Whole exome sequencing and trio analysis to broaden the variant spectrum of genes in idiopathic hypogonadotropic hypogonadism.
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SUBMITTER: Zhang J
PROVIDER: S-EPMC8152424 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:As a rare disease leading to male infertility, idiopathic hypogonadotropic hypogonadism (IHH) has strong heterogeneity of clinical phenotype and gene mutation. At present, there is no effective diagnosis and treatment method for this disease. This study is to explore the possible new pathogenic gene of idiopathic hypogonadotrophic hypogonadism and the pathological mechanism affecting its occurrence. We performed a whole-exome sequencing on 9 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH), 19 varicocele patients with asthenospermia, oligospermia, or azoospermia, 5 patients with simple nonobstructive azoospermia, and 13 normal healthy adult males and carried out comparative analysis, channel analysis, etc. After preliminary sequencing screening, 309-431 genes harbouring variants, including SNPs and indels, were predicted to be harmful per single patient in each group. In genetic variations of nIHH patients' analysis, variants were detected in 10 loci and nine genes in nine patients. And in co-analysis of the three patient groups, nine nIHH patients, 19 VC patients, and five SN patients shared 116 variants, with 28 variant-harbouring genes detected in five or more patients. We found that the NEFH, CCDC177, and PCLO genes and the Gene Ontology pathways GO:0051301: cell division and GO:0090066: regulation of anatomical structure size may be key factors in the pathogenic mechanism of IHH. Our results suggest that the pathogenic mechanism of IHH is not limited to the central nervous system effects of GnRH but may involve other heterogeneous pathogenic genetic variants that affect peripheral organs.
| S-EPMC10784340 | biostudies-literature
Project description:ContextThe olfactory phenotype in patients with idiopathic hypogonadotropic hypogonadism (IHH) ranges from complete anosmia (Kallmann syndrome) to normosmia (normosmic IHH). However, the true prevalence of intermediary olfactory phenotypes (hyposmia) in IHH patients has not yet been assessed, and systematic correlations with anatomical and genetic abnormalities have not been reported.ObjectiveThe objective of this study was to evaluate olfactory function in a large IHH cohort and correlate these findings with olfactory magnetic resonance imaging (MRI) and underlying genetic etiology.Design and settingWe conducted a cross-sectional case-control study at an academic referral center.PatientsA total of 286 IHH patients (201 males and 85 females) and 2183 healthy historic controls (1011 males and 1172 females) were studied.Main outcome measuresWe measured olfactory function using the University of Pennsylvania Smell Identification Test; in 208 subjects, the genetic etiology of IHH was ascertained by DNA sequencing; in a minor subset [39 of 286 subjects (13%)], olfactory structures were determined by MRI.ResultsIn the IHH cohort, 31.5% were anosmic, 33.6% were hyposmic, and 34.9% were normosmic. Most hyposmic (seven of 11) subjects with MRI data exhibited olfactory structure abnormalities. Of hyposmic subjects, 39.5% harbored mutations in genes involved in either GnRH neuronal migration or GnRH secretion.ConclusionsIHH subjects display a broad spectrum of olfactory function, with a significant hyposmic phenotype in nearly one third of subjects. The hyposmic subjects harbor mutations in genes affecting GnRH neuronal migration and its secretion, suggesting a pathophysiological overlap between Kallmann syndrome and normosmic IHH. Accurate olfactory phenotyping in IHH subjects will inform the pathophysiology of this condition and guide genetic testing.
| S-EPMC3251934 | biostudies-literature
Project description:Summary:Hypogonadotropic hypogonadism is characterised by insufficient secretion of pituitary gonadotropins resulting in delayed puberty, anovulation and azoospermia. When hypogonadotropic hypogonadism occurs in the absence of structural or functional lesions of the hypothalamic or pituitary gland, the hypogonadism is defined as idiopathic hypogonadotropic hypogonadism (IHH). This is a rare genetic disorder caused by a defect in the secretion of gonadotropin releasing hormone (GNRH) by the hypothalamus or a defect in the action of GNRH on the pituitary gland. Up to 50% of IHH cases have identifiable pathogenic variants in the currently known genes. Pathogenic variants in the GNRHR gene encoding the GNRH receptor are a relatively common cause of normosmic IHH, but reports of pathogenic variants in GNRH1 encoding GNRH are exceedingly rare. We present a case of two siblings born to consanguineous parents who were found to have normosmic idiopathic hypogonadotropic hypogonadism due to homozygosity of a novel loss-of function variant in GNRH1. Case 1 is a male who presented at the age of 17 years with delayed puberty and under-virilised genitalia. Case 2 is a female who presented at the age of 16 years with delayed puberty and primary amenorrhea. Learning points:IHH is a genetically heterogeneous disorder which can be caused by pathogenic variants affecting proteins involved in the pulsatile gonadotropin-releasing hormone release, action, or both. Currently known genetic defects account for up to 50% of all IHH cases. GNRH1 pathogenic variants are a rare cause of normosmic IHH. IHH is associated with a wide spectrum of clinical manifestations. IHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. Early diagnosis and gonadotrophin therapy can prevent negative physical sequelae and mitigate psychological distress with the restoration of puberty and fertility in affected individuals.
| S-EPMC7077544 | biostudies-literature
Project description:Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by failure to undergo puberty in the setting of low sex steroids and low gonadotropins. IHH is due to abnormal secretion or action of the master reproductive hormone gonadotropin-releasing hormone (GnRH). Several genes have been found to be mutated in patients with IHH, yet to date no mutations have been identified in the most obvious candidate gene, GNRH1 itself, which encodes the preprohormone that is ultimately processed to produce GnRH. We screened DNA from 310 patients with normosmic IHH (nIHH) and 192 healthy control subjects for sequence changes in GNRH1. In 1 patient with severe congenital nIHH (with micropenis, bilateral cryptorchidism, and absent puberty), a homozygous frameshift mutation that is predicted to disrupt the 3 C-terminal amino acids of the GnRH decapeptide and to produce a premature stop codon was identified. Heterozygous variants not seen in controls were identified in 4 patients with nIHH: 1 nonsynonymous missense mutation in the eighth amino acid of the GnRH decapeptide, 1 nonsense mutation that causes premature termination within the GnRH-associated peptide (GAP), which lies C-terminal to the GnRH decapeptide within the GnRH precursor, and 2 sequence variants that cause nonsynonymous amino-acid substitutions in the signal peptide and in GnRH-associated peptide. Our results establish mutations in GNRH1 as a genetic cause of nIHH.
| S-EPMC2710623 | biostudies-literature
Project description:ObjectiveWhat initiates the pubertal process in humans and other mammals is still unknown. We hypothesized that gene(s) taking roles in triggering human puberty may be identified by studying a cohort of idiopathic hypogonadotropic hypogonadism (IHH).MethodsA cohort of IHH cases was studied based on autozygosity mapping coupled with whole exome sequencing.ResultsOur studies revealed three independent families in which IHH/delayed puberty is associated with inactivating SRA1 variants. SRA1 was the first gene to be identified to function through its protein as well as noncoding functional ribonucleic acid products. These products act as co-regulators of nuclear receptors including sex steroid receptors as well as SF-1 and LRH-1, the master regulators of steroidogenesis. Functional studies with a mutant SRA1 construct showed a reduced co-activation of ligand-dependent activity of the estrogen receptor alpha, as assessed by luciferase reporter assay in HeLa cells.ConclusionOur findings strongly suggest that SRA1 gene function is required for initiation of puberty in humans. Furthermore, SRA1 with its alternative products and functionality may provide a potential explanation for the versatility and complexity of the pubertal process.
| S-EPMC5096466 | biostudies-literature
Project description:Idiopathic hypogonadotropic hypogonadism (IHH) due to defects of gonadotropin-releasing hormone (GnRH) secretion and/or action is a developmental disorder of sexual maturation. To date, several single-gene defects have been implicated in the pathogenesis of IHH. However, significant inter- and intrafamilial variability and apparent incomplete penetrance in familial cases of IHH are difficult to reconcile with the model of a single-gene defect. We therefore hypothesized that mutations at different IHH loci interact in some families to modify their phenotypes. To address this issue, we studied 2 families, one with Kallmann syndrome (IHH and anosmia) and another with normosmic IHH, in which a single-gene defect had been identified: a heterozygous FGF receptor 1 (FGFR1) mutation in pedigree 1 and a compound heterozygous gonadotropin-releasing hormone receptor (GNRHR) mutation in pedigree 2, both of which varied markedly in expressivity within and across families. Further candidate gene screening revealed a second heterozygous deletion in the nasal embryonic LHRH factor (NELF) gene in pedigree 1 and an additional heterozygous FGFR1 mutation in pedigree 2 that accounted for the considerable phenotypic variability. Therefore, 2 different gene defects can synergize to produce a more severe phenotype in IHH families than either alone. This genetic model could account for some phenotypic heterogeneity seen in GnRH deficiency.
| S-EPMC1765517 | biostudies-literature
Project description:Autism spectrum disorder (ASD) is a group of clinically and genetically heterogeneous neurodevelopmental disorders. Recent tremendous advances in the whole exome sequencing (WES) enable rapid identification of variants associated with ASD including single nucleotide variations (SNVs) and indels. To further explore genetic etiology of ASD in Chinese children with negative findings of copy number variants (CNVs), we applied WES in 80 simplex families with a single affected offspring with ASD or suspected ASD, and validated variations predicted to be damaging by Sanger sequencing. The results showed that an overall diagnostic yield of 8.8% (9.2% in the group of ASD and 6.7% in the group of suspected ASD) was observed in our cohort. Among patients with diagnosed ASD, developmental delay or intellectual disability (DD/ID) was the most common comorbidity with a diagnostic yield of 13.3%, followed by seizures (50.0%) and craniofacial anomalies (40.0%). All of identified de novo SNVs and indels among patients with ASD were loss of function (LOF) variations and were slightly more frequent among female (male vs. female: 7.3% vs. 8.5%). A total of seven presumed causative genes (CHD8, AFF2, ADNP, POGZ, SHANK3, IL1RAPL1, and PTEN) were identified in this study. In conclusion, WES is an efficient diagnostic tool for diagnosed ASD especially those with negative findings of CNVs and other neurological disorders in clinical practice, enabling early identification of disease related genes and contributing to precision and personalized medicine.
| S-EPMC6284054 | biostudies-literature
Project description:Skeletal dysplasias (SDs) comprise a series of severe congenital disorders that have strong clinical heterogeneity and usually attribute to diverse genetic variations. The pathogenesis of more than half of SDs remains unclear. Additionally, the clinical manifestations of fetal SDs are ambiguous, which poses a big challenge for accurate diagnosis. In this study, eight unrelated families with fetal SD were recruited and subjected to sequential tests including chromosomal karyotyping, chromosomal microarray analysis (CMA), and trio whole-exome sequencing (WES). Sanger sequencing and quantitative fluorescence PCR (QF-PCR) were performed as affirmative experiments. In six families, a total of six pathogenic/likely pathogenic variations were identified in four genes including SLC26A2, FGFR3, FLNB, and TMEM38B. These variations caused disorders following autosomal dominant or autosomal recessive inheritance patterns, respectively. The results provided reliable evidence for the subsequent genetic counseling and reproductive options to these families. With its advantage in variation calling and interpreting, trio WES is a promising strategy for the investigation of fetal SDs in cases with normal karyotyping and CMA results. It has considerable prospects to be utilized in prenatal diagnosis.
| S-EPMC6537022 | biostudies-literature
Project description:Context:Individuals with idiopathic hypogonadotropic hypogonadism (IHH), even those with evidence of some hypothalamic reproductive endocrine activity, fail to complete puberty and fail to respond to physiologic doses of kisspeptin. Objective:This case series examined whether treatment with sex steroids could stimulate kisspeptin responsiveness in patients with IHH. Design:This was a case series. Setting:This study was conducted at an academic medical center. Participants:Seven patients with IHH were studied. Interventions:Participants, both on and off sex steroid therapy, underwent frequent blood sampling to measure LH at baseline, in response to kisspeptin and GnRH. Main Outcome Measures:The main outcome measure was LH responses to kisspeptin on and off sex steroids. Results:All participants responded to exogenous GnRH, but no participant responded to exogenous kisspeptin. Sex steroid treatment did not modify responsiveness to kisspeptin. Conclusions:The functional impairment of the GnRH neuronal network in patients with IHH, as evidenced by their inability to respond to a physiologic dose of kisspeptin, is observed in both sex steroid- deficient and sex steroid-replete states. In this case series, a normalized sex steroid milieu does not appear capable of overcoming the kisspeptin resistance of these patients.
| S-EPMC6223246 | biostudies-literature
Project description:ObjectiveTo evaluate the clinical features of Chinese women with idiopathic hypogonadotropic hypogonadism (IHH).MethodsWe retrospectively reviewed the clinical characteristics, laboratory and imaging findings, therapeutic management and fertility outcomes of 138 women with IHH. All patients had been treated and followed up at an academic medical centre during 1990-2016.ResultsAmong the 138 patients, 82 patients (59.4%) were diagnosed with normosmic IHH and 56 patients (40.6%) were diagnosed with Kallmann syndrome (KS). The patients with IHH experienced occasional menses (4.3%), spontaneous thelarche (45.7%) or spontaneous pubarche (50.7%). Women with thelarche had a higher percentage of pubarche (P? <?0.001) and higher gonadotropin concentrations (P? <?0.01). Olfactory bulb/sulci abnormalities were found during the magnetic resonance imaging (MRI) of all patients with KS. Most patients with IHH had osteopenia and low bone age. Among the 16 women who received gonadotropin-releasing hormone treatment, ovulation induction or assisted reproductive technology, the clinical pregnancy rate was 81.3% and the live birth rate was 68.8%.ConclusionsThe present study revealed that the phenotypic spectrum of women with IHH is broader than typical primary amenorrhoea with no secondary sexual development, including occasional menses, spontaneous thelarche or pubarche. MRI of the olfactory system can facilitate the diagnosis of KS. Pregnancy can be achieved after receiving appropriate treatment.
| S-EPMC5682410 | biostudies-literature