|Ahead of print publication
Whole exome sequencing and trio analysis to broaden the variant spectrum of genes in idiopathic hypogonadotropic hypogonadism
Jian Zhang1, Shu-Yan Tang1, Xiao-Bin Zhu2, Peng Li2, Jian-Qi Lu3, Jiang-Shan Cong1, Ling-Bo Wang1, Feng Zhang1, Zheng Li2
1 Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai 200011, China
2 Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
3 Department of Research Institute, Reproduction Medical Center, The first Hospital of Lanzhou University, Lanzhou 730000, China
|Date of Submission||13-Mar-2020|
|Date of Acceptance||02-Aug-2020|
|Date of Web Publication||17-Nov-2020|
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai 200011
Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080
Source of Support: None, Conflict of Interest: None
Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism (IHH) and an oligogenic etiology has been suggested. However, the associated genes may account for only approximately 50% cases. In addition, a genomic systematic pedigree analysis is still lacking. Here, we conducted whole exome sequencing (WES) on 18 unrelated men affected by IHH and their corresponding parents. Notably, one reported and 10 novel variants in eight known IHH causative genes (AXL, CCDC141, CHD7, DMXL2, FGFR1, PNPLA6, POLR3A, and PROKR2), nine variants in nine recently reported candidate genes (DCAF17, DCC, EGF, IGSF10, NOTCH1, PDE3A, RELN, SLIT2, and TRAPPC9), and four variants in four novel candidate genes for IHH (CCDC88C, CDON, GADL1, and SPRED3) were identified in 77.8% (14/18) of IHH cases. Among them, eight (8/18, 44.4%) cases carried more than one variant in IHH-related genes, supporting the oligogenic model. Interestingly, we found that those variants tended to be maternally inherited (maternal with n = 17 vs paternal with n = 7; P = 0.028). Our further retrospective investigation of published reports replicated the maternal bias (maternal with n = 46 vs paternal with n = 28; P = 0.024). Our study extended a variant spectrum for IHH and provided the first evidence that women are probably more tolerant to variants of IHH-related genes than men.
Keywords: idiopathic hypogonadotropic hypogonadism; maternal inheritance; oligogenic inheritance; whole exome sequencing
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|How to cite this URL:|
Zhang J, Tang SY, Zhu XB, Li P, Lu JQ, Cong JS, Wang LB, Zhang F, Li Z. Whole exome sequencing and trio analysis to broaden the variant spectrum of genes in idiopathic hypogonadotropic hypogonadism. Asian J Androl [Epub ahead of print] [cited 2020 Nov 27]. Available from: https://www.ajandrology.com/preprintarticle.asp?id=300786
Jian Zhang, Shu-Yan Tang
These authors contributed equally to this work.
| Introduction|| |
Idiopathic hypogonadotropic hypogonadism (IHH) is a rare genetic disorder that leads to delayed or absent puberty and infertility due to gonadotropin-releasing hormone (GnRH) insufficiency or deficiency.,, IHH accompanied by anosmia or hyposmia is defined as Kallmann syndrome (KS), whereas IHH with normal olfaction is called normosmic IHH (nIHH). IHH is highly genetically heterogeneous, and more than 50 genes have been found to be related to IHH. However, only approximately 50% of cases were accounted for and presented all forms of classical Mendelian inheritance and oligogenicity.,
With the increasing use of next-generation sequencing (NGS), a variety of IHH-related genes have been explored in recent years.,,, However, the majority of genetic studies applied screening strategies that listed limited genes associated with the GnRH pathway or relevant function of IHH for screening, which cannot take full advantage of NGS and may miss potential causative genes beyond the gene lists. Previous studies were conducted mainly in sporadic cases, and little parental information was available for further investigations on pathogenicity.,
In this study, we first conducted a systematic genomic analysis using whole exome sequencing (WES) to screen for disease-causing variants in all known IHH genes and then identified potentially contributory variants in novel candidate genes by analyzing the remaining genes. We also investigated parental origins of those probably disease-causing variants by trio analysis and literatures mining.
| Participants and Methods|| |
A total of 18 Han Chinese men with IHH and their families were recruited at Shanghai General Hospital (Shanghai, China). Their whole blood samples were obtained with informed consent. All of procedures involving human participants in this study were approved by the Ethics Committee of Shanghai General Hospital (2016KY196). Parenthood was confirmed by an EX20 kit (AGCU ScienTech Incorporation, Wuxi, China). The criteria for the diagnosis of IHH included: (1) absent or incomplete pubertal development by the age of 18 years in men; (2) clinical signs or symptoms of hypogonadism; (3) serum testosterone levels of <100 ng dl−1 (3.5 nmol l−1) in males with low or normal levels of gonadotropin; (4) normal thyroid, adrenal, and growth hormone axes; (5) normal magnetic resonance images of the hypothalamic and pituitary areas; and (6) the absence of sex chromosome abnormalities. Olfactory function was categorized into three groups: normosmia, hyposmia, and anosmia, based on self-reporting and test with familiar odors. Clinical information of probands and their families can be found in [Supplementary Table 1 [Additional file 1]].
Whole exome sequencing and data processing
Genomic DNAs were extracted from the participants' peripheral blood samples using a DNeasy Blood and Tissue Kit (QIAGEN, Dusseldorf, Germany). The NimbleGen SeqCap EZ Exome Library SR version 3.0 (Roche, Basel, Switzerland) and the HiSeq X-TEN platform (Illumina, San Diego, CA, USA) were employed to enrich the human exome and sequencing, respectively. The average read depth was not less than 100× and more than 95% of the targeted region was covered over 20×.
Reads were aligned to the human genome reference assembly (UCSC Genome Browser hg19) with the Burrows-Wheeler Aligner (BWA). The Genome Analysis Toolkit version 4.0 (GATK4.0, Broad Institute, Cambridge, MA, USA) was employed to remove PCR duplicates and evaluate the quality of variants by attaining effective reads, effective base, average coverage depth and coverage ratio. Single-nucleotide variants (SNVs) and short insertions and deletions (indels) were also called by GATK4.0. ANNOVAR was used to functionally annotate variants with Sorting Tolerant From Intolerant (SIFT), PolyPhen-2, MutationTaster, Mendelian Clinically Applicable Pathogenicity (M-CAP), the 1000 Genomes Project, and the Genome Aggregation Database (gnomAD).,,,,, Online Mendelian Inheritance in Man (OMIM), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway and Reactome were also annotated to the genes.,,
All of the final identified variants were confirmed by Sanger sequencing and their pathogenicity classifications were evaluated according to American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines (ACMG/AMP).
Genes selected for screening
A total of 106 genes [Supplementary Table 2 [Additional file 2]] collected from reports in the literatures or databases were classified into two categories as follows: (a) 57 IHH-causative genes associated in human IHH cases with evidence such as functional assays and their mouse models manifesting IHH phenotype and (b) 49 IHH-reported candidate genes that were reported only recently in IHH patients through screening strategies without any functional characterization.
| Results|| |
We applied WES in 18 trios. For quality control, the GATK hard filter criteria and read depth <10 were used to remove low-quality variants. Considering common variants with less functionality and the scarce incidence of IHH, we filtered out the variants with a minor allele frequency (MAF) higher than 0.01. Only loss-of-function (LoF) variants including frameshift indels, canonical splice-site, nonsense and start-loss, and missense variants predicted as damaging by at least two of four algorithms were considered in further analyses [Supplementary Figure 1 [Additional file 3]].
Variant spectrum in IHH genes
The analysis initially screened two groups of all known genes described in the participants and methods section.
Thirteen (72.2%) of 18 patients were identified eleven variants in eight known causative genes, namely AXL receptor tyrosine kinase (AXL), coiled-coil domain containing 141 (CCDC141), chromodomain helicase DNA binding protein 7 (CHD7), Dmx like 2 (DMXL2), fibroblast growth factor receptor 1 (FGFR1), patatin like phospholipase domain containing 6 (PNPLA6), RNA polymerase III subunit A (POLR3A) and prokineticin receptor 2 (PROKR2), see [Table 1] and [Table 2]. The PROKR2 missense variant p. Trp178Ser was recurrently observed in three patients, and was statistically enriched in our IHH cohort compared to the population (3/18 in the IHH cases vs 56/9976 in the gnomAD East Asians, P = 0.00015, one-tailed Fisher's exact test). Furthermore, another PROKR2 missense variant p. Ala103Val was identified in case P15. All of the remaining deleterious variants in the other seven known IHH genes were novel and unreported. Notably, the novel LoF variant FGFR1 c.1664-2A>C in case P05 is de novo and evaluated as pathogenic.
|Table 1: Variant information of known and candidate idiopathic hypogonadotropic hypogonadism genes and novel candidate genes|
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|Table 2: Variant Inheritance of the mutated men with idiopathic hypogonadotropic hypogonadism|
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In nine genes of the second group that were reported in recent NGS studies, we identified one nonsense, one frameshift deletion, and seven missense variants in 9 (50.0%) of 18 families [Table 1]. The epidermal growth factor (EGF) nonsense variant c.3487C>T (p. Arg163*) predicted to attain a truncated protein was also previously detected in a target sequencing study of IHH. Distribution of all the above identified variants in proteins is shown in [Figure 1].
|Figure 1: Distribution of identified variants in the IHH-related proteins. Domains and motifs were predicted by the SMART and InterPro tools. The variants identified in this study are indicated with red arrows. ANK_REP: ankyrin repeat-containing domain; cNMP: cyclic nucleotide-monophosphate binding domain; CTCK_2: cystine knot, C-terminal; DUF3454: domain of unknown function, notch; FN3: fibronectin type III domain; FOLN: follistatin-N-terminal domain-like; HOOK: hook-like protein family; IG: immunoglobulin; I-set: immunoglobulin I-set domain; IHH: idiopathic hypogonadotropic hypogonadism; LAM_G: laminin G domain; LRR: leucine-rich repeat; Neogenin_C: neogenin C-terminus; Patatin: patatin-like phospholipases domain; Pyridoxal_deC: group II pyridoxal-dependent decarboxylases; Rav1p_C: RAVE complex protein Rav1 C-terminal; SAP: a putative DNA/RNA binding domain found in diverse nuclear and cytoplasmic proteins; Sprouty: Sprouty protein; TR: transmembrane region; TRAPPC9-Trs120: transport protein Trs120 or TRAPPC9, TRAPP II complex subunit; TyrKc: tyrosine-protein kinase, catalytic domain; WH1: WH1 domain.|
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Potential novel candidate genes
Our subsequent analysis applied stricter criteria to screen for probably deleterious missense variants predicted as damaging by all of the algorithms. We first searched the remaining genes using annotation keywords (olfactory bulb, brain/nervous system development, hypothalamus, pituitary, and gonadotropin) in the OMIM, GO, KEGG pathway and Reactome pathway. Then we used genes as novel candidate genes if their functions were related to IHH through literatures mining. We finally found evidence of four potential novel candidate genes contributing to IHH: coiled-coil domain containing 88C (CCDC88C), cell adhesion associated, oncogene regulated (CDON), glutamate decarboxylase like 1 (GADL1), and sprouty related EVH1 domain containing 3 (SPRED3).
The CCDC88C missense variant p. Arg1299Cys was heterozygous in case P05. CCDC88Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in CCDC88C were linked to midline brain malformation. Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)p. Gln91Arg, and FGFR1 c.1664-2A>C, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.
One unreported and probably deleterious missense variant p. Val969Ile of another PSIS gene, CDON, was also found in case P17 who carried a missense variant in CHD7, a causative gene of IHH. CDON seems to act similarly as CCDC88C through a digenic/oligogenic model to contribute to IHH.
Case P06 had a missense variant in GADL1 (p. Ser221Cys), predicted as probably damaging. GADL1 expression is present during early brain development and is higher in olfactory bulb than that in other tissues, where is an active area for regeneration and migration of GnRH neurons. Consistent with this observation, case P06 was affected by anosmia, indicating that the function of GADL1 might be involved in the etiology of IHH [Table 2].
A de novoSPRED3 frameshift deletion (p. Gly52Asnfs*14) resulting in truncation of the protein was detected in case P09. SPRED3 is expressed exclusively in the brain.SPRED3 and sprouty RTK signaling antagonist 4 (SPRY4) are family members of SPROUTY (SPRY). The SPRED family functions as inhibitors of fibroblast growth factor (FGF) signaling cascades, while SPRY4 is a known IHH-causative gene, suggesting that SPRED3 may also play a potential role in IHH.
Potential oligogenic inheritance in IHH
Oligogenic inheritance with at least two potential pathogenic variants was observed in nearly half (8/18, 44.4%) of the families in this IHH cohort. Remarkably, one proband even had four potential pathogenic variants [Table 2]. Our findings suggested that the oligogenic inheritance could be common in IHH [Supplementary Figure 2 [Additional file 4]].
Maternal inherent bias of IHH
Of 26 individual variants identified on autosomes in this study, 17 (65.4%) variants were maternally inherited, more than twice the paternal (7/26, 26.9%) variants, and two (7.7%) variants were de novo [Table 2]. The inheritance of IHH-related variants had a preference on maternal origins (P = 0.028, one-tailed Fisher's exact test) compared to the potential deleterious variants of all of the genes except IHH genes in the cases (maternal with n = 1495 vs paternal with n = 1535; [Supplementary Table 3 [Additional file 5]]).
Considering our study's limited sample size, we searched for all of the autosomal variants of IHH genes with pedigree information in the literatures for further validation. Genes with fewer than 9 variants were filtered out. Finally, we ascertained the qualified data of four genes, including CHD7, FGFR1, PROKR2, and gonadotropin releasing hormone receptor (GNRHR). The results consistently supported maternal bias (maternal with n = 46 vs paternal with n = 28; P = 0.024, binomial one-tailed test; [Supplementary Table 4 [Additional file 6]]).
| Discussion|| |
The results of our study extended the variant spectrum of IHH and revealed three reported and 17 novel variants in the known IHH genes. Except for the FGFR1 c.1664-2A>C variant, all of the variants were classified as uncertain significance of pathogenicity, implying that functional studies should be conducted in the future to provide additional evidence for the pathogenicity of those novel variants in IHH.
A total of 24 rare variants were identified in 77.8% (14/18) of the IHH-affected cases in this study. All of those variants were heterozygous, and most were missense and dispersedly distributed in cases, indicating strong complexity and heterogeneity of IHH. PROKR2 had the highest variant frequency (4/18, 22.2%) in our study. Although PROKR2 variant p. Trp178Ser has a relatively high allele population frequency (0.002–0.003) in East Asians, It was proven in previous studies to be functional damaging, using in vitro functional assays and was enriched in our IHH cohort.
A recent study indicated that PLXNA1 has an oligogenic inheritance rate of 77.7% in IHH, while our results indicated an overall oligogenic inheritance rate of 57.1% (8/14) among the detected families by simultaneously screening all causative and candidate genes. The results of our study and the PLXNA1 study consistently suggested that the rate of oligogenic inheritance of IHH genes varies and maintains at high levels.
According to our data, eight patients had at least two IHH gene variants. Two patients carried three variants and one patient even carried four variants. Our data supported “additive effect” and “cumulative mutation burden” that were proposed in studies related to IHH., For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novoFGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects, and the CCDC88C p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.
Six families harbored only one variant of IHH genes, but none had sufficient evidence to be identified as monogenic models. Among these variants, one was frameshift variant, immunoglobulin superfamily member 10 (IGSF10) p. Thr584Serfs*5, and the rest were missense variants. However, the possibility of being loss-of-function intolerant (pLI) value of IGSF10 is zero, which means that single heterozygous LoF variant of IGSF10 is not sufficient to cause disease. Furthermore, proband P18 was only detected one heterozygous variant, PROKR2 p. Trp178Ser, whereas probands P12 and P14 carried the same PROKR2 variant and additional variants in other candidate genes. The families' results consistently support the digenic/oligogenic inheritance in IHH, and novel IHH-associated genes and variants may be elucidated with advances in genetic knowledge (for example, noncoding variants) and genomic technologies (for example, those for detecting complex structural variations).
We also found four novel potential candidate genes for future investigations. Of interest, CCDC88C and CDON are known causative genes of PSIS, one of congenital hypopituitarism. PSIS has similar clinical phenotypes and shares some causative genes with IHH, such as PROKR2, GLI family zinc finger 2(GLI2), and WD repeat domain 11 (WDR11). Most IHH-causative genes are involved in early brain development, which may affect multiple organs and be associated with more than one disorder or syndrome. In addition, the pathophysiology of IHH sometimes involves a combination of genetic variants that affect both neuronal development and the gonadotropic cascade., Therefore, we suggest that the causative genes of associated development disorders should also be studied, such as abnormalities of the hypothalamus, pituitary, or midline brain, and the remaining genes except for known genes should not be ignored.
The prevalence of IHH is 4–5 times more common in men than women, whereas its genetic causes remain elusive. It used to be thought that X-linked inheritance contributes this sex-biased distribution, while there are only a small fraction of genetic findings in previous studies supporting this X-linked hypothesis. Intriguingly, it was previously reported that FGFR1 deleterious variant caused milder phenotypes in female carriers than male carriers. Interestingly, the damaging variants of PROKR2 p. Trp178Ser in three unrelated male cases in this study were all inherited from their unaffected mothers. Furthermore, even if only IHH causative genes are considered, variants also tend to be maternally inherited in our study and previous reports (P = 0.018 and P = 0.024, respectively; [Supplementary Table 3] and [Supplementary Table 4]. Therefore, we proposed that females may be more tolerant to deleterious variants in IHH genes than males, which is an essential implication in the marked male preponderance of IHH. For stronger statistical significance and confirmation, more pedigrees should be enrolled and analyzed in the future. Our study provided new insights into the molecular variant spectrum and mechanism underlying male preponderance of IHH.
| Author Contributions|| |
ZL conceived and supervised the whole research. JZ conducted the whole exome sequencing. SYT designed the study and did the data processing and analysis. SYT and JZ wrote the manuscript. XBZ and PL contributed to patient recruitment, clinical information collection and follow-up. JQL organized the materials and conducted DNA extraction. JSC collected literatures and data of IHH genes with pedigree information. LBW participated in preparing and revising the manuscript. FZ supervised this investigation and prepared and revised the manuscript. All authors read and approved the final manuscript.
| Competing Interests|| |
All authors declared no competing interests.
| Acknowledgments|| |
The authors thank all of the patients and their family for participating in this study. We thank Ms. Liu Liu for her assistance with the pathogenicity classification of the identified variants. This study was supported by the National Key Research and Development Program of China (2016YFC0905100), National Natural Science Foundation of China (31625015 and 31521003), Shanghai Medical Center of Key Programs for Female Reproductive Diseases (2017ZZ01016), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and Shanghai Municipal Commission for Science and Technology (19QA1407500).
Supplementary Information is linked to the online version of the paper on the Asian Journal of Andrology website.
| References|| |
- Parenti G, Rizzolo MG, Ghezzi M, Di Maio S, Sperandeo MP, et al. Variable penetrance of hypogonadism in a sibship with Kallmann syndrome due to a deletion of the KAL gene. Am J Med Genet 1995; 57: 476–8.
- Dode C, Levilliers J, Dupont JM, De Paepe A, Le Du N, et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 2003; 33: 463–5.
- Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L, et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest 2008; 118: 2822–31.
- Kim HG, Kurth I, Lan F, Meliciani I, Wenzel W, et al. Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet 2008; 83: 511–9.
- Kotan LD, Hutchins BI, Ozkan Y, Demirel F, Stoner H, et al. Mutations in FEZF1 cause Kallmann syndrome. Am J Hum Genet 2014; 95: 326–31.
- Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, et al. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet 2013; 92: 725–43.
- Bernard G, Chouery E, Putorti ML, Tetreault M, Takanohashi A, et al. Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet 2011; 89: 415–23.
- Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, et al. Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. N Engl J Med 2009; 360: 2742–8.
- de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 2003; 100: 10972–6.
- de Roux N, Young J, Brailly-Tabard S, Misrahi M, Milgrom E, et al. The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred. J Clin Endocrinol Metab 1999; 84: 567–72.
- Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 2005; 90: 6609–15.
- Dode C, Teixeira L, Levilliers J, Fouveaut C, Bouchard P, et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet 2006; 2: e175.
- Miura K, Acierno JS Jr., Seminara SB. Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH). J Hum Genet 2004; 49: 265–8.
- Phillip M, Arbelle JE, Segev Y, Parvari R. Male hypogonadism due to a mutation in the gene for the beta-subunit of follicle-stimulating hormone. N Engl J Med 1998; 338: 1729–32.
- Saitsu H, Osaka H, Sasaki M, Takanashi J, Hamada K, et al. Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. Am J Hum Genet 2011; 89: 644–51.
- Seminara SB, Acierno JS Jr., Abdulwahid NA, Crowley WF Jr., Margolin DH. Hypogonadotropic hypogonadism and cerebellar ataxia: detailed phenotypic characterization of a large, extended kindred. J Clin Endocrinol Metab 2002; 87: 1607–12.
- Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, et al.TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 2009; 41: 354–8.
- Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X, et al. Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc Natl Acad Sci U S A 2011; 108: 11524–9.
- Weiss J, Axelrod L, Whitcomb RW, Harris PE, Crowley WF, et al. Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone. N Engl J Med 1992; 326: 179–83.
- Young J, Metay C, Bouligand J, Tou B, Francou B, et al. SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development. Hum Reprod 2012; 27: 1460–5.
- Balsamo A, Cicognani A, Gennari M, Sippell WG, Menabo S, et al. Functional characterization of naturally occurring NR3C2 gene mutations in Italian patients suffering from pseudohypoaldosteronism type 1. Eur J Endocrinol 2007; 156: 249–56.
- Cariboni A, Andre V, Chauvet S, Cassatella D, Davidson K, et al. Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome. J Clin Invest 2015; 125: 2413–28.
- Durmaz E, Turkkahraman D, Berdeli A, Atan M, Karaguzel G, et al. A novel DAX-1 mutation presented with precocious puberty and hypogonadotropic hypogonadism in different members of a large pedigree. J Pediatr Endocrinol Metab 2013; 26: 551–5.
- Cassatella D, Howard SR, Acierno JS, Xu C, Papadakis GE, et al. Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures. Eur J Endocrinol 2018; 178: 377–88.
- Kansakoski J, Fagerholm R, Laitinen EM, Vaaralahti K, Hackman P, et al. Mutation screening of SEMA3A and SEMA7A in patients with congenital hypogonadotropic hypogonadism. Pediatr Res 2014; 75: 641–4.
- Kelberman D, Rizzoti K, Avilion A, Bitner-Glindzicz M, Cianfarani S, et al. Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest 2006; 116: 2442–55.
- Newbern K, Natrajan N, Kim HG, Chorich LP, Halvorson LM, et al. Identification of HESX1 mutations in Kallmann syndrome. Fertil Steril 2013; 99: 1831–7.
- Reynaud R, Barlier A, Vallette-Kasic S, Saveanu A, Guillet MP, et al. An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain. J Clin Endocrinol Metab 2005; 90: 4880–7.
- Salian-Mehta S, Xu M, Knox AJ, Plummer L, Slavov D, et al. Functional consequences of AXL sequence variants in hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2014; 99: 1452–60.
- Vaaralahti K, Tommiska J, Tillmann V, Liivak N, Kansakoski J, et al.De novo SOX10 nonsense mutation in a patient with Kallmann syndrome and hearing loss. Pediatr Res 2014; 76: 115–6.
- Kotan LD, Cooper C, Darcan S, Carr IM, Ozen S, et al. Idiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA1. J Clin Res Pediatr Endocrinol 2016; 8: 125–34.
- Quaynor SD, Bosley ME, Duckworth CG, Porter KR, Kim SH, et al. Targeted next generation sequencing approach identifies eighteen new candidate genes in normosmic hypogonadotropic hypogonadism and Kallmann syndrome. Mol Cell Endocrinol 2016; 437: 86–96.
- Turan I, Hutchins BI, Hacihamdioglu B, Kotan LD, Gurbuz F, et al. CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism. J Clin Endocrinol Metab 2017; 102: 1816–25.
- Bouilly J, Messina A, Papadakis G, Cassatella D, Xu C, et al. DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development. Hum Mol Genet 2018; 27: 359–72.
- Gregory LC, Gaston-Massuet C, Andoniadou CL, Carreno G, Webb EA, et al. The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism. Clin Endocrinol (Oxf) 2015; 82: 728–38.
- Howard SR, Guasti L, Ruiz-Babot G, Mancini A, David A, et al. IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty. EMBO Mol Med 2016; 8: 626–42.
- Hutchins BI, Kotan LD, Taylor-Burds C, Ozkan Y, Cheng PJ, et al. CCDC141 Mutation Identified in Anosmic Hypogonadotropic Hypogonadism (Kallmann Syndrome) Alters GnRH Neuronal Migration. Endocrinology 2016; 157: 1956–66.
- Kotan LD, Isik E, Turan I, Mengen E, Akkus G, et al. Prevalence and associated phenotypes of PLXNA1 variants in normosmic and anosmic idiopathic hypogonadotropic hypogonadism. Clin Genet 2019; 95: 320–4.
- Xu C, Messina A, Somm E, Miraoui H, Kinnunen T, et al. KLB, encoding beta-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism. EMBO Mol Med 2017; 9: 1379–97.
- Zhou C, Niu Y, Xu H, Li Z, Wang T, et al. Mutation profiles and clinical characteristics of Chinese males with isolated hypogonadotropic hypogonadism. Fertil Steril 2018; 110: 486–95.e5.
| References|| |
Bianco SD, Kaiser UB. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol
2009; 5: 569–76.
Boehm U, Bouloux PM, Dattani MT, de Roux N, Dode C, et al.
Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment. Nat Rev Endocrinol
2015; 11: 547–64.
Young J, Xu C, Papadakis GE, Acierno JS, Maione L, et al.
Clinical management of congenital hypogonadotropic hypogonadism. Endocr Rev
2019; 40: 669–710.
Maione L, Dwyer AA, Francou B, Guiochon-Mantel A, Binart N, et al.
Genetics in endocrinology: genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing. Eur J Endocrinol
2018; 178: R55–80.
Cangiano B, Swee DS, Quinton R, Bonomi M. Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease. Hum Genet
2020. Doi: 10.1007/s00439-020-02147-1. [Epub ahead of print]
Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, et al.
Mutations in FGF17
, and FLRT3
are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet
2013; 92: 725–43.
Zhou C, Niu Y, Xu H, Li Z, Wang T, et al.
Mutation profiles and clinical characteristics of Chinese males with isolated hypogonadotropic hypogonadism. Fertil Steril
2018; 110: 486–95.e5.
Men M, Wu J, Zhao Y, Xing X, Jiang F, et al.
Genotypic and phenotypic spectra of FGFR1
, and FGF17
mutations in a Chinese cohort with idiopathic hypogonadotropic hypogonadism. Fertil Steril
2020; 113: 158–66.
Cangiano B, Duminuco P, Vezzoli V, Guizzardi F, Chiodini I, et al.
Evidence for a common genetic origin of classic and milder adult-onset forms of isolated hypogonadotropic hypogonadism. J Clin Med
2019; 8: 14.
Laitinen EM, Vaaralahti K, Tommiska J, Eklund E, Tervaniemi M, et al.
Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland. Orphanet J Rare Dis
2011; 6: 41.
Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics
2010; 26: 589–95.
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, et al.
The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res
2010; 20: 1297–303.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res
2010; 38: e164.
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc
2009; 4: 1073–81.
Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods
2014; 11: 361–2.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, et al.
A method and server for predicting damaging missense mutations. Nat Methods
2010; 7: 248–9.
Jagadeesh KA, Wenger AM, Berger MJ, Guturu H, Stenson PD, et al.
M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. Nat Genet
2016; 48: 1581–6.
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, et al.
The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020; 581: 434–43.
Amberger JS, Bocchini CA, Scott AF, Hamosh A. OMIM.org: leveraging knowledge across phenotype-gene relationships. Nucleic Acids Res
2019; 47: D1038–43.
Jassal B, Matthews L, Viteri G, Gong C, Lorente P, et al.
The reactome pathway knowledgebase. Nucleic Acids Res
2020; 48: D498–503.
The Gene Ontology Consortium. The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Res
2019; 47: D330–8.
Richards S, Aziz N, Bale S, Bick D, Das S, et al.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med
2015; 17: 405–24.
Zhu Q, Ge D, Maia JM, Zhu M, Petrovski S, et al.
A genome-wide comparison of the functional properties of rare and common genetic variants in humans. Am J Hum Genet
2011; 88: 458–68.
Zwaveling-Soonawala N, Alders M, Jongejan A, Kovacic L, Duijkers FA, et al.
Clues for polygenic inheritance of pituitary stalk interruption syndrome from exome sequencing in 20 patients. J Clin Endocrinol Metab
2018; 103: 415–28.
Bashamboo A, Bignon-Topalovic J, Rouba H, McElreavey K, Brauner R. A nonsense mutation in the hedgehog receptor CDON
associated with pituitary stalk interruption syndrome. J Clin Endocrinol Metab
2016; 101: 12–5.
Winge I, Teigen K, Fossbakk A, Mahootchi E, Kleppe R, et al.
Mammalian CSAD and GADL1 have distinct biochemical properties and patterns of brain expression. Neurochem Int
2015; 90: 173–84.
Cox KH, Oliveira LM, Plummer L, Corbin B, Gardella T, et al.
Modeling mutant/wild-type interactions to ascertain pathogenicity of PROKR2
missense variants in patients with isolated GnRH deficiency. Hum Mol Genet
2018; 27: 338–50.
Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L, et al.
Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. J Clin Endocrinol Metab
2008; 93: 3551–9.
Kotan LD, Isik E, Turan I, Mengen E, Akkus G, et al.
Prevalence and associated phenotypes of PLXNA1
variants in normosmic and anosmic idiopathic hypogonadotropic hypogonadism. Clin Genet
2019; 95: 320–4.
Raivio T, Sidis Y, Plummer L, Chen H, Ma J, et al.
Impaired fibroblast growth factor receptor 1 signaling as a cause of normosmic idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab
2009; 94: 4380–90.
Lichiardopol C, Albulescu DM. Pituitary stalk interruption syndrome: report of two cases and literature review. Acta Endocrinol (Buchar)
2017; 13: 96–105.
Topaloglu AK. Update on the genetics of idiopathic hypogonadotropic hypogonadism. J Clin Res Pediatr Endocrinol
2017; 9: 113–22.
Stamou MI, Cox KH, Crowley WF Jr. Discovering genes essential to the hypothalamic regulation of human reproduction using a human disease model: adjusting to life in the “-omics” era. Endocr Rev
2015; 36: 603–21.
Swee DS, Quinton R. Managing congenital hypogonadotrophic hypogonadism: a contemporary approach directed at optimizing fertility and long-term outcomes in males. Ther Adv Endocrinol Metab
2019; 10: 2042018819826889.
[Table 1], [Table 2]