DNA icon

Hypogonadotropic Hypogonadism/Kallmann Syndrome via the PROK2 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
15193 PROK2 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15193PROK281479 81479(x2) $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

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

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

Idiopathic hypogonadotropic hypogonadism (IHH) is a group of reproductive disorders due to gonadotropin-releasing hormone (GnRH) deficiency (Buck et al. 2013). IHH is characterized by absent or incomplete pubertal development, low levels of circulating gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone), and no other abnormalities of the hypothalamic-pituitary axis. IHH can be divided into two major phenotypes: normosmic hypogonadotropic hypogonadism (nHH), in which hypothalamic GnRH gene regulation or GnRH synthesis, secretion, or signaling is impaired; and Kallmann syndrome (KS), in which the migratory pathway of GnRH and olfactory neurons from the nasal region into the hypothalamus is disrupted (Layman 2013).

Kallmann syndrome is characterized by an impaired sense of smell (hyposmia or anosmia) alongside delayed or absent puberty. Due to hypothalamic GnRH deficiency, infant boys with KS often demonstrate micropenis and cryptorchidism. Adult males with KS present failure to undergo normal puberty and absence of secondary sexual characteristics. Females with KS usually present with primary amenorrhea or infertility. The degree of both the hypogonadism and the smell deficiency vary significantly even within affected family members (Buck et al. 2013).

Genetics

To date, ten different genes have been identified to cause KS and nHH (Layman 2013). PROK2, which encodes prokineticin-2, is one of these genes. PROK2 is a secreted cysteine-rich protein that signals, through G protein-coupled receptors, prokineticin receptor PROKR2. The PROK2 signaling system regulates diverse biological activities, including olfactory bulb morphogenesis and reproduction, by the activation of downstream signaling pathways (Lin et al. 2002). Autosomal recessive transmission of PROK2-related disease has been found in some patients, but most patients carrying pathogenic variants in PROK2 are heterozygotes (Dode et al. 2006; Pitteloud et al. 2007; Cole et al. 2008). At least 19 pathogenic variants in the PROK2 gene have been identified in individuals with KS and nHH. Notably, most of these variants are missense (Human Gene Mutation Database). These pathogenic variants decrease the protein's activity, affecting the ligand targeting of its receptor. Studies have shown that a loss of PROK2 signaling disrupts the migration and survival of olfactory neurons and GnRH-producing neurons, resulting in defective olfactory bulb morphogenesis, arrested GnRH neuron migration, and consequent hypogonadotropic hypogonadism (Cole et al. 2008; Monnier et al. 2009).

Clinical Sensitivity - Sequencing with CNV PG-Select

This test is predicted to detect pathogenic variants in 2-3 % of all patients with Kallmann syndrome or normosmic hypogonadotropic hypogonadism (Cole et al. 2008; Dode et al. 2013).

To date, only one gross duplication has been reported involving PROK2 (Basaran et al. 2013).

Testing Strategy

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the PROK2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Candidates for this test are patients with symptoms consistent with Kallmann syndrome or normosmic hypogonadotropic hypogonadism, and family members of patients with known pathogenic variants.

Gene

Official Gene Symbol OMIM ID
PROK2 607002
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Kallmann Syndrome 4 AD 610628

Citations

  • Basaran Y. et al. 2013. Endokrynologia Polska. 64: 285-92. PubMed ID: 24002956
  • Buck C. et al. 2013. Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. 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: 20301509
  • Cole L.W. et al. 2008. The Journal of Clinical Endocrinology and Metabolism. 93: 3551-9. PubMed ID: 18559922
  • Dodé C. et al. 2006. Plos Genetics. 2: e175. PubMed ID: 17054399
  • Dodé C., Rondard P. 2013. Frontiers in Endocrinology. 4: 19. PubMed ID: 23596439
  • Human Gene Mutation Database (Bio-base).
  • Layman L.C. 2013. Molecular and Cellular Endocrinology. 370: 138-48. PubMed ID: 23499866
  • Lin D.C. et al. 2002. The Journal of Biological Chemistry. 277: 19276-80. PubMed ID: 11886876
  • Monnier C. et al. 2009. Human Molecular Genetics. 18: 75-81. PubMed ID: 18826963
  • Pitteloud N. et al. 2007. Proceedings of the National Academy of Sciences of the United States of America. 104: 17447-52. PubMed ID: 17959774

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

loading Loading... ×

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.
Total Price: $
×
Copy Text to Clipboard
×