Hypogonadotropic Hypogonadism/Kallmann Syndrome via the WDR11 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 WDR11 gene have been implicated in hypogonadotropic hypogonadism (HH) and Kallmann syndrome (KS). Individuals with loss-of-function variants in WDR11 present with congenital hypogonadism with or without anosmia (Kim et al. 2010. PubMed ID: 20887964; Cassatella et al. 2018. PubMed ID: 29419413). Pituitary dysgeneis has also been reported in this group of patients (Kim et al. 2018. PubMed ID: 29263200).

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 WDR11, 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 variants in these genes haven been reported to disrupt the migratory pathway of GnRH and olfactory neurons from the nasal region into the hypothalamus.

Heterozygous missense variants in WDR11 have been reported in individuals diagnosed with HH with or without anosmia, but parental studies were not performed (Kim et al. 2010. PubMed ID: 20887964; Cassatella et al. 2018. PubMed ID: 29419413). The most commonly reported pathogenic variant is c.1303 G>A (p.Ala35Thr) with a frequency of 0.046% (Genome Aggregation Database). A de novo chromosomal balanced t(10;12) translocation involving WDR11 has been found in a patient of Kallmann syndrome (Kim et al. 2010. PubMed ID: 20887964). One splicing variant in WDR11 has been reported in a patient with combined pituitary hormone deficiency, but parental studies were not done (Izumi et al. 2014. PubMed ID: 25064402). Protein-truncating nonsense and frameshift variants and exon-level large deletions or duplications have not been found in this gene to date (Human Gene Mutation Database).

WDR11 encodes WD repeat domain 11 which interacts with EMX1, a homeobox transcription factor involved in specifying cell fates in the developing central nervous system and in the development of olfactory neurons. WDR11 regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and GnRH production. Wdr11-deficient mice show hypothalamic GnRH deficiency and pituitary dysgenesis. Wdr11 knockdown in zebrafish causes developmental defects associated with aberrant Hh signal and ciliogenesis (Kim et al. 2018. PubMed ID: 29263200).

Pathogenic variants in WDR11 have been identified in <1% of the HH/KS patients (Kim et al. 2010. PubMed ID: 20887964).

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 WDR11 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).