The Invitae 3-Methylglutaconic Aciduria Panel analyzes 8 genes that are associated with elevations 3-methylglutaconic acid on urine organic acid analysis. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants can also provide accurate risk assessment and carrier status for at -risk relatives.
AUH CLPB CPS1 DNAJC19 OPA3 SERAC1 TAZ TMEM70
AUH CLPB CPS1 DNAJC19 OPA3 SERAC1 TAZ TMEM70
For a broader analysis of the genetics of organic acidemia:
|AUH||3-methylglutaconyl-CoA hydratase deficiency|
|CLPB||3-methylglutaconic aciduria with cataracts, neurologic involvement and neutropenia (MEGCANN)|
|CPS1||carbamoyl phosphate synthetase 1 deficiency|
|DNAJC19||dilated cardiomyopathy with ataxia (DCMA) syndrome|
|TMEM70||mitochondrial complex 5 deficiency|
Elevated 3-methylglutaconic acid may be detected on urine organic acid analysis due to multiple inherited disorders. Primary 3-methylglutaconic aciduria is due to 3-methylglutaconyl-CoA hydratase deficiency. Patients with this disorder can present in childhood or later in life. Features have included intellectual disability, seizures, hepatopathy, encephalopathy, dysarthria, ataxia, athetoid movement disorder, and progressive leukoencephalopathy, but findings are variable from patient to patient.
Secondary 3-methylglutaconic aciduria is caused by a heterogenous group of disorders that can affect phospholipid remodeling, are associated with the mitochondrial membrane, or remain unknown. Patients with Barth syndrome have cardiomyopathy, neutropenia, skeletal muscle weakness, growth retardation, and intellectual disability. Presentation and severity are variable. In addition to 3-methylglutaconic aciduria, patients with MEGDEL syndrome (also known as MEGDHEL) have deafness, hepatic involvement, encephalopathy, and Leigh syndrome. Hepatic involvement can range anywhere from neonatal hypoglycemia to fulminant liver failure. Regression, dystonia, spasticity, and seizures often present by 2 years of age. Costeff syndrome patients have infantile onset bilateral optic atrophy. Other features include spasticity, extrapyramidal signs, ataxia, dysarthria, and cognitive deficits. DCMA syndrome is characterized by early onset dilated cardiomyopathy and ataxia in addition to 3-methylglutaconic aciduria. Patients with a TMEM70 defect have a variable phenotype which may include, hypertrophic cardiomyopathy, myopathy, dysmorphism, cataracts, psychomotor retardation, lactic acidosis and hyperammonemia. Roughly half of the patients survive past the first week of life. CLPB deficiency (also known as MEGCANN deficiency) ranges from a severe disorder to mild with most patients having a severe neonatal onset. Features include neutropenia accompanied by neurological abnormalities such as hyperekplexia, tonal abnormalities, dysphagia, respiratory insufficiency, microcephaly and seizures. The degree of neutropenia and extent of neurological abnormalities depend on the severity of the disorder. Patients with CPS1 deficiency, a proximal urea cycle disorder, have recently been shown to have 3-methylglutaconic aciduria. CPS1 patients have a severe clinical course often includes hyperammonemic encephalopathy with symptoms such as lethargy, poor feeding, vomiting, and seizures that can lead to coma and death if untreated.
Primary and secondary 3-methylglutaconic aciduria that causes persistent elevations of 3-methylglutaconic acid is very rare. Due to the rarity of this condition, the percent of 3-methylglutaconic aciduria attributed to pathogenic variants in genes on this panel is currently unknown.
Most genetic causes of 3-methylglutaconic aciduria that are tested on this panel are inherited in an autosomal recessive manner. Barth syndrome is inherited in an X-linked manner.
A recent newborn screening study in the U.S. has estimated that the prevalence of 3-methylglutaconic aciduria is 1 in 1,000,000 (PMID: 22766612).
This panel may be appropriate for:
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|