This study aimed to investigate alterations in spontaneous brain activity in Kallmann syndrome (KS) and their associations with cognitive impairment and genetic mutations. We prospectively enrolled 100 patients with KS and 100 matched healthy controls. All participants underwent brain MRI and neuropsychological assessment targeting global cognition (Montreal-Cognitive-Assessment, MoCA), executive function (Stroop-Color-and-Word-Test, SCWT), cognitive flexibility (Trail-Making-Test), and working memory (Digit-Span-Test, DST; Visual-Reproduction, VR). Regional brain activity was quantified using the amplitude of low-frequency fluctuation (ALFF) metric. We further conducted brain-cognition correlations, genetic association analysis with whole-exome sequencing, and extrapolated neuroimaging-transcription-association analysis. Compared to the controls, patients with KS exhibited significant cognitive deficits across most domains, with 36

Perrault syndrome (PRLTS) is an autosomal recessive disease with sensorineural hearing loss and ovarian dysfunction in girls, and either a fluctuating neurological phenotype or not. PRLTS type 2 is known to be caused by pathogenic variants of the CLPP gene that encodes mitochondrial ATP-dependent protease. This paper involved clinical and genetic studies on a Pakistani family with PRLTS. Whole-exome sequencing identified a novel homozygous CLPP missense mutation (NM_006012.4: c.250 A > C; p.Ile84Leu). Its pathogenicity was assessed with the help of multiple sequence alignment, AlphaFold protein modeling, and docking with CLPX with the help of ClusPro. Auditory brainstem responses and tympanometry were in clinical assessment. The individuals were found to have a uniform phenotype of severe sensorineural hearing loss, mild intellectual disability, ataxia and frequent fever. There was one patient in whom the unilateral Eustachian tube dysfunction was hinted at by Tympanometry. At the molecular level, the identified CLPP variant involved a highly conserved residue. Structural modeling showed preserved protein architecture, whereas docking simulations revealed disrupted CLPP-CLPX interaction, suggesting a basis for impaired proteostasis. We report a novel CLPP missense variant (p.I84L) in a Pakistani family with PRLTS, expanding the mutational spectrum of CLPP. To the best of our knowledge, recurrent fever was reported in PRLTS for the first time, which expanded the PRLTS phenotype spectrum.

Background Congenital hypogonadotropic hypogonadism (CHH) arises from defective development or dysfunction of GnRH neurons. Olfactory bulb (OB) malformations frequently accompany CHH, a condition termed Kallmann syndrome (KS). Nevertheless, approximately 50% of CHH cases remain genetically undefined. Methods Leveraging our 15-year effort in building one of Asia’s largest CHH cohorts (812 unrelated patients, and 49 CHH families), we identified a pathogenic ZBTB20 mutation (p.R300C) in a four-generation CHH family with seven affected members. We generated nervous system-specific Zbtb20 conditional knockout (cKO) mice to assess phenotypic and mechanistic consequences. Molecular analyses, including transcriptional regulation assays, were performed to explore downstream pathways. Findings Four additional heterozygous ZBTB20 variants were detected in the CHH cohort. Zbtb20 cKO mice recapitulated hallmark CHH features: GnRH neuron deficiency, hypogonadism, and infertility. Notably, migration of GnRH neurons in Zbtb20-deficient embryos was stalled along the defective terminal nerve (TN) scaffold. Furthermore, Zbtb20 deficiency impaired proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) and disrupted their migration via the rostral migratory stream (RMS) to the OB. We also identified Thbs4 as a key downstream target, as ZBTB20 transcriptionally activates Thbs4, which is critical for SVZ NSCs migration. Interpretation Our study establishes ZBTB20 as a CHH-associated gene and demonstrates its essential role in SVZ-OB neurogenesis. Loss of ZBTB20 function leads to OB atrophy, disrupted terminal nerves, GnRH deficiency and CHH pathogenesis. Funding This project is financially supported by National Natural Science Foundation of China, and the Natural Science Foundation of Hunan Province.

OBJECTIVES:To characterize whole-brain cortical thickness alteration in Kallmann syndrome (KS), assess its correlation with cognitive impairment, and explore the genetic association and extrapolated transcriptional underpinning. METHODS:We prospectively recruited 100 patients with KS and 100 age- and sex-matched healthy controls. All participants underwent high-resolution structural MRI and a comprehensive neuropsychological assessment targeting global cognition (Montreal Cognitive Assessment, MoCA), executive function and inhibitory control (Stroop Color and Word Test, SCWT), cognitive flexibility (Trail Making Test, TMT), working memory (Digit Span Test, DST), and visuospatial memory (Visual Reproduction task, VR). Cortical thickness and subcortical volumes were quantified using FreeSurfer. In the KS cohort, we examined brain-cognition correlations, performed exploratory genetic association analysis using whole-exome sequencing, and conducted extrapolated neuroimaging-transcription analysis using the Allen Human Brain Atlas (http://human.brain-map.org/) to identify underlying biological pathways. RESULTS:Compared to the healthy controls, patients with KS exhibited significant cognitive deficits, with 36% MoCA scoring below the clinical cutoff for cognitive impairment. Domain-specific analysis revealed impairments in SCWT-C, DST-Backward, TMT-B, and VR (all P-value < .05). Structurally, patients showed bilateral increased cortical thickness predominantly in the fronto-limbic circuit (orbitofrontal and subgenual cingulate cortices) and default mode network (voxel P-value < .001, cluster random field theory corrected P-value < .05), alongside bilateral hippocampal enlargement (P-FDR = .048). Crucially, the cortical thickness in these fronto-limbic regions was negatively correlated with SCWT-C and DST. Exploratory genetic analysis linked variants in genes such as OTUD4 and FGFR1 to cognitive variability (TMT-A and VR). Furthermore, the spatial pattern of cortical thickening was significantly associated with extrapolated gene expression profiles enriched for neurodevelopment, neuronal migration, and synaptic function. CONCLUSIONS:This study identified cortical thickening involved in fronto-limbic and default mode network as key neuroanatomical signatures of the patients with KS, which was associated with cognitive impairment. Specific genetic variants may further modulate the structural alterations and cognitive functioning in patients with KS.

To determine the prevalence of CHD7, FGFR1 and ANOS1 variants and the impacts of their splicing variants on mis-splicing in patients with congenital hypogonadotropic hypogonadism (CHH). Based on the whole-exome sequencing data from 280 CHH probands, we identified 15 potential splice-site variants in CHD7, ANOS1 and FGFR1 by using in silico software. The functional consequences of these variants were analyzed by the minigene assay or RT-PCR analyses of RNA taken from the peripheral lymphocytes. Detailed phenotyping was performed in the CHH patients harboring deleterious variants and their available family members. 11 out of 15 potential splice-site variants were demonstrated to cause mis-splicing, resulting in loss of function through deletion, insertion or frameshift of amino acids in the proteins. Most patients with deleterious splice-site variants in CHD7, ANOS1, FGFR1 presented with gene-specific non-reproductive phenotypes, confirming the pathogenic contribution of these variants to CHH. Our study indicated that splice-site variants in CHD7, ANOS1, FGFR1 underlie the genetic basis of ~3.9% of CHH patients, warranting the inclusion of potential splice-site variants for genetic diagnosis and counseling of CHH.

This study delineates brain metabolic signatures underlying neuroendocrine-psychosocial interactions in Kallmann syndrome (KS), a rare genetic disorder characterized by congenital hypogonadism and anosmia. In this prospective case-control study, 30 KS patients and 30 matched healthy controls (HCs) underwent brain [18F]FDG PET scans, sex hormone assays, and standardized neuropsychological assessments. A voxel-wise group comparison analysis was conducted to identify clusters of brain metabolic patterns between KS patients and HCs. Subsequently, correlation and mediation analyses were performed to investigate the interrelationships and mediating effect among brain metabolic patterns, sex hormone levels, and psychosocial factors. We identified six hypermetabolic clusters in KS patients, predominantly located in the fronto-limbic system and the default mode network (DMN) in KS patients. These clusters of hypermetabolism were significantly associated fertility anxiety scale (FAS), health information avoidance scale (HIAS) and health information overload scale (HIOS). In addition, mediation analysis indicated that bilateral basal ganglia hypermetabolism acted as a significant mediator between HIAS and FAS (β = 0.274, P = 0.031). Patients with KS exhibited a distinct hypermetabolism pattern in the DMN-prefrontal circuit, which functionally bridges neuroendocrine dysfunction and reproductive health anxiety.

OBJECTIVES:Kallmann syndrome (KS) is a rare inherited disorder characterized by congenital hypogonadotropic hypogonadism and reduced or absent olfactory function. In addition to gonadal dysgenesis and structural abnormalities, KS patients may present with extensive psychosocial dysfunction and behavioral changes. This study aims to evaluate the effects of self-stigma, impulsivity, and insomnia on anxiety and depression in KS patients and to explore the interrelationships among these factors. METHODS:A total of 206 patients with confirmed KS were recruited from the Xiangya Hospital and Henan Provincial People's Hospital. Multivariable Logistic regression analysis was used to identify independent factors associated with anxiety and depression, and a serial multiple-mediator model was applied to characterize pathway effects. RESULTS:The cohort of KS patients demonstrated substantial psychological and social burden, including self-stigma, impulsivity, insomnia, loneliness, anxiety, depression, and overall social isolation tendencies. Logistic regression analysis indicated that self-stigma (OR=1.112, P=0.003), loneliness (OR=1.198, P=0.007), and insomnia (OR=1.098, P=0.017) were independent factors the presence of anxiety and depression in KS patients. Mediation-effect modeling further showed that impulsivity and insomnia significantly mediated the effect of self-stigma on anxiety and depression in KS (indirect effect 3=0.013, P=0.008; 95% CI 0.004 to 0.024; c'=0.147, P<0.001; 95% CI 0.091 to 0.201). CONCLUSIONS:This study preliminarily identified the major modifiable factors associated with anxiety and depression in KS patients, including self-stigma, loneliness, and insomnia. Impulsivity and insomnia demonstrated significant serial mediation effects linking self-stigma to affective outcomes. Multidimensional intervention strategies targeting stigma reduction, impulsivity regulation, and sleep-quality improvement may help alleviate anxiety-depression symptoms and ultimately improve overall quality of life in patients with KS.

Objective:To understand the relationship between lipid accumulation product (LAP) and hyperuricemia in physical examination population.Methods:This was a cross-sectional study. The analysis was based on baseline data from a retrospective cohort study. Total of 44 294 people who received physical examination in the Health Management Center of Xiangya Hospital of Central South University from January to December 2012 were selected as subjects with whole-group sampling method. All the subjects aged ≥18 years with complete study variables. The minimum waist circumference of the subjects was calculated to determine the criteria for calculating LAP in those population. With LAP as the observed variable and hyperuricemia as the outcome variable, LAP was divided into four groups according to the interquartile interval (Q 1-Q 4 groups): group Q 1<10.56 cm·mmol/L, 10.56 cm·mmol/L≤Q 2<20.79 cm·mmol/L, 20.79 cm·mmol/L≤Q 3<38.94 cm·mmol/L, Q 4≥38.94 cm·mmol/L. Five models were constructed with logistic regression analysis. No confounding factors was adjusted in Model 1, model 2 was adjusted for age and gender; and model 3 was further adjusted for body mass index, hypertension, hyperlipidemia, creatinine and glomerular filtration rate; model 4 was further adjusted education level, occupation, health insurance, smoking, drinking, diet scores and physical exercise; model 5 was further adjusted the family history of gout, diabetes and hypertension. And the relationship between different LAP levels and hyperuricemia was analyzed. Results:In this study, the minimum waist circumference in the physical examination population was 58 cm and 53 cm for men and women, respectively. The total incidence of hyperuricemia was 13.4% in this population, 5.94% for women and 19.40% for men. When the confounding factors were not adjusted (model 1), the risk of hyperuricemia in women′s LAP Q 2 to Q 4 groups was 1.76 times (95% CI: 1.42-2.17), 5.08 times (95% CI: 4.20-6.14) and 12.58 times (95% CI: 10.43-15.18), and it was 1.68 times (95% CI: 1.43-1.96), 2.74 times (95% CI: 2.36-3.18), and 5.32 times (95% CI: 4.62-6.14) in men, respectively. After gender stratification and adjustment for confounding factors (model 5), the risk still existed, compared with that in Q 1 group of LAP, the risk of hyperuricemia in women in Q 4 group was 8.28 times higher (95% CI: 2.50-27.38) and 3.31 times higher in men (95% CI: 1.57-6.95). Conclusion:The risk of hyperuricemia in health examination population increases with LAP, especially in women.

Isolated hypogonadotropic hypogonadism (IHH) is a rare disease with hypogonadism and infertility caused by the defects in embryonic migration of hypothalamic gonadotropin-releasing hormone (GnRH) neurons, hypothalamic GnRH secretion or GnRH signal transduction. PROKR2 gene, encoding a G-protein coupled receptor PROKR2, is one of the most frequently mutated genes identified in IHH patients. However, the functional consequences of several PROKR2 mutants remain elusive. In this study, we systematically analyzed the Gαq, Gαs and ERK1/2 signaling of 23 IHH-associated PROKR2 mutations which are yet to be functionally characterized. We demonstrate that blockage of Gαq, instead of MAPK/ERK pathway, inhibited PROK2-induced migration of PROKR2-expressing cells, implying that PROKR2-related IHH results primarily due to Gαq signaling pathway disruption. Combined with previous reports, we categorized a total of 63 IHH-associated PROKR2 mutations into four distinct groups according Gαq pathway functionality: (i) neutral (N, >80% activity); (ii) low pathogenicity (L, 50-80% activity); (iii) medium pathogenicity (M, 20-50% activity) and (iv) high pathogenicity (H, <20% activity). We further compared the cell-based functional results with in silico mutational prediction programs. Our results indicated that while Sorting Intolerant from Tolerant predictions were accurate for transmembrane region mutations, mutations localized in the intracellular and extracellular domains were accurately predicted by the Combined Annotation Dependent Depletion prediction tool. Our results thus provide a functional database that can be used to guide diagnosis and appropriate genetic counseling in IHH patients with PROKR2 mutations.

Background and aims: Lipid accumulation product (LAP) is a novel, sex-specific, index -describing lipid over accumulation. Previous studies used baseline LAP for predicting hyperuri-caemia; however, the relationship between them is unclear. We aimed to investigate the rela-tionship between LAP and the risk of hyperuricaemia in the Central Chinese population. Methods and results: This large-scale observational study comprised a cross-sectional population sample and a prospective cohort of 44,294 healthy subjects. This study examined the association between LAP and the risk of hyperuricaemia in the total sample and subgroups using multiple logistic regression analysis and multivariate cox proportional hazards model analysis. As a result, there was a dose-response relationship between LAP and the risk of hyperuricaemia. The prev-alence of hyperuricaemia was 13.4% in the cross-sectional study. During 9 years of follow-up, hy-peruricaemia occurred in 928 (19 .8%) participants. The corresponding hazard ratios after multiple adjustments of hyperuricaemia in the second, third and fourth quartile were 1.34 (95% confidence interval [CI], 1.04-1.72), 2.01 (95% CI, 1.54-2.63), and 2.44 (95% CI, 1.80-3.30)-fold higher vs. the first quartile, respectively. Subgroup analyses showed that the associ-ation between LAP and the risk of hyperuricaemia was more pronounced in females, in-dividuals <= 49 years old and subjects with eGFR >= 60 ml/min/1.73 m2. Conclusion: LAP was positively related to the risk of hyperuricaemia in the Central Chinese pop-ulation, particularly in women, individuals <= 49 years old and adults with relatively normal renal function. These findings suggested the potential of LAP as an independent risk indicator in pre-venting hyperuricaemia. (c) 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Ital-ian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

OBJECTIVES Congenital hypogonadotropic hypogonadism (CHH) is a rare congenital gonadal dysplasia caused by defects in the synthesis, secretion or signal transduction of hypothalamic gonadotropin releasing hormone. The main manifestations of CHH are delayed or lack puberty, low levels of sex hormones and gonadotropins, and may be accompanied with other clinical phenotypes. Some patients with CHH are also accompanied with anosmia or hyposmia, which is called Kalman syndrome (KS). ANOS1, located on X chromosome, is the first gene associated with CHH in an X-linked recessive manner. This study aims to provide a basis for the genetic diagnosis of CHH by analyzing the gene variant spectrum of ANOS1 in CHH and the relationship between clinical phenotype and genotype. METHODS In this study, whole exome sequencing (WES) was used to screen rare sequencing variants (RSVs) of ANOS1 in a Chinese cohort of 165 male CHH patients. Four commonly used in silico tools were used to predict the function of the identified RSVs in coding region, including Polyphen2, Mutation Taster, SIFT, and Combined Annotation Dependent Depletion (CADD). Splice Site Prediction by Neural Network (NNSPLICE) was employed to predict possibilities of intronic RSVs to disrupt splicing. American College of Medical Genetics and Genomics (ACMG) guidelines was used to assess the pathogenicity of the detected RSVs. The ANOS1 genetic variant spectrum of CHH patients in Chinese population was established. The relationship between clinical phenotype and genotype was analyzed by collecting detailed clinical data. RESULTS Through WES analysis for 165 CHH patients, ANOS1 RSVs were detected in 17 of them, with the frequency of 10.3%. A total of 13 RSVs were detected in the 17 probands, including 5 nonsense variants (p.T76X, p.R191X, p.W257X, p.R262X, and p.W589X), 2 splicing site variants (c.318+3A>C, c.1063-1G>C), and 6 missense variants (p.N402S, p.N155D, p.P504L, p.C157R, p.Q635P, and p.V560I). In these 17 CHH probands with ANOS1 RSVs, many were accompanied with other clinical phenotypes. The most common associated phenotype was cryptorchidism (10/17), followed by unilateral renal agenesis (3/17), dental agenesis (3/17), and synkinesia (3/17). Eight RSVs, including p.T76X, p.R191X, p.W257X, p.R262X, p.W589X, c.318+3A>C, c.1063-1G>C, and p.C157R, were predicted to be pathogenic or likely pathogenic ANOS1 RSVs by ACMG. Eight CHH patients with pathogenic or likely pathogenic ANOS1 variants had additional features. In contrast, only one out of nine CHH patients with non-pathogenic (likely benign or uncertain of significance) ANOS1 variants according to ACMG exhibited additional features. And function of the non-pathogenic ANOS1 variants accompanied with other CHH-associated RSVs. CONCLUSIONS The ANOS1 genetic spectrum of CHH patients in Chinese population is established. Some of the correlations between clinical phenotype and genotype are also established. Our study indicates that CHH patients with pathogenic or likely pathogenic ANOS1 RSVs tend to exhibit additional phenotypes. Although non-pathogenic ANOS1 variants only may not be sufficient to cause CHH, they may function together with other CHH-associated RSVs to cause the disease.

Abstract Background Isolated hypogonadotropic hypogonadism (IHH) is a clinical syndrome described by failure of gonadal function secondary to defects on the synthesis, secretion, or action of the gonadotropin‐releasing hormone (GnRH). The secreted glycoprotein SEMA3A binds its receptors NRP1 or NRP2 and PLXNA to participate in axonal projection, dendritic branching, synaptic formation, and neuronal migration. Deficiency in SEMA3A, NRP1, NRP2, and PLXNA1 have been related to abnormal GnRH neuron development in mice and IHH in humans. Methods The aim of this study was to examine the genotypic and phenotypic spectra of the NRP1, NRP2, and PLXNA1 genes in a large cohort of IHH probands from China. We screened NRP1, NRP2, and PLXNA1 variants in Chinese IHH patients by whole exome sequencing and pedigree analysis. Results We identified 10 heterozygous missense variants in PLXNA1, five heterozygous missense variants in NRP1, and two heterozygous missense variants in NRP2. NRP1 variants were found only in IHH patients with defective olfaction (i.e., Kallmann syndrome, KS). In addition, 85% (17/20) of patients harbored variants in other IHH‐associated genes. Conclusion Our study greatly enriched the genotypic and phenotypic spectra of PLXNA1, NRP1, and NRP2 in IHH. It may be conducive to the genetic counseling, diagnosis, and treatment of IHH with mutations in the PLXNA1, NRP1, and NRP2 genes. Furthermore, our results indicated that NRP1 were strongly linked to hearing loss.

BACKGROUND:FGF8-FGFR1 signalling is involved in multiple biological processes, while impairment of this signalling is one of the main reasons for isolated hypogonadotropic hypogonadism (IHH). Recently, several negative modulators of FGF8-FGFR1 signalling were also found to be involved in IHH, including DUSP6, IL17RD, SPRY2 and SPRY4. The aim of this study was to investigate the genotypic and phenotypic spectra of these genes in a large cohort of Chinese patients with IHH.METHODS:A total of 196 patients with IHH were enrolled in this study. Whole-exome sequencing was performed to identify variants, which was verified by PCR and Sanger sequencing.RESULTS:Four heterozygous DUSP6 variants (p.S157I, p.R83Q, p.P188L and p.N355I) were found in six patients. Cryptorchidism, dental agenesis, syndactyly and blue colour blindness were commonly observed in patients with DUSP6 mutations. Six heterozygous IL17RD variants (p.P191L, p.G35V, p.S671L, p.A221T, p.I329M and p.I329V) were found in seven patients. Segregation analysis indicated that 100% (5/5) of probands inherited the IL17RD variants from their unaffected parents, and oligogenicity was found in 4/7 patients. One rare SPRY4 variant (p.T68S) was found in a female patient with Kallmann syndrome who also carried a PLXNA1 mutation.CONCLUSION:Our study greatly enriched the genotypic and phenotypic spectra of DUSP6, IL17RD and SPRY4 in IHH. Mutations in DUSP6 alone seem sufficient to cause IHH in an autosomal dominant manner, whereas IL17RD or SPRY4 mutations may cause IHH phenotypes in synergy with variants in other IHH-associated genes.

Objective: To identify CCDC141 variants in a large Chinese cohort with congenital hypogonadotropic hypogonadism (CHH) and to assess the contribution of CCDC141 to CHH. Design: Detailed phenotyping was conducted in CHH patients with CCDC141 variants and co-segregation analysis was performed, when possible. Methods: Whole-exome sequencing was performed in 177 CHH patients and 450 unrelated, ethnically matched controls from China. Results: Seven novel CCDC141 rare sequencing variants (RSVs) were identified in 12 CHH pedigrees. Four of the variants were private mutations; however, p.Q409X, p.Q871X and p.G1488S were identified in more than one patient. Up to 75% (9/12) of patients had mutations in other CHH-associated genes, which is significantly higher than CHH patients without CCDC141 RSVs. The co-segregation analysis for eight CHH families showed that 75% (6/8) CCDC141 RSVs were inherited from their fertile parents. Over half (58.3%, 8/18) of the patients exhibited other clinical deformities in addition to hypogonadism. One patient harbouring a CCDC141 RSV showed a reversal of CHH after sex-steroid replacement. Conclusions: Our results broaden the genotypic spectrum of CCDC141 in CHH, as CCDC141 RSVs alone do not appear sufficient to cause CHH. The phenotypic spectrum in patients with CCDC141 RSVs is much wider than originally believed.

hypogonadism (IHH) and to characterize the clinical presentations and therapeutic outcomes of IHH patients with FGFR1, FGF8, and FGF17 mutations. Design: Retrospective cohort. Setting: University hospital. Patient(s): A total of 145 IHH probands (125 men and 20 women) were recruited for this study. Interventions(s): Hormone assays. Main Outcome Measure(s): Whole-exome sequencing, polymerase chain reaction-Sanger sequencing, in silico functional prediction. Result(s): Six novel mutations (p.154_158del, p.E496Rfs*12, p.W190X, p.S134D, p.W10X, and c.1552 + 3insT) in FGFR1, two novel mutations (p.E176K and p.R184C) in FGF8, three novel mutations (p.48_52del, p.P120L, and p.K191R) in FGF17, and five reported mutations (p.W289X, p.G237S, p.V102I, p.R250Q, and p.T340M) in FGFR1 were identified in 18 IHH patients. The functional consequences of all mutations were analyzed in silico. In addition to hypogonadotropic hypogonadism, 44.4% (8/18) patients exhibited other clinical deformities, including dental agenesis (3/18, 16.7%), hearing loss (3/18, 16.7%), and hand malformation (2/18, 11.1%). hCG/hMG therapy was effective in promoting sexual development in IHH patients with FGFR1, FGF8, and FGF17 mutations. Conclusion(s): We extended the mutational spectrum of FGFR1, FGF8, and FGF17 in IHH patients. The prevalence of FGFR1, FGF8, and FGF17 mutations in IHH was 12.4%. hCG/hMG therapy was effective to acquire fertility for patients with FGFR1, FGF8, and FGF17 mutations but has a risk of transmitting the mutations and IHH to the next generation. (C) 2019 by American Society for Reproductive Medicine.)

Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder characterized by impaired sexual development and infertility, caused by the deficiency of hypothalamic gonadotropin-releasing hormone neurons. IHH is named Kallmann's syndrome (KS) or normosmic IHH (nIHH) when associated with a defective or normal sense of smell. Variants in SEMA3A have been recently identified in patients with KS. In this study, we screened SEMA3A variants in a cohort of Chinese patients with IHH by whole exome sequencing. Three novel heterozygous SEMA3A variants (R197Q, R617Q and V458I) were identified in two nIHH and one KS patients, respectively. Functional studies indicated that R197Q and R617Q variants were ineffective in activating the phosphorylation of FAK (focal adhesion kinase) in GN11 cells, despite normal production and secretion in HEK293T cells. The V458I SEMA3A had defect in secretion as it was not detected in the conditioned medium from HEK293T cells. Compared with wild type SEMA3A protein, all three SEMA3A mutant proteins were ineffective in inducing the migration of GN11 cells. Our study further showed the contribution of SEMA3A loss-of-function variants to the pathogenesis of IHH.

PURPOSE:Idiopathic hypogonadotropic hypogonadism (IHH) and CHARGE (C, coloboma; H, heart abnormalities; A, choanal atresia, R, retardation of growth and/or development; G, gonadal defects; E, ear deformities and deafness) syndrome are 2 distinct developmental disorders sharing features of hypogonadism and/or impaired olfaction. CHD7 variants contribute to >60% CHARGE syndrome and ~10% IHH patients. A variety of extended CHARGE-like features are frequently reported in CHARGE patients harboring CHD7 variants. In this study, we aimed to systematically analyze the diagnostic CHARGE features and the extended CHARGE-like features in patients with IHH with CHD7 variants. METHODS:Rare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 177 IHH probands. Detailed phenotyping was performed in the IHH patients harboring CHD7 variants and their available family members. RESULTS:CHD7 RSVs were identified in 10.2% (18/177) of the IHH probands. Two diagnostic CHARGE features, hearing loss and ear deformities, were significantly enriched in patients with CHD7 variants. Furthermore, CHD7 variants were significantly associated with a panel of extended CHARGE-like phenotypes, including mild ocular defects, dyspepsia/gastroesophageal reflux disease and skeletal defects. We also developed a predictive model for prioritizing CHD7 genetic testing in IHH patients. CONCLUSION:CHD7 variants rarely cause isolated IHH. Surveillance of symptoms in CHARGE syndrome-affected organs will facilitate the proper treatment for these patients. Certain clinical features can be useful for prioritizing CHD7 genetic screening.

Background: Waardenburg syndrome (WS) is a rare disorder characterized by varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair and skin. WS is classified into four subtypes (WS1–WS4) based on additional symptoms. Dystopia canthorum is a hallmark of WS type 1. There are two genes linked to WS type 1, including PAX3 and EDNRB. Objective: This study aimed to investigate the genetic etiology of WS type 1 in a pair of twins from China with profound hearing loss, blond hair and eyebrows, dystopia canthorum, and brown irides. Methods: The target capture sequencing and Whole-exome sequencing were performed to detect mutations in WS-related genes. Results: A novel de novo frameshift mutation, p.L341Rfs∗18 in MITF was identified in the twins. Hearing thresholds showed substantial improvements following cochlear implantation with a pure-tone average of 30 dB in free-field conditions. Conclusions: The study showed the new genotype–phenotype correlations of MITF to WS type 1. Further molecular analysis is necessary to reappraise the current classification on WS.

Background. Waardenburg syndrome (WS) is one of the most common forms of syndromic deafness with heterogeneity of loci and alleles and variable expressivity of clinical features. Methods. The technology of single-nucleotide variants (SNV) and copy number variation (CNV) detection was developed to investigate the genotype spectrum of WS in a Chinese population. Results. Ninety WS patients and 24 additional family members were recruited for the study. Fourteen mutations had not been previously reported, including c.808C>G, c.117C>A, c.152T>G, c.803G>T, c.793-3T >G, and c.801delT on PAX3; c.642_650delAAG on MITF; c.122G>T and c.127C>T on SOX10; c.230C>G and c.365C>T on SNAI2; and c.481A>G, c.1018C>G, and c.1015C>T on EDNRB. Three CNVs were de novo and first reported in our study. Five EDNRB variants were associated with WS type 1 in the heterozygous state for the first time, with a detection rate of 22.2%. Freckles occur only in WS type 2. Yellow hair, amblyopia, congenital ptosis, narrow palpebral fissures, and pigmentation spots are rare and unique symptoms in WS patients from China. Conclusions. EDNRB should be considered as another prevalent pathogenic gene in WS type 1. Our study expanded the genotype and phenotype spectrum of WS, and diagnostic next-generation sequencing is promising for WS.