Invitae Elevated C4 Panel


Test description

The Invitae Elevated C4 Panel analyzes three 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)


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.

Isobutyryl-CoA dehydrogenase deficiency, short chain acyl-CoA dehydrogenase (SCAD) deficiency, ethylmalonic encephalopathy

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. American College of Medical Genetics. NBS ACT Sheet. Short-Chain Acyl-CoA Dehydrogenase (SCAD) Deficiency. Accessed February 2016.
  2. Baby's first test. Newborn screening. Accessed February 2016.
  3. Dweikat, I, et al. Ethylmalonic encephalopathy associated with crescentic glomerulonephritis. Metab Brain Dis. 2012; 27(4):613-6. PMID: 22584649
  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. 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
  6. Papetti, L, et al. Severe early onset ethylmalonic encephalopathy with West syndrome. Metab Brain Dis. 2015; :None. PMID: 26194623
  7. 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
  8. 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
  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. 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
  11. 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

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