. 2012; 14(11):937-45. PMID: 22766612
  5. Morris AMA, Spiekerkoetter U. Inborn metabolic diseases: diagnosis and treatment. 5th ed. Heidelberg: Springer; 2012. Chapter 13, Disorders of mitochondrial fatty acid oxidation and related metabolic pathways; p. 201–216.
  6. Popa, FI, et al. 3-hydroxyacyl-coenzyme a dehydrogenase deficiency: identification of a new mutation causing hyperinsulinemic hypoketotic hypoglycemia, altered organic acids and acylcarnitines concentrations. JIMD Rep. 2012; 2:71-7. PMID: 23430856
  7. Treacy, EP, et al. Short-chain hydroxyacyl-coenzyme A dehydrogenase deficiency presenting as unexpected infant death: A family study. J. Pediatr. 2000; 137(2):257-9. PMID: 10931422
  8. 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.

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
HADH NM_005327.4