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  • Test code: 06218
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Fumarase Deficiency Test

Test description

The Invitae Fumarase Deficiency Test analyzes the FH gene that is associated with Fumarase deficiency. The FH gene encodes the fumarate hydratase enzyme. Fumarase deficiency is a disorder of brain and muscle with infantile or childhood onset. Affected individuals have markedly elevated urinary levels of fumaric acid. This test is useful for the diagnosis of patients whose clinical symptoms or biochemical findings indicate Fumarase deficiency. Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants provide risk assessment and carrier status for at-risk relatives.

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Primary panel (1 gene)
  • fumarase deficiency

The FH gene encodes the fumarate hydratase enzyme which catalyzes the conversion of fumarate to malate in the tricarboxylic acid (TCA)/Krebs cycle. Biallelic pathogenic mutations in the FH gene cause fumarase deficiency. Affected individuals show elevated urinary fumaric acid levels and often have microcephaly, distinctive facial features, structural abnormalities of the brain and developmental delay. In severely affected individuals, FH deficiency causes infantile encephalopathy, along with symptoms of failure to thrive, hypotonia, lethargy, and seizures. Mildly affected individuals are less likely to develop epilepsy or present structural abnormalities of the brain and may have developmental delays with a diagnosis of mild or moderate intellectual disability during childhood. Carriers of a single pathogenic FH mutation have an increased risk to develop hereditary leiomyomatosis and renal cell cancer.

FH is the only gene known to be associated with fumarase deficiency. However, due to the rarity of this condition, the percent of fumarase deficiency attributed to pathogenic variants in FH is currently unknown.

Fumarate hydratase deficiency is inherited in an autosomal recessive manner. FH-associated hereditary leiomyomatosis and renal cell cancer is inherited in an autosomal dominant manner.

Fumarase deficiency is a very rare disorder, the prevalence of this condition in the general population is unknown.

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
FH NM_000143.3