Ovarian Dysgenesis via the BMP15 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
733 BMP15$490.00 81479 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
Depending on the population, anywhere from 1 to 10% of women with primary or secondary amenorrhea have been found to have a mutation in the BMP15 gene (Dixit et al. 2006; Di Pasquale et al. 2006; Laissue et al. 2006).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 BMP15$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Features
Premature Ovarian Failure (POF) is a condition of female infertility characterized by the cessation of menstruation for at least four consecutive months prior to the age of 40. POF is thought to affect 1-2% of all women under 40 years old (Goswami & Conway, 2005). Although there are many potential causes of ovarian failure, Ovarian Dysgenesis (ODG) likely accounts for about half of the known POF cases. The symptoms of ODG include pubertal delay, primary or secondary amenorrhea, and hypoplastic ovaries. Often times, ODG is caused by major alterations of the X chromosome, such as Turner mosaics, large deletions, translocations or trisomy X. However, in patients with a normal 46 XX karyotype, mutations in a few specific genes, including FSHR, BMP15, and GDF9, have been found to cause ODG and POF (Aittomaki et al. 1995; Di Pasquale et al. 2004; Laissue et al. 2006). ODG Type 2 (ODG2; OMIM 300510), also called X-linked hypergonadotropic ovarian failure, is known to be specifically caused by heterozygous mutations in the Bone Morphogenetic Protein 15 gene (BMP15).
The first patients described with a mutation in the BMP15 gene were two female siblings with a normal 46 XX karyotype who presented with pubertal delay, primary amenorrhea and streak ovaries (Di Pasquale et al. 2004). Both sisters were heterozygous for a missense variant (p.Tyr235Lys). Interestingly, BMP15 is encoded on the X chromosome, and the p.Tyr235Lys variant was inherited from the unaffected father. Ovarian Dysgenesis caused by BMP15 is an intriguing example of an X-linked dominant disorder, which exclusively affects heterozygous females who inherit the genetic mutation from their father. Consistent with this pattern of inheritance, the p.Tyr235Lys variant was shown to exert a dominant-negative effect on the proliferation of cultured granulosa cells (Di Pasquale et al. 2004), a cell-type restricted to female ovaries. To date, all but one of the additional causative mutations found in BMP15 have been heterozygous missense (Dixit et al. 2006; Di Pasquale et al. 2006; Laissue et al. 2006), and at least two of these (p.Arg68Trp and p.Arg138His) clearly exert a dominant-negative effect in an in vitro functional assay (Rossetti et al. 2009). The one exception to this pattern of inheritance is the finding of a homozygous nonsense mutation (p.Glu211Stop) in a patient presenting with secondary amenorrhea and POF at the age of 28 (Dixit et al. 2006).
Testing Strategy
This test involves bidirectional DNA sequencing of both exons of the BMP15 gene plus ~10 bp of flanking non-coding DNA on either side of each exon. 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
Candidates for this test are women with primary or secondary amenorrhea and normal 46,XX karyotype, and relatives of patients with a verified BMP15 germline mutation.


Official Gene Symbol OMIM ID
BMP15 300247
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Ovarian Dysgenesis 2 300510

Related Tests

Male and Female Infertility via the FSHB Gene
Ovarian Dysgenesis via the FSHR Gene


Genetic Counselors
  • Aittomaki, K., (1995). "Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure." Cell 82(6): 959-68. PubMed ID: 7553856
  • Di Pasquale, E., (2004). "Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene." Am J Hum Genet 75(1): 106-11. PubMed ID: 15136966
  • Di Pasquale, E., (2006). "Identification of new variants of human BMP15 gene in a large cohort of women with premature ovarian failure." J Clin Endocrinol Metab 91(5): 1976-9. PubMed ID: 16464940
  • Dixit, H., (2006). "Missense mutations in the BMP15 gene are associated with ovarian failure." Hum Genet 119(4): 408-15. PubMed ID: 16508750
  • Goswami, D., Conway, G. S. (2005). "Premature ovarian failure." Hum Reprod Update 11(4): 391-410. PubMed ID: 15919682
  • Laissue, P., (2006). "Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure." Eur J Endocrinol 154(5): 739-44. PubMed ID: 16645022
  • Rossetti, R., (2009). "BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein." Hum Mutat 30(5): 804-10. PubMed ID: 19263482
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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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