Disorders of Fatty Acid Oxidation (FAOD) Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10381 ACAD8 81479,81479 Order Options and Pricing
ACAD9 81479,81479
ACADM 81479,81479
ACADS 81405,81479
ACADSB 81479,81479
ACADVL 81406,81479
ACAT1 81479,81479
CPT1A 81479,81479
CPT2 81404,81479
ECHS1 81479,81479
ETFA 81479,81479
ETFB 81479,81479
ETFDH 81479,81479
FLAD1 81479,81479
GLUD1 81406,81479
HADH 81479,81479
HADHA 81406,81479
HADHB 81406,81479
HMGCL 81479,81479
HMGCS2 81479,81479
HSD17B10 81479,81479
LPIN1 81479,81479
MLYCD 81479,81479
NADK2 81479,81479
PPARG 81479,81479
SLC22A5 81405,81479
SLC25A20 81405,81404
SLC25A32 81479,81479
SLC52A1 81479,81479
SLC52A2 81479,81479
SLC52A3 81479,81479
TAFAZZIN 81406,81479
TANGO2 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10381Genes x (33)81479 81404(x2), 81405(x3), 81406(x5), 81479(x56) $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • McKenna Kyriss, PhD

Clinical Features and Genetics

Clinical Features

Fatty acid oxidation (FAO) is required for the generation of energy when glucose supply is limited. A number of clinical disorders have been described that are caused by defects in the enzymes and protein transporters required for FAO. Three main types of clinical presentation are associated with disorders of FAO: (1) a cardiac presentation, which may include cardiomyopathy, arrhythmias and conduction defects, and is often observed in newborns and infants; (2) a hepatic presentation, which includes fasting hypoketotic hypoglycemia with encephalopathy, hepatomegaly and liver dysfunction, and is often first observed during infancy, commonly between ~6-12 months of age; (3) a more mild clinical form that is primarily myopathic in nature, and that can include myalgia, weakness, hypotonia, rhabdomyolysis and myoglobinuria, and may be observed during adolescence and adulthood (Kompare and Rizzo. 2008. PubMed ID: 18708005; Baruteau et al. 2013. PubMed ID: 23053472; Murphy et al. 2016; Houten et al. 2016. PubMed ID: 26474213; Nyhan et al. 2017; Knottnerus et al. 2018. PubMed ID: 29926323; Merritt et al. 2018. PubMed ID: 30740404). In addition, disorders of FAO may first present as sudden infant death syndrome (SIDS), which may later be attributed to a disorder of FAO after a second affected child is identified (van Rijt et al. 2016. PubMed ID: 26907928; Nyhan et al. 2017). Additional symptoms associated with specific disorders may also be observed, such as polyneuropathy or retinopathy (Houten et al. 2016. PubMed ID: 26474213).

Biochemically, patients may be found to have an abnormal acylcarnitine profile, and some patients may also have lactic acidosis, hyperammonemia, elevated liver enzymes, elevated creatine kinase (CK) levels, and/or elevated uric acid. Clinical symptoms are often episodic in nature, and are typically precipitated via some type of stress, such as prolonged exercise, fasting or viral illness. Patients that are treated promptly often fully recover, though they may always be at risk for metabolic decompensation. However, some patients may suffer irreversible neurological damage (Kompare and Rizzo. 2008. PubMed ID: 18708005; Baruteau et al. 2013. PubMed ID: 23053472; Murphy et al. 2016; Houten et al. 2016. PubMed ID: 26474213; Nyhan et al. 2017; Knottnerus et al. 2018. PubMed ID: 29926323; Merritt et al. 2018. PubMed ID: 30740404).

Two of the genes in this panel (HSD17B10, associated with 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, and TAZ, associated with Barth syndrome) are inherited in an X-linked manner. Both males and females with pathogenic HSD17B10 variants may be affected, although females tend to be more mildly affected and may also be asymptomatic (Zschocke. 2012. PubMed ID: 22127393). Female carriers of TAZ genes are typically unaffected, although in rare cases females with other X chromosome abnormalities (such as 45,X, structural abnormalities of the X chromosome, or skewed X-inactivation) may be symptomatic (Ferreira et al. 2020. PubMed ID: 25299040; Sabbah. 2020. PubMed ID: 33001359).

The overall incidence of fatty acid oxidation disorders is estimated at 1/5,000 - 10,000 births, although incidence of specific disorders can be quite variable. The most common disorder in Northern European Caucasians is medium-chain acyl-CoA dehydrogenase deficiency (MCADD), with an estimated prevalence of ~1:20,000 in North America (Merritt et al. 2018. PubMed ID: 30740404). 

Molecular testing is useful to confirm the genetic cause of a clinical diagnosis, which may then be useful for determining appropriate treatment measures, assessment of recurrence risks, and may allow for appropriate screening for potential future symptoms.

Genetics

This sequencing panel includes genes that have been associated with fatty acid oxidation disorders or disorders with overlapping clinical symptoms. The majority of the disorders due to defects in these genes are inherited in an autosomal recessive manner. The only exceptions are GLUD1PPARG, and SLC52A1, which exhibit autosomal dominant inheritance, CPT2, which can exhibit both autosomal dominant and recessive inheritance, and HSD17B10 and TAZ, which exhibit X-linked inheritance. Pathogenic defects in the genes in this panel include missense, nonsense, splicing site variants, small deletions, small insertions/duplications, small indels, and exon-level large deletions (Human Gene Mutation Database).

The genes included in this test are associated with disorders that can be broadly classified into several categories based on the pathways within the cell that are disrupted:

Disorders of Amino Acid or Ketone Metabolism: GLUD1, HMGCL, HMGCS2, HSD17B10

Disorders of Cytoplasmic Triglyceride Metabolism: LPIN1

Disorders of Fatty Acid Oxidation and Transport: ACAD9, ACADM, ACADS, ACADSB, ACADVL, CPT1A, CPT2, ETFA, ETFB, ETFDH, HADH,  HADHA, HADHB, MLYCD, SLC22A5, SLC25A20, TANGO2

Disorders of Niacin, NAD or Riboflavin Metabolism: FLAD1, NADK2, SLC25A32, SLC52A1, SLC52A2, SLC52A3

Disorders of Nuclear Encoded Mitochondrial Genes: TAZ

Regulation of Adipocyte Development and Function: PPARG

Of the genes included in this test, large copy number variants (gross deletions or duplications/insertions) are only a common cause of disease in TANGO2. For the remainder of the genes on this panel, large copy number variants are a relatively rare cause of disease. It should also be noted that, to our knowledge, de novo variants are not commonly reported for the majority of genes in this panel, although they have been reported in GLUD1, PPARG, SLC52A1 and TAZ.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Clinical Sensitivity - Sequencing with CNV PGxome

Due to the genetic heterogeneity of the fatty acid oxidation disorders, the clinical sensitivity of this specific grouping of genes is difficult to estimate. The clinical sensitivity of sequencing the individual genes is high in patient groups with biochemical and/or enzymatic diagnoses of the relevant disorders. 

Clinical sensitivity estimates are available for some of the more commonly reported disorders (see below).

For individuals with a diagnosis of medium-chain acyl-CoA dehydrogenase deficiency (MCADD), ~98% of patients are reported to have pathogenic variants detectable via sequencing (Merritt and Chang. 2019. PubMed ID: 20301597). Of note, the variant c.985A>G (p.Lys304Glu) is found on approximately 70% of pathogenic alleles in individuals of Northern European descent (Merritt et al. 2018. PubMed ID: 30740404).

In one study of individuals with newborn screening results suggestive of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), 44/46 patients (~96%) had biallelic ACADVL variants (Pena et al. 2016. PubMed ID: 27209629). 

Different detection rates of SLC22A5 causative variants have been reported based on different patient identification methods. In one study, ~70% of 70 infants identified based on a positive newborn screen were found to have at least one SLC22A5 variant. In the same study, ~27% of 52 patients identified based on clinical presentation were found to have at least one SLC22A5 variant (Li et al. 2010. PubMed ID: 20574985). However, in studies of patients with more in-depth biochemical analyses or cellularly confirmed carnitine transport deficiency the detection rate is higher. For example, Rose et al. (2012. PubMed ID: 21922592) reported 54 pathogenic alleles in 28 individuals, while Han et al. (2014. PubMed ID: 25132046) reported 39 pathogenic alleles in 20 patients. Based on these studies, clinical sensitivity would be estimated at ~96-98% in patients with confirmed systemic primary carnitine deficiency (SPCD).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.9% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Patients with clinical and/or biochemical features suggestive of a fatty acid oxidation disorder, particularly patients with hypoketotic hypoglycemia and/or an abnormal acylcarnitine profile, are good candidates for this test.

Diseases

Name Inheritance OMIM ID
2,4-dienoyl-CoA reductase deficiency AR 616034
2-Methyl-3-Hydroxybutyric Aciduria XL 300438
2-Methylbutyryl-CoA Dehydrogenase Deficiency AR 610006
3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency AR 246450
3-Methylglutaconic Aciduria Type 2 XL 302060
Alpha-Methylacetoacetic Aciduria AR 203750
Brown-Vialetto-Van Laere Syndrome AR 211530
Brown-Vialetto-Van Laere syndrome 2 AR 614707
Carnitine Palmitoyltransferase I Deficiency AR 255120
Carnitine Palmitoyltransferase II Deficiency, Infantile AR 600649
Carnitine Palmitoyltransferase II Deficiency, Late-Onset AD,AR 255110
Carnitine Palmitoyltransferase II Deficiency, Lethal Neonatal AR 608836
Carnitine-Acylcarnitine Translocase Deficiency AR 212138
Deficiency Of 3-Hydroxyacyl-CoA Dehydrogenase AR 231530
Deficiency Of Butyryl-CoA Dehydrogenase AR 201470
Deficiency Of Isobutyryl-CoA Dehydrogenase AR 611283
Exercise intolerance, riboflavin-responsive AR 616839
Fazio-Londe Disease AR 211500
Glutaric Aciduria, Type 2 AR 231680
Hyperinsulinemic Hypoglycemia, Familial 6 AD 606762
Lipid Storage Myopathy Due to Flavin Adenine Dinucleotide Synthetase Deficiency AR 255100
Lipodystrophy, Familial Partial, Type 3 AD 604367
Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency AR 609016
Malonyl-CoA Decarboxylase Deficiency AR 248360
Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency AR 201450
Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration AR 616878
Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency AR 605911
Mitochondrial Complex I Deficiency due to ACAD9 Deficiency AR 611126
Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency AR 616277
Myoglobinuria, Acute Recurrent, Autosomal Recessive AR 268200
Riboflavin deficiency AD 615026
Systemic Carnitine Deficiency AR 212140
Trifunctional Protein Deficiency AR 609015
Very Long Chain Acyl-CoA Dehydrogenase Deficiency AR 201475

Related Tests

Name
PGxome®
Glutaric Acidemia Type II Panel
Medium Chain Acyl-CoA Dehydrogenase Deficiency via the ACADM Gene
Metabolic Myopathies, Rhabdomyolysis and Exercise Intolerance Panel
Systemic Primary Carnitine Deficiency via the SLC22A5 Gene
Very Long Chain Acyl-CoA Dehydrogenase Deficiency via the ACADVL Gene

Citations

  • Baruteau et al. 2013. PubMed ID: 23053472
  • Ferreira et al. 2020. PubMed ID: 25299040
  • Han et al. 2014. PubMed ID: 25132046
  • Houten et al. 2016. PubMed ID: 26474213
  • Human Gene Mutation Database (Bio-base).
  • Knottnerus et al. 2018. PubMed ID: 29926323
  • Kompare and Rizzo. 2008. PubMed ID: 18708005
  • Li et al. 2010. PubMed ID: 20574985
  • Merritt and Chang. 2019. PubMed ID: 20301597
  • Merritt et al. 2018. PubMed ID: 30740404
  • Murphy et al. 2016. Fatty Acid Oxidation, Electron Transfer and Riboflavin Metabolism Defects. In: Hollak and Lachmann, editors. Inherited Metabolic Disease in Adults: A Clinical Guide. New York: Oxford University Press, p 55-67.
  • Nyhan et al. 2017. Approach to the Child Suspected of Having a Disorder of Fatty Acid Oxidation. In: Hoffmann, Nyhan and Zschocke, editors. Inherited Metabolic Diseases: A Clinical Approach. Berlin: Springer, p 107-111.
  • Pena et al. 2016. PubMed ID: 27209629
  • Rose et al. 2012. PubMed ID: 21922592
  • Sabbah. 2020. PubMed ID: 33001359
  • van Rijt et al. 2016. PubMed ID: 26907928
  • Zschocke. 2012. PubMed ID: 22127393

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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