Trimethylaminuria via the FMO3 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesPriceCPT Code Copy CPT Codes
8503 FMO3$890 81479,81479 Add to Order

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

The great majority of tests are completed within 26 days.

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Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Trimethylaminuria (TMAU, OMIM 602079), also called fish-odor syndrome, is a metabolic disease that is due to the malfunction of the hepatic enzyme flavin-containing monooxygenase 3 (FMO3). The FMO3 enzyme catalyzes the oxidation of fishy-smelling trimethylamine, found in foods rich in choline and carnitine, into odorless trimethylamine-N-oxide. In patients with TMAU, FMO3 malfunction results in the accumulation of trimethylamine in the body and subsequent release in the breath, saliva, sweat, urine, and other body secretions (Cashman et al. Curr Drug Metab 4:151-170, 2003). Symptoms are intermittent and usually begin in childhood. They are exacerbated by environmental factors including diet, emotional stress, and physical activity; they may lead to psychological problems (Rehman Postgrad Med J 75:451-452, 1999). TMAU is more common and more pronounced in women than men.

Genetics

Trimethylaminuria (TMAU) is inherited in an autosomal recessive manner and is caused by mutations in the FMO3 gene (Dolphin et al. Nat Genet 17:491-494, 1997). To date, about 50 FMO3 mutations have been reported. The majority of mutations are missense. Other rare mutations include nonsense, splicing, and small and large deletions. Homozygous mutations in families with or without history of consanguinity and compound heterozygous mutations were detected. Heterozygous carriers may develop a transient form of the disease (Allerston Mol Genet Metab 98:198-202, 2009). The FMO3 gene encodes the flavin-containing monooxygenase 3, one of several enzymes involved in the metabolism of chemical compounds that contain nitrogen, sulfur or phosphorous.

Testing Strategy

For this Next Generation Sequencing (NGS) test, sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for regions not captured or with insufficient number of sequence reads.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This test provides full coverage of all coding exons of the FMO3 gene 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 full coverage as >20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Clinical Sensitivity - Sequencing with CNV

Unknown at this time.

Indications for Test

Patients with strong body odor and increased free trimethylamine excretion in urine, with reduced trimethylamine-N-oxide. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in FMO3.

Gene

Official Gene Symbol OMIM ID
FMO3 136132
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Trimethylaminuria AR 602079

Citations

  • Allerston, C. K., et.al. (2009). "A novel mutation in the flavin-containing monooxygenase 3 gene (FMO3) of a Norwegian family causes trimethylaminuria." Mol Genet Metab 98(1-2): 198-202. PubMed ID: 19577495
  • Cashman, J. R., et.al. (2003). "Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria." Curr Drug Metab 4(2): 151-70. PubMed ID: 12678693
  • Dolphin, C. T., et.al. (1997). "Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome." Nat Genet 17(4): 491-4. PubMed ID: 9398858
  • Rehman, H. U. (1999). "Fish odor syndrome." Postgrad Med J 75(886): 451-2. PubMed ID: 10646019

Ordering/Specimens

Ordering Options

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

Specimen Types

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