Ovarian Hyperstimulation Syndrome via the FSHR Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
738 FSHR$860.00 81479 Add to Order
Targeted Testing

For ordering sequencing of 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
The sensitivity of this test is currently unknown.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 FSHR$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Features
More than one million couples worldwide seek reproductive assistance each year because of infertility (Chandra et al. 2005; Nyboe Andersen et al. 2009). In at least 75% of the cases, ovarian stimulation, to induce the development of multiple dominant follicles and maturation of many oocytes, is an integral part of the treatment regimen. Typically, ovarian stimulation is achieved by administering exogenous human Menopausal Gonadotropin (hMG), i.e. a natural mixture of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotropin (hCG) (Macklon et al. 2006). Ovarian Hyperstimulation Syndrome (OHSS) is an iatrogenic complication due to the exogenous administration of hMG and affects upwards of 5% of all women undergoing treatment for infertility (Delvigne & Rozenberg, 2002; Abramov et al. 1999). In addition, OHSS can spontaneously occur in women during the third month of an otherwise normal pregnancy. In these cases, increased endogenous levels of hCG from the ongoing pregnancy is thought to be the cause (Elchalal & Schenker, 1997). The primary symptoms of OHSS are abdominal discomfort, nausea, vomiting and diarrhea due to enlarged polycystic ovaries. In the most severe instances, rupture and hemorrhaging of ovarian cysts, organ failure and death can occur (Delvigne & Rozenberg, 2003).
OHSS can be caused by dominant mutations in the Follicle Stimulating Hormone Receptor gene (FSHR). Normally, FSHR protein is exclusively activated by FSH. However, changes at four different amino acids (Ser128, Thr449, Ile545, and Asp567) of FSHR decrease its specificity for FSH and increase its sensitivity to other hormones, such as LH and hCG (De Leener et al. 2008; De Leener et al. 2006; Smits et al.  2003; Vasseur et al. 2003). Thus, patients who have a heterozygous mutation of one of these four amino acids are likely to develop OHSS during the course of treatment for infertility, particularly if hMG is used to stimulate ovulation. In addition, three mutations within the promoter region of FSHR have been documented to influence protein expression, and likely increase the probability of developing OHSS during the course of artificial ovarian stimulation (Wunsch et al. 2005).
Testing Strategy
The Bi-Directional Sanger Sequencing test (#732) interrogates all 10 coding exons (1-10) of the FSHR gene, plus ~10 bp of flanking non-coding DNA on either side of each exon. It also includes targeted testing of three regulatory variants: c.-37A>G,  c.-123A>G and c.-138A>T (Wunsch et al., 2005). We will also sequence and single exon (Test #100) in family members of patients with a known mutation or to confirm research results.
Indications for Test
This test is for women who will receive exogenous hMG during the course of treatment for infertility and women with symptoms of spontaneous OHSS.


Official Gene Symbol OMIM ID
FSHR 136435
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Ovarian Hyperstimulation Syndrome 608115

Related Test

Ovarian Dysgenesis via the FSHR Gene


Genetic Counselors
  • Abramov, Y., (1999). "Severe OHSS: An 'epidemic' of severe OHSS: a price we have to pay?." Hum Reprod 14(9): 2181-3. PubMed ID: 10469676
  • Chandra, A., (2005). "Fertility, family planning, and reproductive health of U.S. women: data from the 2002 National Survey of Family Growth." Vital Health Stat 23 (25): 1-160. PubMed ID: 16532609
  • De Leener, A., (2006). "Presence and absence of follicle-stimulating hormone receptor mutations provide some insights into spontaneous ovarian hyperstimulation syndrome physiopathology." J Clin Endocrinol Metab 91(2): 555-62. PubMed ID: 16278261
  • De Leener, A., (2008). "Identification of the first germline mutation in the extracellular domain of the follitropin receptor responsible for spontaneous ovarian hyperstimulation syndrome." Hum Mutat 29(1): 91-8. PubMed ID: 17721928
  • Delvigne, A., Rozenberg, S. (2002). "Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review." Hum Reprod Update 8(6): 559-77. PubMed ID: 12498425
  • Delvigne, A., Rozenberg, S. (2003). "Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS)." Hum Reprod Update 9(1): 77-96. PubMed ID: 12638783
  • Elchalal, U., Schenker, J. G. (1997). "The pathophysiology of ovarian hyperstimulation syndrome--views and ideas." Hum Reprod 12(6): 1129-37. PubMed ID: 9221989
  • Macklon, N. S., (2006). "The science behind 25 years of ovarian stimulation for in vitro fertilization." Endocr Rev 27(2): 170-207. PubMed ID: 16434510
  • Nyboe Andersen, A., (2009). "Assisted reproductive technology and intrauterine inseminations in Europe, 2005: results generated from European registers by ESHRE: ESHRE. The European IVF Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE)." Hum Reprod 24(6): 1267-87. PubMed ID: 19225009
  • Smits, G., (2003). "Ovarian hyperstimulation syndrome due to a mutation in the follicle-stimulating hormone receptor." N Engl J Med 349(8): 760-6. PubMed ID: 12930928
  • Vasseur, C., (2003). "A chorionic gonadotropin-sensitive mutation in the follicle-stimulating hormone receptor as a cause of familial gestational spontaneous ovarian hyperstimulation syndrome." N Engl J Med 349(8): 753-9. PubMed ID: 12930927
  • Wunsch, A., (2005). "Single-nucleotide polymorphisms in the promoter region influence the expression of the human follicle-stimulating hormone receptor." Fertil Steril 84(2): 446-53. PubMed ID: 16084888
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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.

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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.
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