Hereditary Leiomyomatosis and Renal Cell Cancer or Fumarase Deficiency via the FH Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
Order Kits


Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1286 FH$750.00 81405 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
Pathogenic variants in the FH gene will be detected by sequencing in 80-100% of individuals suspected of having hereditary leiomyomatosis and renal cell cancer or fumarase deficiency (Pithukpakorn and Toro. GeneReviews, 2010; Ewbank et al. GeneReviews, 2013).

See More

See Less

Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 FH$990.00 81479 Add to Order
Pricing Comment

# of Genes Ordered

Total Price









Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity
Gross deletions and duplications will be detected in up to 14% of individuals affected with HLRCC (Pithukpakorn and Toro. GeneReviews, 2010; Campione et al. J Invest Dermatol 127(9): 2271-2273, 2007). A gross deletion has been reported for fumarase deficiency (Mroch et al. Am J Med Genet A 158A(1): 155-158, 2011).

See More

See Less

Clinical Features
Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is characterized by cutaneous leiomyomata, which is a benign tumor of smooth muscle origin, uterine leiomyomata (fibroids), and/or renal tumors (Badeloe et al. Eur J Dermatol 19(6): 545-551, 2009). The cutaneous leiomyomata occur in the majority of individuals and are located on the trunk, extremities, and sometimes on the face. These skin colored/brown nodules or papules appear at an average age of 25 years and increase in size and number with age. Females are affected with uterine leiomyomata and tend to have irregular or heavy menstruation and pelvic pain. A single aggressive kidney tumor occurs in up to one-third of families, at a median age of 44 years, and can cause hematuria and lower back pain (Pithukpakorn and Toro. GeneReviews. 2010; Sudarshan et al. Nat Clin Pract Urol 4(2):104-110, 2007). Approximately 50% of these renal tumors result in metastasis. Most renal tumors are papillary, but other kidney tumor types include tubulo-papillary renal cell carcinomas to collecting-duct renal cell carcinomas (Badeloe et al., 2009).

Fumurase Hydratase Deficiency, also known as fumaric aciduria and fumarase deficiency, is an inborn error of metabolism that causes rapid progressive neurologic impairment including hypotonia, seizures, and cerebral atrophy (Deschauer et al. Mol Genet Metab. 88(2): 146–152, 2006). The disease is heterogeneous as patients can show different clinical and biochemical features (Ottolenghi et al. Hum Mutat 32(9): 1046–1052, 2011). Most individuals survive only a few months and during this time no leiomyomata or renal tumors have been observed. A parent who is a carrier of a FH mutation for fumurase hydratase deficiency is at an increased risk of HLRCC (Pithukpakorn and Toro., 2010).
HLRCC is inherited in an autosomal dominant manner with high penetrance and is caused by mutations in the FH gene. The FH gene is thought to be a tumor suppressor encoding fumurate hydratase, which is involved in the conversion of fumurate to L-malate in the tricarboxylic acid (Krebs) cycle (Maher. Nephron Exp Nephrol 118(1):e21–e26, 2011; Sudarshan et al. (2007)). It is thought that mutations result in a loss of function leading to increases in cellular fumurate. This increase causes decreased hypoxia-inducible factor (HIF) degradation and overexpression of genes further downstream in the HIF pathway leading to tumor formation (Pithukpakorn and Toro., 2010; Badeloe et al., 2009). No clear genotype-phenotype observations have been observed and HLRCC can occur sporadically or can be inherited. Mutations are located throughout the FH gene with the majority represented by missense, nonsense and small deletions, however small insertions, splicing mutations, and large deletions and insertions have also been reported (Human Gene Mutation Database; Bayley et al. BMC Medical Genetics 9:20, 2008). The second hit within the tumor is thought to occur through loss of the wild-type allele through a mechanism of loss of heterozygosity. There is no strong evidence that somatic mutations of FH have a significant role in sporadic kidney cancer (Sudarshan et al., 2007).

Fumurase Hydratase Deficiency is inherited in an autosomal recessive manner and is caused by a homozygous FH mutation or compound heterozygous mutations in the FH gene. HLRCC vs. fumurase deficiency are likely distinguished as the result of FH gene dosage (Pithukpakorn and Toro., 2010). Mutations are located throughout the FH gene with the majority represented by missense mutations, however nonsense, small deletions and insertions, splicing mutations, and large deletions have also been reported (Human Gene Mutation Database; Bayley et al., 2008).
Testing Strategy
Fumarate hydratase is encoded by exons 1-10 of the FH gene on chromosome 1q42.1.  Testing is accomplished by amplifying each coding exon and ~10 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard dideoxy Sanger sequencing methods and a capillary electrophoresis instrument. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.
Indications for Test
This test is recommended for individuals who have multiple cutaneous leiomyomas (at least one histologically confirmed) or a single leiomyoma and a positive family history of HLRCC or individuals with a biochemical test showing reduced fumarate hydratase enzyme activity or increased concentration of fumaric acid on urine organic acid analysis or carrier testing for Fumurase Hydratase Deficiency. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.


Official Gene Symbol OMIM ID
FH 136850
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Birt-Hogg-Dube Syndrome via FLCN Gene Sequencing with CNV Detection
Hereditary Papillary Renal Cell Carcinoma via the MET Gene
Primary Macronodular Adrenal Hyperplasia via ARMC5 Gene Sequencing with CNV Detection
Von Hippel-Lindau Disease via VHL Gene Sequencing with CNV Detection


Genetic Counselors
  • Badeloe et al. 2009. Clinical and molecular genetic aspects of hereditary multiple cutaneous leiomyomatosis. Eur J Dermatol 19(6): 545-551. PubMed ID: 19939761
  • Bayley et al. (2008). "The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency." BMC Medical Genetics 9: 20. PubMed ID: 18366737
  • Campione et al. (2007). "Cerebral cavernomas in a family with multiple cutaneous and uterine leiomyomas associated with a new mutation in the fumarate hydratase gene." J Invest Dermatol 127(9): 2271-2273. PubMed ID: 17476294
  • Deschauer et al. (2006). "Molecular and biochemical investigations in fumarase deficiency." Mol Genet Metab 88(2): 146–152. PubMed ID: 16510303
  • Ewbank et al. (2013). "Fumarate Hydratase Deficiency." GeneReviews. PubMed ID: 20301679
  • Human Gene Mutation Database (Bio-base).
  • Maher ER. 2011. Genetics of Familial Renal Cancers. Nephron Experimental Nephrology 118: e21–e26. PubMed ID: 21071978
  • Mroch et al. (2011). "Detection of a novel FH whole gene deletion in the propositus leading to subsequent prenatal diagnosis in a sibship with fumarase deficiency." Am J Med Genet A 158A(1): 155-158. PubMed ID: 22069215
  • Ottolenghi et al. (2011). "Clinical and Biochemical Heterogeneity Associated with Fumarase Deficiency." Hum Mutat 32(9): 1046–1052. PubMed ID: 21560188
  • Pithukpakorn M, Toro JR. 1993. Hereditary Leiomyomatosis and Renal Cell Cancer. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle,. PubMed ID: 20301430
  • Sudarshan et al. (2007). "Mechanisms of disease: hereditary leiomyomatosis and renal cell cancer--a distinct form of hereditary kidney cancer." Nat Clin Pract Urol 4(2):104-110. PubMed ID: 17287871
Order Kits

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

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.
  • 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.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
loading Loading... ×