Hypogonadotropic Hypogonadism/Kallmann Syndrome via the HS6ST1 Gene

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).

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).

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).

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.