The Invitae 3-Methylcrotonyl-CoA Carboxyalse Deficiency Panel analyzes the two genes that are associated with 3-Methylcrotonyl-CoA Carboxyalse (3MCC) deficiency. This test is useful for the diagnosis of patients who are suspected to have 3MCC deficiency according to clinical symptoms, biochemical findings, or abnormal newborn-screening results.
The Invitae Organic Acidemias Panel and the Invitae Elevated C5-OH Panel have been designed to provide a broad genetic analysis of these classes of disorders. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. They can be ordered at no additional cost.
Patients with 3MCC deficiency show a wide range of phenotypic severity, from asymptomatic to more severe. Traditionally, diagnosis relied on ascertainment of symptomatic patients. A wide range of symptoms have been reported, including developmental delay, intellectual disability, seizures, hypotonia, hypoglycemia, metabolic acidosis, ketosis, Reye syndrome, hyperammonemia, secondary carnitine depletion, and even coma or death; however, with the advent of expanded newborn screening, it is now recognized that the vast majority (>90%) of diagnosed individuals are asymptomatic, despite the presence of the characteristic biochemical abnormalities. No phenotype-genotype correlations exist, and recent studies have suggested that symptoms in at least some clinically affected individuals may have an alternative underlying cause.
Patients with 3MCC deficiency typically have biochemical laboratory findings, including elevations of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine on urine organic acid analysis; and elevation of 3-hydroxyisovalerylcarnitine (C5-OH) on newborn screening or plasma acylcarnitine analysis. Asymptomatic mothers may also be diagnosed due to elevated C5-OH in their healthy babies’ newborn-screening result.
Approximately 99% of patients with isolated 3MCC deficiency will have two pathogenic variants in either the MCCC1 or MCCC2 gene.
3MCC deficiency is inherited in an autosomal recessive pattern.
The general prevalence for 3MCC deficiency is estimated at 1 in 41,700–84,700 individuals.
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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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
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|