Organic Aciduria Panel

The organic acidurias (OAs) are a heterogeneous group of disorders characterized biochemically by the accumulation of non-amino organic acids in the urine and blood (Kölker et al. 2013. PubMed ID: 23512157). OAs arise as a result of a defect in an enzyme or transport protein that typically plays a role in one of the metabolic pathways required for the catabolism of amino acids, carbohydrates, or lipids (Villani et al. 2017. PubMed ID: 27613073). Although newborns appear clinically unaffected, onset of symptoms often occurs within hours to months of birth in many patients (Burton. 1998. PubMed ID: 9832597). Other patients may remain asymptomatic in the early years, instead presenting with a late-onset or intermittent form of disease (Burton. 1998. PubMed ID: 9832597; Villani et al. 2017. PubMed ID: 27613073). 

The clinical presentations of OAs can vary, but include lethargy that may progress to coma without quick treatment, feeding difficulties, failure to thrive, developmental delays, seizures, abnormalities in muscle tone, movement disorders, cardiomyopathy, optic nerve atrophy, abnormalities of the basal ganglia and liver, pancreatitis, respiratory distress, and vomiting due to protein intolerance. Biochemically, these patients experience persistent overwhelming or intermittent episodic occurrences of metabolic decompensation, during which metabolic acidosis with an increased anion gap is observed. This may be accompanied by ketoacidosis, lactic acidosis, and hyperammonemia (Burton. 1998. PubMed ID: 9832597; Kölker et al. 2013. PubMed ID: 23512157; Villani et al. 2017. PubMed ID: 27613073; Dimitrov et al. 2021. 32412122). During episodes of decompensation, affected individuals are at risk of developing irreversible, life-threatening organ damage unless treated quickly (Kölker et al. 2013. PubMed ID: 23512157). 

Only one of the genes in this panel (HSD17B10, associated with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency) is 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). 

Although the individual OAs are rare disorders, collectively the incidence of OAs is estimated at between ~1/3,000-12,500 (Villani et al. 2017. PubMed ID: 27613073; Waters et al. 2018. PubMed ID: 30479748). 

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

This sequencing panel includes genes that have been associated with organic acidurias 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 exception is HSD17B10, which exhibits X-linked inheritance, and DHTKD1, which can exhibit both autosomal dominant and recessive inheritance. Pathogenic defects in the genes in this panel include missense, nonsense, splice 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 Biotin Metabolism: HLCS

Disorders of Amino Acid Metabolism: ACADSB, ACSF3, ALDH6A1, AUH, BCKDHA, BCKDHB, DBT, DHTKD1, DLD, ECHS1, GCDH, GSS, HIBCH, HMGCL, HSD17B10, IVD, MCCC1, MCCC2, MCEE, MLYCD, MMUT, PCCA, PCCB

Disorders of Cobalamin Metabolism: CD320, MMAA, MMAB, MMACHC, MMADHC

Disorders of Fatty Acid and Ketone Metabolism: ACAT1, HADHA, OXCT1

Disorders of Nuclear Encoded Mitochondrial Genes: SERAC1, SLC25A1, TMEM70

Disorders of Riboflavin Metabolism Regulation: ETFA, ETFB, ETFDH

Disorders Related to the Citric Acid Cycle: D2HGDH, IDH2, L2HGDH

Of the genes included in this test, no large copy number variants (gross deletions or duplications/insertions) have been observed in the ACADSB,   ALDH6A1, CD320, DHTKD1, DLD, ETFB, HIBCH, HSD17B10, MCCC2, MCEE, MMAB, MMADHC, or SLC25A1 genes. Large copy number variants have been reported as a relatively common cause of disease in the BCKDHA, BCKDHB, DBT, HMGCL, L2HGDH, MLYCD, and PCCA genes. Copy number variants have been reported as a more rare cause of disease in the remaining genes on this panel. To our knowledge, de novo variants have not been reported for the genes in this panel.

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

The clinical sensitivity of this specific grouping of genes is difficult to estimate as we are unaware of any reports in the literature in which these genes have been sequenced together in a patient cohort with suspected organic acidemia as the primary indication for testing. The clinical sensitivity of sequencing the individual genes is high in patient groups with biochemical or enzymatic diagnoses of the relevant disorders. Analytical sensitivity is expected to be high as most variants reported in these genes are detectable via sequencing.

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

This panel typically provides 99.8% 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).

For the IDH2 gene, this test only includes sequencing of exon 4 containing the c.418 and c.419 nucleotides, plus 20 bp of flanking DNA on each side. At this time, IDH2 sequence variants not located at nucleotides c.418 or c.419 will not be reported (see the IDH2 gene summary for further details).

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).