Hypogonadotropic Hypogonadism/Kallmann Syndrome via the SEMA3A Gene

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).

Pathogenic variants in the SEMA3A gene have been implicated to cause Kallmann syndrome (KS). Individuals with loss-of-function variants in SEMA3A present with congenital hypogonadism and anosmia (Hanchate et al. 2012. PubMed ID: 22927827; Young et al. 2012. PubMed ID: 22416012). To date, no significant enrichment for any specific nonreproductive feature has been apparent in this group of patients.

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 SEMA3A, 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 SEMA3A including frameshift, splicing and missense variants, and exonic deletions have been reported to cause Kallmann syndrome, (Hanchate et al. 2012. PubMed ID: 22927827; Young et al. 2012. PubMed ID: 22416012; Cassatella et al. 2018. PubMed ID: 29419413), while biallelic loss-of-function variants in SEMA3A have been reported in patients with short stature and multiple congenital anomalies (Hofmann et al. 2013. PubMed ID: 24124006; Baumann et al. 2017. PubMed ID: 28075028). The most commonly reported pathogenic variant is c.1289G>A (p.Arg730Gln) with an allele frequency of 0.01% (Genome Aggregation Database). Pathogenic variants have been reported in mildly affected parents (Young et al. 2012. PubMed ID: 22416012). Of note, di-/oligogenic inheritance of HH has been reported (Hanchate et al. 2012. PubMed ID: 22927827), and it seems possible that SEMA3A might have a role in modifying the KS phenotype, although conclusive evidence is still lacking.

SEMA3A encodes semaphoring-3a, a secreted protein involved in the navigation of olfactory nerve fibers during embryogenesis. Sema3A knock-out mice have a reduced number of GnRH neurons in their brains, with Sema3A being essential for the patterning of vomeronasal axons (Cariboni et al. 2011. PubMed ID: 21059704).

Pathogenic variants in SEMA3A have been identified in 1-2% of KS patients (Hanchate et al. 2012. PubMed ID: 22927827; Zhou. 2018 et al. PubMed ID: 30098700).

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 SEMA3A 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.