Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism

Abstract

Traditionally, idiopathic hypogonadotropic hypogonadism (IHH) is divided into two major categories: Kallmann syndrome (KS) and normosmic IHH (nIHH). To date, inactivating variants in more than 50 genes have been reported to cause IHH. These mutations are estimated to account for up to 50% of all apparently hereditary cases. Identification of further causative gene mutations is expected to be more feasible with the increasing use of whole exome/genome sequencing. Presence of more than one IHH-associated mutant gene in a given patient/pedigree (oligogenic inheritance) is seen in 10-20% of all IHH cases. It is now well established that about 10-20% of IHH cases recover from IHH either spontaneously or after receiving some sex steroid replacement therapy. Moreover, there may be an overlap or transition between constitutional delay in growth and puberty (CDGP) and IHH. It has been increasingly observed that oligogenic inheritance and clinical recovery complicates the phenotype/genotype relationship in IHH, thus making it challenging to find new IHH-associated genes. In a clinical sense, recognizing those IHH genes and associated phenotypes may improve our diagnostic capabilities by enabling us to prioritize the screening of particular gene(s) such as synkinesia (ANOS1), dental agenesis (FGF8/FGFR1) and hearing loss (CHD7). Also, IHH-associated gene studies may be translated into new therapies such as for polycystic ovary syndrome. In a scientific sense, the most significant contribution of IHH-associated gene studies has been the characterization of the long-sought gonadotropin releasing hormone pulse generator. It appears that genetic studies of IHH will continue to advance our knowledge in both the biological and clinical domains.

Prevalence and associated phenotypes of PLXNA1 variants in normosmic and anosmic idiopathic hypogonadotropic hypogonadism

“…A total of 215 whole exome sequencing (WES) data from the IHH cohort patients consisting of 178 probands and 37 affected sibling/family members were screened for potentially harmful, rare sequence variants in the PLXNA1 . Subsequently, patients with rare PLXNA1 variants were further screened specifically for additional variants in genes known to be associated with nIHH ( TAC3 , TACR , KISS1 , KISS1R , GNRH1 , GNRHR , PNPLA6 , SRA1 , LEP , LEPR , FSHB , LHB , NR0B1 , DMXL2 , OTUD4 , POLR3A , POLR3B , RAB18 , RAB3GAP1 , RAB3GAP2 , RNF216 , STUB1 , TBC1D20 , TUBB3 , and PCSK1 ) or with KS ( ANOS1 , FGFR1 , FGFR8 , PROK2 , PROKR2 , FEZF1 , CCDC141 , IGSF10 , CHD7 , AXL , SOX10 , WDR11 , SEMA3A , SEMA3E , DUSP6 , FGF17 , FLRT3 , HESX1 , IL17RD , NSMF , SMCHD1 , HS6ST1 , SPRY4 , and KLB ) . In order to confirm the presence of detected candidate variants, genetic analyses were performed by Sanger sequencing on an Applied Biosystems PRISM 3130 auto sequencer (Supporting Information).…”

“…According to olfactory function, IHH patients can be divided into two major categories, those with a normal sense of smell (normosmic IHH, nIHH) and those with an impaired ability to smell (Kallmann syndrome, KS) . To date nearly 50 genes have been suggested to cause IHH . This genetically heterogeneous disorder can be transmitted through oligogenic inheritance in about 10% to 20% of all cases …”

Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice

“…To date, more than 40 genes have been identified as pathogenic cause in the background of the disease (Boehm et al 2015;Maione et al 2018;Stamou and Georgopoulos 2018). Analysis the individual CHH genes (Table 1) one by one exceeds the goal of our study, but these are excellently reviewed in recent papers (Topaloglu and Kotan 2016;Topaloğlu 2018;Maione et al 2018). Genes implicated in the pathogenesis of CHH are usually divided into two major categories (Boehm et al 2015;Topaloğlu 2018;Maione et al 2018;Stamou and Georgopoulos 2018).…”

Pubertal orchestration of hormones and testis in primates

“…Such neurons expressing three peptides are referred to as “KNDy (Kisspeptin‐Neurokinin B and Dynorphin) neurons” (Lehman, Coolen, & Goodman, ). Interestingly, loss of function mutations in man in either Neurokinin B or its receptor ( Tac3‐Receptor ) is associated with hypogonadotropic hypogonadism manifesting delayed puberty or sometimes loss of pubertal onset of spermatogenesis, cause being the lack of sufficient gonadotropins (Topaloğlu, ). In male rhesus monkeys, neurokinin B has been reported to induce GnRH release, indirectly via the production of kisspeptin (Ramaswamy et al, ).…”