Oligogenic basis of isolated gonadotropin-releasing hormone deficiency

Abstract

Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients (n = 397), family members, and unaffected subjects (n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls (P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases.rare variant | idiopathic hypogonadotropic hypogonadism | Kallmann syndrome | digenic | FGFR1

Heparan sulfate 6-O-sulfotransferase 1 , a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism

“…FGFR1 R250 is involved in binding FGF8 (32), and was independently associated with another case of GnRH deficiency (33). Because FGFR1 requires HS 6-O-sulfation for interaction with FGF8 (32), the HS6ST1 R296W and FGFR1 R250Q mutations may synergize to compromise FGF signaling, consistent with prior reports of digenicity (17,24,34,35). The fact that carriers of HS6ST1 mutations do not always manifest IHH (pedigrees I, III, and IV) is consistent with the presence of monoallelic gene defects in IHH-associated genes in as many as 10% of unaffected controls (24).…”

“…Several lines of evidence suggest a functional relationship between KAL1, HS6ST1, and possibly FGFR1 and FGF8. First, mutations in FGF/ FGFR signaling and in KAL1 are the most frequent among the known genetic lesions associated with nIHH/KS (found in 10% and 5% of patients, respectively) (24). Second, anosmin-1 can directly bind FGFR1 in vitro, and it colocalizes with FGFR1 in cell culture experiments (19).…”

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…Remarkably, mutations in each Kallmann syndrome or CHH gene identified so far account for <10% of cases. 11,21,127 CHH has classically been categorized as a monogenic disorder, which means that one defective gene is sufficient to account for the disease phenotype. As such, CHH and Kallmann syndrome caused by mutations in GNRHR (a recessive gene) and KAL1 (ANOS1; an X-linked gene),…”

“…Such an observation led to the hypothesis that multiple gene defects could synergize to produce a more severe CHH phenotype (that is, oligo genicity). 30,128 Studies in large CHH cohorts indicate that at least 20% of cases are oligogenic 11,21 (Table 1). …”

“…8,9 In addition, hormonal therapies are being personalized to maximize fertility outcomes. 10 Over the past few years, the traditional Mendelian view of CHH as a monogenic disorder has been revised following the identification of oligogenic forms of CHH, 11 which has altered the approach adopted for genetic testing and genetic counselling of patients with CHH. Finally, the availability of next-generation sequencing has started to unravel the complex molecular basis of CHH.…”