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Invitae Elevated C4-DC Panel

Test description

The Invitae Elevated C4-DC Panel analyzes up to two genes that are associated with elevations of C4-DC acylcarnitine on plasma acylcarnitine analysis. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.

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Primary panel (2 genes)

SUCLA2-related mitochondrial DNA depletion syndrome/mitochondrial DNA depletion syndrome-5
SUCLG1-related mitochondrial DNA depletion syndrome/mitochondrial DNA depletion syndrome-9

Elevation of C4-DC acylcarnitine may be detected during newborn screening or acylcarnitine analysis and may be due to SUCLA2-related mitochondrial DNA depletion syndrome (MTDPS5) or SUCLG1-related mitochondrial DNA depletion syndrome (MTDPS9). Patients affected by either of these disorders may present with elevated C4-DC and mildly elevated methylmalonic acid in addition to unique, variable phenotypic expression. Patients with MTDPS5 may present with failure to thrive, facial diplegia, hearing loss, hypotonia, delayed motor development, cognitive impairment, spasticity, seizures, early onset encephalomyopathy, dystonia, and Leigh-like MRI abnormalities (PMID: 28358460). Metabolic features include lactic acidosis. MTDPS9 may present with features similar to MTDPS5 or as a severe neonatal form with multiorgan failure and early death (PMID: 20301762).

This panel covers the two known genetic conditions that can cause isolated C4-DC on acylcarnitine analysis.

The genetic causes of elevated C4-DC are inherited in an autosomal recessive manner.

The prevalence of elevated C4-DC is dependent on laboratory cutoffs and ethnicity. The exact prevalence of confirmed genetic causes of elevated C4-DC are unknown. However, less than 100 individuals have been reported with MTDPS5 and MTDPS9 (PMID: 28358460, 20301762). MTDPS9 has a high incidence of 1 in 1700 and a carrier frequency of 1 in 33 in the Faroe Islands due to a founder effect (PMID: 20301762).

This test may be appropriate for patients:

  • with elevated C4-DC on plasma acylcarnitine analysis
  • with elevated urine methylmalonic acid

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
SUCLA2 NM_003850.2
SUCLG1 NM_003849.3