Ovarian Dysgenesis via the BMP15 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
9139 BMP15 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9139BMP1581479 81479(x2) $890 Order Options and Pricing

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.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

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

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

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

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Fang Xu, PhD, FACMG

Clinical Features and Genetics

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, variants 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 variants in the bone morphogenetic protein 15 gene (BMP15).

Genetics

The first patients described with a variant 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 variant 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 variants 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 variant (p.Glu211Stop) in a patient presenting with secondary amenorrhea and POF at the age of 28 (Dixit et al. 2006).

Clinical Sensitivity - Sequencing with CNV PGxome

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

Testing Strategy

This test provides full coverage of all coding exons of the BMP15 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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Candidates for this test are women with primary or secondary amenorrhea and a normal 46,XX karyotype, and relatives of patients with a verified BMP15 germline variant.

Gene

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

Disease

Name Inheritance OMIM ID
Ovarian Dysgenesis 2 300510

Related Test

Name
Male and Female Infertility via the FSHB Gene

Citations

  • Aittomaki, K., et.al. (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., et.al. (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., et.al. (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., et.al. (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
  • Di Pasquale, E., et.al. (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., et.al. (2006). "Missense mutations in the BMP15 gene are associated with ovarian failure." Hum Genet 119(4): 408-15. PubMed ID: 16508750
  • Dixit, H., et.al. (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., et.al. (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
  • Laissue, P., et.al. (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
  • Laissue, P., et.al. (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., et.al. (2009). "BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein." Hum Mutat 30(5): 804-10. PubMed ID: 19263482

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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