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Invitae Organic Acidemias Panel
Test description
The Invitae Organic Acidemias Panel analyzes up to 56 genes that are associated with organic acidemia. This panel may be appropriate for patients who have the signs and symptoms of an organic acidemia, including increased levels of urine organic acids, metabolic acidosis with increased anion gap, and metabolic decompensation during periods of illness, fasting, trauma, or surgery. Sick infants may present as if they have sepsis. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions.
Genes tested
Primary panel
ACAD8 ACADSB ACAT1 ACSF3 ASPA AUH BCKDHA BCKDHB BTD D2HGDH DBT DNAJC19 ETFA ETFB ETFDH ETHE1 FBP1 FTCD GCDH GSS HIBCH HLCS HMGCL HSD17B10 IDH2 IVD L2HGDH MCCC1 MCCC2 MCEE MLYCD MMAA MMAB MMACHC MMADHC MUT OPA3 OPLAH OXCT1 PCCA PCCB POLG PPM1K SERAC1 SLC25A1 SUCLA2 SUCLG1 TAZ TMEM70
Add-on Kreb Cycle Defect Genes
DHTKD1 DLD FH NFU1 OGDH SLC13A5 SLC25A19
The inherited disorders of Kreb cycle metabolism will cause elevations of Kreb cycle intermediates on urine organic acid analysis. Young infants and urine samples that are very dilute will also have elevations of Kreb cycle intermediates on urine organic acid analysis. Given the elevations that can arise on urine organic acid analysis, analyzing the genes associated with these disorders may be appropriate. These genes can be included at no additional charge.
Order test
Primary panel (49 genes)
Customized gene selection (0 included, 0 excluded)
ACAD8 ACADSB ACAT1 ACSF3 ASPA AUH BCKDHA BCKDHB BTD D2HGDH DBT DNAJC19 ETFA ETFB ETFDH ETHE1 FBP1 FTCD GCDH GSS HIBCH HLCS HMGCL HSD17B10 IDH2 IVD L2HGDH MCCC1 MCCC2 MCEE MLYCD MMAA MMAB MMACHC MMADHC MUT OPA3 OPLAH OXCT1 PCCA PCCB POLG PPM1K SERAC1 SLC25A1 SUCLA2 SUCLG1 TAZ TMEM70
Add-on Kreb Cycle Defect Genes (7 genes)
Customized gene selection (0 included, 0 excluded)
The inherited disorders of Kreb cycle metabolism will cause elevations of Kreb cycle intermediates on urine organic acid analysis. Young infants and urine samples that are very dilute will also have elevations of Kreb cycle intermediates on urine organic acid analysis. Given the elevations that can arise on urine organic acid analysis, analyzing the genes associated with these disorders may be appropriate. These genes can be included at no additional charge.
DHTKD1 DLD FH NFU1 OGDH SLC13A5 SLC25A19
Clinical information
Disorders tested
| Gene | Disorder |
|---|---|
| ACAD8 | isobutyryl-CoA dehydrogenase (IBD) deficiency |
| ACADSB | short-branched chain acyl-CoA dehydrogenase (SBCAD) deficiency |
| ACAT1 | beta-ketothiolase deficiency |
| ACSF3 | combined malonic and methylmalonic aciduria |
| ASPA | Canavan disease |
| AUH | 3-methylglutaconic acidemia type I |
| BCKDHA | maple syrup urine disease (MSUD) |
| BCKDHB | maple syrup urine disease (MSUD) |
| BTD | biotinidase deficiency |
| D2HGDH | D-2-hydroxyglutaric aciduria type I |
| DBT | maple syrup urine disease (MSUD) |
| DNAJC19 | dilated cardiomyopathy with ataxia syndrome (causes 3-methylglutaconic aciduria) |
| ETFA | multiple acyl-CoA dehydrogenase deficiency (a.k.a. glutaric aciduria type II) |
| ETFB | multiple acyl-CoA dehydrogenase deficiency (a.k.a. glutaric aciduria type II) |
| ETFDH | multiple acyl-CoA dehydrogenase deficiency (a.k.a. glutaric aciduria type II) |
| ETHE1 | ethylmalonic encephalopathy |
| FBP1 | fructose 1,6-Bisphosphatase deficiency |
| FTCD | glutamate formiminotransferase deficiency (FIGLU |
| GCDH | glutaric acidemia type I |
| GSS | glutathione synthetase deficiency |
| HIBCH | 3-hyroxyisobutyryl-CoA hydrolase deficiency |
| HLCS | holocarboxylase synthetase deficiency |
| HMGCL | 3-hydroxy-3-methylglutaryl-CoA lyase (3HMG) deficiency |
| HSD17B10 | 2-methyl-3-hydroxybutyric aciduria (2M3HBA) |
| IDH2 | D-2-hydroxyglutaric aciduria type II |
| IVD | isovaleric acidemia (IVD) |
| L2HGDH | L-2-hydroxyglutaric aciduria |
| MCCC1 | 3-methylcrotonyl-CoA carboxylase (3MCC) deficiency |
| MCCC2 | 3-methylcrotonyl-CoA carboxylase (3MCC) deficiency |
| MCEE | methylmalonic acidemia |
| MLYCD | malonic acidemia |
| MMAA | cobalamin A deficiency |
| MMAB | cobalamin B deficiency |
| MMACHC | cobalamin C deficiency |
| MMADHC | cobalamin D deficiency |
| MUT | methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency |
| OPA3 | Costeff syndrome / 3-methylglutaconic aciduria type III |
| OPLAH | 5-oxoprolinase deficiency |
| OXCT1 | SCOT deficiency |
| PCCA | propionic acidemia |
| PCCB | propionic acidemia |
| POLG | causes 3-methylglutaconic aciduria |
| PPM1K | maple syrup urine disease (MSUD), variant type |
| SERAC1 | Megdel Syndrome |
| SLC25A1 | D,L-2-hydroxyglutaric aciduria |
| SUCLA2 | succinate-CoA ligase deficiency, methylmalonic aciduria |
| SUCLG1 | succinate-CoA ligase deficiency, methylmalonic aciduria |
| TAZ | Barth syndrome |
| TMEM70 | causes 3-methylglutaconic aciduria |
Clinical description
Organic acidemias are a group of inherited metabolic disorders that are caused by a disruption of intermediary metabolism. Deficiencies or absence of specific enzymes involved in amino acid metabolism (particularly branched-chain amino acid metabolism) lead to increased accumulation of toxic intermediates called organic acids. The increased amounts of organic acids are detectable in the urine by urine organic acid analysis. The main types of organic acidemia are methylmalonic acidemia, propionic acidemia, isovaleric acidemia, and maple syrup urine disease. Affected infants often present with poor feeding, hypotonia, abnormal liver function tests, neutropenia, unusual odor, vomiting, metabolic acidosis with increased anion gap, ketoacidosis, seizures, and lethargy progressing to coma or death if untreated. Secondary hypoglycemia, carnitine deficiency, and hyperammonemia may also be present. Some patients may also have cardiomyopathy or pancreatitis. Early diagnosis is crucial to avoid neurologic involvement and death. Many organic acidemias have characteristic profiles on urine organic acid analysis. Some patients may only excrete the biochemical abnormalities during metabolic crisis and others may be low excretors; in these cases, molecular testing may be needed to make the diagnosis.
Inheritance
The majority of the organic acidemias are inherited in an autosomal recessive fashion. 2-methyl-3-hydroxybutyric aciduria is inherited in an X-linked manner.
Prevalence/Incidence
The organic acidemias are individually rare, with incidences ranging between 1 in 50,000 and 1 in 100,000 births. Collectively, the incidence has been reported at 1 in 7,400 newborns. Certain ethnicities may have a higher prevalence for organic acidemias.
Considerations for testing
This test is appropriate for:
- patients who present with lethargy, hypotonia, metabolic acidosis with increased anion gap, and ketoacidosis, with or without hyperammonemia
- patients with nonspecific findings on urine organic acid analysis, in whom an organic acidemia is still suspected
References
- Nizon, M, et al. Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias. Orphanet J Rare Dis. 2013; 8:148. PMID: 24059531
- Baumgartner, MR, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014; 9:130. PMID: 25205257
- Feuchtbaum, L, et al. Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet. Med. 2012; 14(11):937-45. PMID: 22766612
- American College of Medical Genetics. NBS ACT Sheets and Algorithm Table. http://www.ncbi.nlm.nih.gov/books/NBK55827/ Accessed February 2016.
- Schiff M, Ogier de Baulny H, Dionisi-Vici C. Inborn metabolic diseases: diagnosis and treatment. 6th ed. Heidelberg: Springer; 2016. Chapter 18, Branched-chain organic acidurias/acidaemias; p. 289–293.
Management guidelines
For management recommendations please refer to:
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 |
|---|---|---|---|
| ACAD8 | NM_014384.2 | ||
| ACADSB | NM_001609.3 | ||
| ACAT1 | NM_000019.3 | ||
| ACSF3 | NM_174917.4 | ||
| ASPA | NM_000049.2 | ||
| AUH | NM_001698.2 | ||
| BCKDHA | NM_000709.3 | ||
| BCKDHB | NM_183050.2 | ||
| BTD | NM_000060.3 | ||
| D2HGDH | NM_152783.4 | ||
| DBT | NM_001918.3 | ||
| DHTKD1 | NM_018706.6 | ||
| DLD | NM_000108.4 | ||
| DNAJC19 | NM_145261.3 | ||
| ETFA | NM_000126.3 | ||
| ETFB | NM_001985.2 | ||
| ETFDH | NM_004453.3 | ||
| ETHE1 | NM_014297.3 | ||
| FBP1 | NM_000507.3 | ||
| FH | NM_000143.3 | ||
| FTCD | NM_006657.2 | ||
| GCDH | NM_000159.3 | ||
| GSS | NM_000178.2 | ||
| HIBCH | NM_014362.3 | ||
| HLCS | NM_000411.6 | ||
| HMGCL | NM_000191.2 | ||
| HSD17B10 | NM_004493.2 | ||
| IDH2 | NM_002168.3 | ||
| IVD | NM_002225.3 | ||
| L2HGDH | NM_024884.2 | ||
| MCCC1 | NM_020166.4 | ||
| MCCC2 | NM_022132.4 | ||
| MCEE | NM_032601.3 | ||
| MLYCD | NM_012213.2 | ||
| MMAA | NM_172250.2 | ||
| MMAB | NM_052845.3 | ||
| MMACHC | NM_015506.2 | ||
| MMADHC | NM_015702.2 | ||
| MUT | NM_000255.3 | ||
| NFU1 | NM_001002755.2 | ||
| OGDH | NM_002541.3 | ||
| OPA3 | NM_025136.3 | ||
| OPLAH | NM_017570.4 | ||
| OXCT1 | NM_000436.3 | ||
| PCCA | NM_000282.3 | ||
| PCCB | NM_000532.4 | ||
| POLG | NM_002693.2 | ||
| PPM1K | NM_152542.4 | ||
| SERAC1 | NM_032861.3 | ||
| SLC13A5 | NM_177550.4 | ||
| SLC25A1 | NM_005984.4 | ||
| SLC25A19 | NM_021734.4 | ||
| SUCLA2 | NM_003850.2 | ||
| SUCLG1 | NM_003849.3 | ||
| TAZ | NM_000116.4 | ||
| TMEM70 | NM_017866.5 |
Resources
References
- American College of Medical Genetics. NBS ACT Sheets and Algorithm Table. http://www.ncbi.nlm.nih.gov/books/NBK55827/ Accessed February 2016.
- Baumgartner, MR, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014; 9:130. PMID: 25205257
- Feuchtbaum, L, et al. Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet. Med. 2012; 14(11):937-45. PMID: 22766612
- Nizon, M, et al. Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias. Orphanet J Rare Dis. 2013; 8:148. PMID: 24059531
- Schiff M, Ogier de Baulny H, Dionisi-Vici C. Inborn metabolic diseases: diagnosis and treatment. 6th ed. Heidelberg: Springer; 2016. Chapter 18, Branched-chain organic acidurias/acidaemias; p. 289–293.
