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Invitae Fatty Acid Oxidation Defects Panel
Test description
The Invitae Fatty Acid Oxidation Defects Panel analyzes up to 35 genes that are known to be associated with steps in the fatty acid oxidation pathway. Each fatty acid oxidation disorder (FAOD) is due to a specific enzyme or transporter defect in the fatty acid oxidation metabolic pathway. The FAODs are genetically heterogeneous.
This test may be appropriate for anyone in whom a diagnosis of an FAOD is suspected based on clinical symptoms, laboratory findings, or a combination of both. Additionally, many of these genes cause conditions tested on the US Newborn Screening (NBS) panel. The Invitae FAOD Panel may be appropriate for infants who have a presumptive positive biochemical test on NBS, for sick or premature infants with confounding factors complicating NBS interpretation, and even for infants with a normal result on a prior NBS. Many FAODs are episodic, and abnormal metabolites may only be detected during a period of physiologic stress or metabolic crisis.
Genes tested
Primary panel
ACADM ACADS ACADSB ACADVL CPT1A CPT2 ETFA ETFB ETFDH HADH HADHA HADHB HMGCL HMGCS2 MLYCD SLC22A5 SLC25A20
Add-on 2,4-dienoyl-CoA reductase deficiency gene
NADK2
In addition to the primary panel, clinicians can also choose to include NADK2, a gene that has preliminary evidence of association with 2,4-Dienoyl-CoA reductase deficiency. At this time, the association of NADK2 with 2,4-Dienoyl-CoA reductase deficiency remains uncertain, but some clinicians may wish to include genes that may prove to be clinically significant in the future. These genes can be added at no additional charge.
Add-on Riboflavin Transporter Deficiency Genes
SLC52A1 SLC52A2 SLC52A3
Patients with riboflavin transporter deficiency can have elevations on plasma acylcarnitine analysis similar to patients with Multiple-Acyl CoA dehydrogenase (MAD) deficiency. Given the biochemical overlap between riboflavin transporter deficiency and MAD deficiency, analyzing these genes may be appropriate. These genes can be included at no additional charge.
Add-on muscle glycogen storage disorders
ALDOA ENO3 GAA GBE1 GYG1 GYS1 LAMP2 LDHA PFKM PGAM2 PHKA1 PHKB PYGM RBCK1
Order test
Primary panel (17 genes)
Customized gene selection (0 included, 0 excluded)
ACADM ACADS ACADSB ACADVL CPT1A CPT2 ETFA ETFB ETFDH HADH HADHA HADHB HMGCL HMGCS2 MLYCD SLC22A5 SLC25A20
Add-on 2,4-dienoyl-CoA reductase deficiency gene (1 gene)
Customized gene selection (0 included, 0 excluded)
In addition to the primary panel, clinicians can also choose to include NADK2, a gene that has preliminary evidence of association with 2,4-Dienoyl-CoA reductase deficiency. At this time, the association of NADK2 with 2,4-Dienoyl-CoA reductase deficiency remains uncertain, but some clinicians may wish to include genes that may prove to be clinically significant in the future. These genes can be added at no additional charge.
NADK2
Add-on Riboflavin Transporter Deficiency Genes (3 genes)
Customized gene selection (0 included, 0 excluded)
Patients with riboflavin transporter deficiency can have elevations on plasma acylcarnitine analysis similar to patients with Multiple-Acyl CoA dehydrogenase (MAD) deficiency. Given the biochemical overlap between riboflavin transporter deficiency and MAD deficiency, analyzing these genes may be appropriate. These genes can be included at no additional charge.
SLC52A1 SLC52A2 SLC52A3
Add-on muscle glycogen storage disorders (14 genes)
Customized gene selection (0 included, 0 excluded)
ALDOA ENO3 GAA GBE1 GYG1 GYS1 LAMP2 LDHA PFKM PGAM2 PHKA1 PHKB PYGM RBCK1
Clinical information
Disorders tested
- fatty-acid oxidation disorders
- 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2D) deficiency
- carnitine-acylcarnitine translocase (CACT) deficiency
- carnitine palmitoyltransferase type I (CPT I) deficiency
- carnitine palmitoyltransferase type II (CPT II) deficiency
- HMG-CoA Lyase deficiency also known as 3-hydroxy-3-methylglutaryl-CoA lyase deficiency
- long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
- malonyl-CoA decarboxylase deficiency
- medium chain acyl-CoA dehydrogenase (MCAD) deficiency
- medium/short chain acyl-CoA dehydrogenase (M/SCHAD) deficiency
- mitochondrial trifunctional protein (TFP) deficiency
- multiple acyl-CoA dehydrogenase (MCAD) deficiency (MADD) – also known as glutaric acidemia type II
- NAD kinase 2 (NADK2) deficiency
- primary carnitine deficiency – also known as carnitine transporter deficiency
- short chain acyl-CoA (SCAD) dehydrogenase deficiency
- short-branched chain acyl-CoA dehydrogenase (SBCAD) deficiency – also known as 2-methylbutyryl-CoA dehydrogenase
- systemic primary carnitine deficiency
- very long chain acyl-CoA dehydrogenase (VLCAD) deficiency
Clinical description
Fatty acid oxidation disorders are a broad group of inherited metabolic conditions that result from the inability to adequately metabolize fats for energy. In individuals with an FAOD, fats cannot be broken down, so fatty acids accumulate in tissues, there is a decrease in available ATP, gluconeogenesis cannot occur, and sufficient ketones cannot be generated. This results in an overall lack of energy for tissues and the potential for an acute metabolic crisis.
Fatty acid oxidation disorders have wide clinical heterogeneity, with specific symptoms and laboratory findings corresponding to the location of the metabolic block. In general, symptoms are episodic and correlate with periods of fasting or physiologic stress. During these crises, many patients experience lethargy, fasting hypoketotic hypoglycemia that may progress to metabolic acidosis, liver dysfunction, hypoglycemic seizures, coma, and death. Muscle tissues (both cardiac and skeletal) consume large quantities of fats when glucose is not available;consequently, many individuals with FAOD experience muscular symptoms such as cardiomyopathy, exercise intolerance, and muscle damage due to significant muscle cramping or rhabdomyolysis during a metabolic crisis. Undiagnosed FAODs have also been hypothesized to be the cause of up to 5% of unexpected sudden infant death syndrome (SIDS) cases and other instances of unexplained sudden death. Laboratory findings can include hypoketotic hypoglycemia, elevated creatinine kinase, elevated dicarboxylic acids on urine organic acids, decreased free carnitine, and increased acylcarnitine species corresponding to the metabolic block.
FAODs can present at any time during an individual’s lifespan, and some conditions have infantile through adult presentations. FAODs are often unmasked during a period that combines fasting with physiologic stress, such as illness. These periods increase the metabolic rate and are often accompanied by a diminished appetite; consequently, the body turns to fats for energy. The long-term prognosis for FAOD is generally good once a diagnosis is obtained and interventions such as dietary modifications, medications, and illness protocols are implemented.
Inheritance
All conditions covered by this test are inherited in an autosomal recessive manner. Males and females are equally affected.
Prevalence/Incidence
Fatty acid oxidation disorders are one of the most common groups of inherited metabolic disorders. Collectively, the overall incidence of all FAODs is 1 in 10,000–14,000 live births.
Incidence of individual FAOD is variable. The incidences of some of the more common conditions are listed below. Adult-onset forms are under-recognized and these numbers are likely low:
- MCAD: California 1 in 19,000; Northern Germany 1 in 4,900; Japan 1 in 51,000
- VLCAD: United States 1 in 30,000
Considerations for testing
This test may be appropriate for:
- patients who present with lethargy and hypoketotic hypoglycemia, with or without hyperammonemia
- patients with nonspecific, negative, or unavailable findings on plasma acylcarnitines or urine organic acid analysis in whom a fatty-acid oxidation defect is still suspected
References
- Kompare, M, Rizzo, WB. Mitochondrial fatty-acid oxidation disorders. Semin Pediatr Neurol. 2008; 15(3):140-9. PMID: 18708005
- Rinaldo, P, et al. Sudden and unexpected neonatal death: a protocol for the postmortem diagnosis of fatty acid oxidation disorders. Semin. Perinatol. 1999; 23(2):204-10. PMID: 10331471
- Wilcox, RL, et al. Postmortem screening for fatty acid oxidation disorders by analysis of Guthrie cards with tandem mass spectrometry in sudden unexpected death in infancy. J. Pediatr. 2002; 141(6):833-6. PMID: 12461502
- Leslie, ND, et al. Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. 2009 May 28. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301763
- Matern, D, Rinaldo, P. Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. 2000 Apr 20. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301597
- Michot, C, et al. LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood. Hum. Mutat. 2010; 31(7):E1564-73. PMID: 20583302
- Michot, C, et al. Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia. J. Inherit. Metab. Dis. 2012; 35(6):1119-28. PMID: 22481384
Assay
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 |
|---|---|---|---|
| ACADM | NM_000016.5 | ||
| ACADS | NM_000017.3 | ||
| ACADSB | NM_001609.3 | ||
| ACADVL | NM_000018.3 | ||
| ALDOA | NM_000034.3 | ||
| CPT1A | NM_001876.3 | ||
| CPT2 | NM_000098.2 | ||
| ENO3 | NM_053013.3 | ||
| ETFA | NM_000126.3 | ||
| ETFB | NM_001985.2 | ||
| ETFDH | NM_004453.3 | ||
| GAA* | NM_000152.3 | ||
| GBE1 | NM_000158.3 | ||
| GYG1 | NM_004130.3 | ||
| GYS1 | NM_002103.4 | ||
| HADH | NM_005327.4 | ||
| HADHA | NM_000182.4 | ||
| HADHB | NM_000183.2 | ||
| HMGCL | NM_000191.2 | ||
| HMGCS2 | NM_005518.3 | ||
| LAMP2 | NM_002294.2 | ||
| LDHA | NM_005566.3 | ||
| MLYCD | NM_012213.2 | ||
| NADK2 | NM_001085411.2 | ||
| PFKM | NM_000289.5 | ||
| PGAM2 | NM_000290.3 | ||
| PHKA1 | NM_002637.3 | ||
| PHKB | NM_000293.2; NM_001031835.2 | ||
| PYGM | NM_005609.3 | ||
| RBCK1 | NM_031229.3 | ||
| SLC22A5 | NM_003060.3 | ||
| SLC25A20 | NM_000387.5 | ||
| SLC52A1 | NM_017986.3 | ||
| SLC52A2 | NM_024531.4 | ||
| SLC52A3 | NM_033409.3 |
GAA: Analysis includes the promoter variant NM_000152.3:c.-32-13T>G as well as the common exon 18 deletion.
Resources
References
- Kompare, M, Rizzo, WB. Mitochondrial fatty-acid oxidation disorders. Semin Pediatr Neurol. 2008; 15(3):140-9. PMID: 18708005
- Leslie, ND, et al. Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. 2009 May 28. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301763
- Matern, D, Rinaldo, P. Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. 2000 Apr 20. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301597
- Michot, C, et al. LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood. Hum. Mutat. 2010; 31(7):E1564-73. PMID: 20583302
- Michot, C, et al. Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia. J. Inherit. Metab. Dis. 2012; 35(6):1119-28. PMID: 22481384
- Rinaldo, P, et al. Sudden and unexpected neonatal death: a protocol for the postmortem diagnosis of fatty acid oxidation disorders. Semin. Perinatol. 1999; 23(2):204-10. PMID: 10331471
- Wilcox, RL, et al. Postmortem screening for fatty acid oxidation disorders by analysis of Guthrie cards with tandem mass spectrometry in sudden unexpected death in infancy. J. Pediatr. 2002; 141(6):833-6. PMID: 12461502
