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Hypogonadotropic Hypogonadism/Kallmann Syndrome via the HS6ST1 Gene

Summary and Pricing

Test Method

Bi-Directional Sanger Sequencing
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
1749 HS6ST1 81479 81479 $540 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
1749HS6ST181479 81479 $540 Order Options and Pricing

Pricing Comments

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.

Turnaround Time

4 weeks on average for standard orders or 2 weeks 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 (IGD), 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 and Crowley. 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 and Crowley. 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 and Crowley. 2017. PubMed ID: 20301509).

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 HS6ST1, account for about half of all HH. These genes are known to be involved in the formation and migration of GnRH and olfactory neurons. Pathogenic variants in these genes have been reported to disrupt the migratory pathway of GnRH and olfactory neurons from the nasal region into the hypothalamus. The HS6ST1 gene has 2 coding exons that encode heparan sulfate 6-O-sulfotransferase 1, a member of the heparan sulfate biosynthetic enzyme family. This enzyme introduces a sulfate specifically in the 6-O-position of the glucosamine sugar moiety within heparan sulfate. It is highly expressed in the nervous system, particularly in hypothalamus and olfactory bulbs in mice (Sedita et al. 2004. PubMed ID: 15499561; Howard et al. 2018. PubMed ID: 29931354). In experiments in C. elegans, it was shown to specifically regulates neural branching in concert with other genes that are associated with HH, including KAL1, FGF8, and FGFR1 (Tornberg et al. 2011. PubMed ID: 21700882).

Heterozygous missense variants in HS6ST1 have been reported in individuals diagnosed with HH with or without anosmia (Tornberg et al. 2011. PubMed ID: 21700882; Miraoui et al. 2013. PubMed ID: 23643382; Marcos et al. 2014. PubMed ID: 25077900; Howard et al. 2018. PubMed ID: 29931354). These variants have not been de novo. Protein-truncating (nonsense, frameshift and splicing) variants and exon-level large deletions or duplications have not been found in this gene (Human Gene Mutation Database).

Clinical Sensitivity - Sanger Sequencing

HS67ST1 pathogenic variants have been identified in up to 2% of patients with Hypogonadotropic hypogonadism/Kallmann syndrome (Tornberg et al. 2011. PubMed ID: 21700882; Howard et al. 2018. PubMed ID: 29931354).

Testing Strategy

This test involves bidirectional Sanger sequencing of all coding exons and splice sites of the HS6ST1 gene. The full coding sequence of each exon plus ~10 bp of flanking DNA on either side are sequenced. We will also sequence any 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 patients with symptoms consistent with hypogonadotropic hypogonadism/Kallmann syndrome.

Gene

Official Gene Symbol OMIM ID
HS6ST1 604846
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Female Infertility Panel
Hypogonadotropic Hypogonadism/Kallmann Syndrome Panel

Citations

  • Balasubramanian and Crowley. 2017. PubMed ID: 20301509
  • Boehm et al. 2015. PubMed ID: 26194704
  • Howard et al. 2018. PubMed ID: 29931354
  • 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
  • Marcos et al. 2014. PubMed ID: 25077900
  • Marino et al. 2014. PubMed ID: 25254043
  • Miraoui et al. 2013. PubMed ID: 23643382
  • Sedita et al. 2004. PubMed ID: 15499561
  • Seminara et al. 1998. PubMed ID: 9793755
  • Tornberg et al. 2011. PubMed ID: 21700882

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

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ORDER OPTIONS

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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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