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Hypogonadotropic Hypogonadism/Kallmann Syndrome via the FGF8 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
12651 FGF8 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
12651FGF881479 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

Hypogonadotropic hypogonadism (HH), also known as gonadotropin-releasing hormone (GnRH) deficiency, is a genetic condition that is characterized by delayed or absent sexual development and infertility due to an impaired secretion of gonadotropins. Hypogonadotropic hypogonadism is divided into two major clinical phenotypes depending on the presence of an intact sense of smell: anosmic hypogonadotropic hypogonadism (Kallmann syndrome, KS) and normosmic hypogonadotropic hypogonadism (nHH) (Marino et al. 2014. PubMed ID: 25254043; Boehm et al. 2015. PubMed ID: 26194704; Kim. 2015. PubMed ID: 26790381; Balasubramanian et al. 2017. PubMed ID: 20301509). The prevalence of HH has been estimated to range from 1:10,000 to 1:86,000 individuals depending on different populations (for example 1:10,000 in French and 1:86,000 in Sardinian). A recent study in Finland showed a minimal incidence of KS which accounts for nearly two thirds of individuals with HH of 1:30,000 in males and 1:125,000 in females (Laitinen et al. 2011. PubMed ID: 21682876). Males predominate in HH with a male-to-female ratio of nearly 4:1 (Seminara et al. 1998. PubMed ID: 9793755).

HH is typically diagnosed in patients presenting with absent or incomplete puberty, low serum testosterone or estradiol due to absence of circulating gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone), but no other abnormalities of the hypothalamic-pituitary axis (Balasubramanian et al. 2017. PubMed ID: 20301509). Infant boys with HH often demonstrate micropenis and cryptorchidism. Adult males with HH present failure to undergo normal puberty and absence of secondary sexual characteristics. Females with HH usually have little or no breast development, primary amenorrhea or infertility. In addition to reproductive symptoms, many KS patients exhibit a wide variety of additional signs and symptoms. Commonly recognized non-reproductive features that may be present in KS patients include: digital synkinesia, unilateral renal agenesis, cleft lip and /or palate, dental agenesis, hearing loss, and abnormal eye movements (Kaplan et al. 2010. PubMed ID: 20949504; Layman 2013. PubMed ID: 23650337; Balasubramanian et al. 2017. PubMed ID: 20301509).

Most patients harboring heterozygous FGF8 pathogenic variants have been reported to exhibit KS, although normosmic HH has also been reported. Individuals with FGF8 variants present a broad spectrum of pubertal development ranging from absent to partial to complete puberty (in males with adult-onset HH). The associated nonreproductive phenotypes include hearing loss and a range of skeletal features (high arched palate, cleft lip/palate, severe osteoporosis, camptodactyly, and hyperlaxity of the digits). Variable expressivity is evident in family members harboring the identical variant (Falardeau et al. 2008. PubMed ID: 18596921; Trarbach et al. 2010. PubMed ID: 20463092).

Hormone replacement with testosterone in males and estrogen in females is the classic treatment for hypogonadism. Hypogonadotropic hypogonadism is one of the rare conditions in which specific medical treatment can reverse infertility. Early intervention can promote the development of and maintain secondary sexual characteristics and normal sexual function, prevent low bone density and related complications, and also provides the opportunity for fertility (Boehm et al. 2015. PubMed ID: 26194704).

Genetics

HH is a clinically and genetically heterogeneous disorder. To date, pathogenic variants in more than 35 genes, including FGF8, account for about half of all HH ((Marino et al. 2014. PubMed ID: 25254043; Balasubramanian et al. 2017. PubMed ID: 20301509). These genes are known to be involved in the formation and migration of GnRH and olfactory neurons. Pathogenic variant in these genes haven been reported to disrupt the migratory pathway of GnRH and olfactory neurons from the nasal region into the hypothalamus.

Heterozygous loss-of-function variants in FGFR8 including frameshift, splicing and missense variants have been reported to be causative for KS and normosmic HH (Falardeau et al. 2008. PubMed ID: 18596921; Trarbach et al. 2010. PubMed ID: 20463092; Suzuki et al. 2014. PubMed ID: 24280688). De novo frameshift variants have been documented (Suzuki et al. 2014. PubMed ID: 24280688). Exon-level large deletions or duplications have not been reported in this gene (Human Gene Mutation Database). The most commonly reported pathogenic variant is c.385C>T (p.Arg129*) with an allele frequency of 0.003% (Genome Aggregation Database).

FGF8 encodes fibroblast growth factor 8. It was discovered as the critical ligand for FGFR1 in GnRH ontogeny. Mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration (Falardeau et al. 2008. PubMed ID: 18596921).

Clinical Sensitivity - Sequencing with CNV PGxome

Pathogenic variants in FGF8 have been identified in 1-2% of KS patients (Falardeau et al. 2008. PubMed ID: 18596921).

Testing Strategy

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

This test provides full coverage of all coding exons of the FGF8 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 patients with symptoms consistent with hypogonadotropic hypogonadism/Kallmann syndrome.

Gene

Official Gene Symbol OMIM ID
FGF8 600483
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Kallmann Syndrome 6 AD 612702

Related Tests

Name
Female Infertility Panel
Hypogonadotropic Hypogonadism/Kallmann Syndrome Panel
Kallmann Syndrome (KS) Panel

Citations

  • Balasubramanian et al. 2017. PubMed ID: 20301509
  • Boehm et al. 2015. PubMed ID: 26194704
  • Falardeau et al. 2008. PubMed ID: 18596921
  • Human Gene Mutation Database (Biobase).
  • Kaplan et al. 2010. PubMed ID: 20949504
  • Kim. 2015. PubMed ID: 26790381
  • Laitinen et al. 2011. PubMed ID: 21682876
  • Layman. 2013. PubMed ID: 23650337
  • Marino et al. 2014. PubMed ID: 25254043
  • Seminara et al. 1998. PubMed ID: 9793755
  • Suzuki et al. 2014. PubMed ID: 24280688
  • Trarbach et al. 2010. PubMed ID: 20463092

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.
Total Price: $
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