Jing Zhai

All Publications

• Clinical and genetic basis of congenital gonadotropin deficiency. Human reproduction open Wang, Y., Zhai, J., Habibi, I., Kolesińska, Z., de Azevedo Correa, F., Zouaghi, Y., Ameti, A., Boizot, A., Perdices-López, C., Todisco, T., Niederländer, N. J., Acierno, J. S., Messina, A., Santoni, F., Pitteloud, N. 2026; 2026 (2): hoag017

  Abstract

  What is the clinical and genetic overlap across subtypes of congenital gonadotropin (Gn) deficiency?This study reveals substantial clinical and genetic overlap among Gn deficiency disorders, with shared genetic and developmental features across congenital hypogonadotropic hypogonadism (CHH), combined pituitary hormone deficiency (CPHD), and syndromic forms of Gn deficiency.Congenital Gn deficiency includes a subset of hypogonadotropic hypogonadism (HH) and can result from defects at the level of the hypothalamus or the pituitary. It includes (i) CHH, further classified into normosmic CHH (nCHH) and Kallmann syndrome (KS); (ii) CPHD; and (iii) syndromic forms such as CHARGE syndrome and septo-optic dysplasia (SOD).The study included all probands with Gn deficiency recruited at a tertiary care center between 2011 and 2024 (n = 568), including 276 KS, 247 nCHH, 29 CPHD, and 16 syndromic Gn deficiency cases. All individuals underwent detailed clinical phenotyping followed by DNA sequencing.Genetic analysis focused on pathogenic (P) and likely pathogenic (LP) variants and variants of uncertain significance (VUS) within established CHH and CPHD genes. Oligogenicity was assessed in the CHH/syndromic HH cohort (n = 523) compared with controls from 1000 Genomes (n = 601). Genetic overlap among CHH, CPHD, and syndromic Gn deficiency was systematically investigated.Cleft lip/palate, dental agenesis, and ear abnormalities were recurrent across all Gn-deficient groups. Notably, some CPHD and SOD patients exhibited anosmia and a preserved Gn response to LH-releasing hormone (LHRH) stimulation, indicating a hypothalamic component to their HH. Rare variants in CHH genes were identified in 53% of KS probands (40% P/LP, 13% VUS) and 33% of nCHH probands (23% P/LP, 10% VUS). FGFR1, ANOS1, and PROKR2 were most frequently mutated in KS, while GNRHR, FGFR1, and KISS1R predominated in nCHH. Oligogenic inheritance was detected in 15% of CHH cases, with variants in FGFR1 being most commonly involved. Importantly, a substantial proportion (14%) of CHH patients without a molecular diagnosis carried rare variants predicted to be P or LP in genes typically associated with CPHD (e.g. ROBO1, BRAF, FAT2, and DCHS2). Conversely, several CHH-associated genes such as FGFR1 and FGF8, already implicated in CPHD, were also identified in patients with CPHD and syndromic GN deficiency, further supporting a shared genetic architecture between CHH and CPHD.N/A.Non-coding and copy number variants were not studied. Functional studies of the new candidate genes for CHH were not undertaken.This study highlights the importance of comprehensive clinical evaluation and broadened genetic testing in patients with Gn deficiency.This work was supported by the Swiss National Foundation (NP) (Grant No. 310030B_201275 to N.P.) and the Natural Science Foundation of Beijing (Grant No. 7244338 to Y.W.). The authors declare no competing interests.

  View details for DOI 10.1093/hropen/hoag017

  View details for PubMedID 41873429

  View details for PubMedCentralID PMC13005924

• Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis. Science (New York, N.Y.) Collado-Sole, A., Borjini, N., Zhai, J., Ruiz-Pino, F., Soria-Alcaide, G., Folgueira, C., García-Vilela, C., Romero-de la Rosa, B., Lopez, V., Zouaghi, Y., Jacobs, A., Mora-Romero, B., Barranco, A., Yoldi, G., Rizzoti, K., Sabio, G., Perez-Chacon, G., Santamaria, P. G., Esteban, J. A., Journiac, N., Prevot, V., Pascual, A., Fernández-Chacón, R., Tena-Sempere, M., Pitteloud, N., Gonzalez-Suarez, E. 2026: eaeb6999

  Abstract

  The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We identified a role of hypothalamic microglia in controlling the HPG axis through receptor activator of nuclear factor κβ (Rank) signaling. Whole-body and microglia Rank depletion led to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) neuron function. In addition, we identified rare gene variants of RANK in patients with HH. Transcriptional profiling upon Rank loss revealed defective microglia activation and morphological alterations in the median eminence, decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH neuronal responses to kisspeptin. Overall, our data uncover the microglia as regulator of GnRH neuronal function through Rank signaling, with potential implications for reproductive maturation and fertility.

  View details for DOI 10.1126/science.aeb6999

  View details for PubMedID 41818388

• Pleiotropic genes linking congenital hypogonadotropic hypogonadism and cleft lip/palate: evidence from a genomic CHH cohort study. European journal of human genetics : EJHG Correa, F. d., Habibi, I., Zhai, J., Adamo, M., Wang, Y., Boizot, A., Zouaghi, Y., Rauch, A., Pekic, S., Quinton, R., Bonomi, M., Cangiano, B., Dhillo, W. S., Fluck, C. E., Nemeth, A., Bouloux, P. M., Ferrara, J. M., Pignatelli, D., Halász, Z., Perdices-Lopez, C., Messina, A., Niederländer, N. J., Santoni, F., Acierno, J. S., Pitteloud, N. 2026; 34 (3): 340-347

  Abstract

  Congenital hypogonadotropic hypogonadism (CHH) is a rare and genetically heterogeneous disorder characterized by absent or incomplete puberty due to impaired gonadotropin-releasing hormone (GnRH) function. A subset of individuals with CHH also present with developmental anomalies, including midline defects such as cleft lip and/or palate (CLP). This study investigates the genetic overlap between CHH and CLP. A total of 336 individuals diagnosed with CHH were clinically assessed for associated phenotypes, including CLP. High-throughput sequencing was performed using a targeted gene panel encompassing known CHH- and CLP-related genes. Variants were analyzed and classified according to the American College of Medical Genetics and Genomics (ACMG) criteria for pathogenicity. CLP was present in 21 patients with CHH (6%). Pathogenic or likely pathogenic variants in genes associated with both CHH and CLP-such as FGFR1 and CHD7-were identified in eight individuals. Furthermore, 17% of the patients with CHH without CLP harbored deleterious variants in genes implicated in clefting, including DVL3, PLCB4, NIPBL, and EDNRA. Evidence of digenic inheritance involving both CHH- and CLP-related genes was observed in multiple cases. FGFR1 variants were the most frequently detected and were commonly associated with anosmia and additional developmental anomalies. These findings highlight a genetic and phenotypic continuum between CHH and CLP, underscoring the involvement of shared developmental pathways. The high prevalence of FGFR1 variants in patients with CHH and CLP supports its role as a pleiotropic gene. Understanding the overlapping genetic mechanisms may enhance diagnostic precision and inform personalized management strategies for affected individuals.

  View details for DOI 10.1038/s41431-025-02005-6

  View details for PubMedID 41535479

  View details for PubMedCentralID PMC12963409

• The transcription factor TBX3 is mutated in congenital hypogonadotropic hypogonadism Perdices-Lopez, C., Zouaghi, Y., Habibi, I., Zhai, J., Wang, Y., Avendano, M. S., Guerrero, Y., Correa, F., Todisco, T., Howard, S., Gong, C., Niederlander, N., Messina, A., Acierno, J. S., Santoni, F., Tena-Sempere, M., Pitteloud, N. SPRINGERNATURE. 2025: 572

  View details for Web of Science ID 001671157902158

• Oligogenic inheritance in congenital hypogonadotropic hypogonadism Habibi, I., Wang, Y., Zouaghi, Y., Zhai, J., Ameti, A., Correa, F., Todisco, T., Adamo, M., Jacobs, A., Perdices-Lopez, C., Kolesinska, Z., Papadakis, G., Phan-Hug, F., Pekic, S., Duarte, P., Bonomi, M., Cools, M., de Paepe, A., Geffner, M., Mamoojee, Y., Persani, L., Popovic, V., Quinton, R., Dhillo, W., Sato, N., Boizot, A., Millar, R., Ambrin, F., Ansar, M., Messina, A., Niederlander, N. J., Acierno, J., Santoni, F., Pitteloud, N. SPRINGERNATURE. 2025: 166-167

  View details for Web of Science ID 001688659400159

• GenMasterTable: a user-friendly desktop application for filtering, summarising, and visualising large-scale annotated genetic variants. BMC bioinformatics Zhai, J., Pitteloud, N., Santoni, F. A. 2025; 26 (1): 211

  Abstract

  BACKGROUND: The rapid expansion of next-generation sequencing (NGS) technologies has generated vast amounts of genomic data, creating a growing demand for secure, scalable, and accessible tools to support variant interpretation. However, many existing solutions are command-line based, rely on cloud or server infrastructures that may pose data privacy risks, lack flexibility in supporting both VCF, CSV and TSV formats, or struggle to handle the scale and complexity of modern genomic datasets. There is a clear need for a user-friendly, locally operated application capable of efficiently processing annotated variant data for large-scale cohort level analysis. RESULTS: We introduce GenMasterTable, a free, secure, and cross-platform desktop application designed to simplify variant analysis through an intuitive graphical user interface (GUI). As the first tool to enable comprehensive cohort-level analysis from VCF, CSV to TSV files, GenMasterTable provides advanced functionality for concatenation, filtering, summarizing, and visualizing large-scale annotated datasets. Tailored for users without programming expertise, it enables rapid and accurate exploration of genetic variants, making it a practical solution for both research and clinical settings. CONCLUSION: GenMasterTable addresses critical limitations in current variant analysis workflows by combining usability, data security, and scalability. Its support for multiple input formats and locally executed operations empowers clinicians, geneticists, and researchers to perform comprehensive variant analysis efficiently without the need for programming expertise.

  View details for DOI 10.1186/s12859-025-06238-6

  View details for PubMedID 40804356

  View details for PubMedCentralID PMC12344886

• Trio analyses of patients with congenital hypopituitarism reveals novel candidate genes Correa, F., Habibi, I., Kolesinska, Z., Zouaghi, Y., Zhai, J., Phan-Hug, F., Antoniou, M., Pignatelli, D., Lang-Muritano, M., Marek, N., l'Allemands, D., Papadakis, G., Ameti, A., Messina, A., Niederlander, N. J., Boizot, A., Santoni, F., Acierno, J. S., Pitteloud, N. KARGER. 2023: 119-120

  View details for Web of Science ID 001091262800187