Gonadotropin releasing hormone (GnRH) deficiency is a disorder characterized by absent or delayed puberty, with largely unknown genetic causes. The purpose of this study was to obtain and exploit gene expression profiles of GnRH neurons during development to unveil novel biological mechanisms and genetic determinants underlying GnRH deficiency (GD). Here, we combined bioinformatic analyses of primary embryonic and immortalized GnRH neuron transcriptomes with exome sequencing from GD patients to identify candidate causative genes. Among differentially expressed and filtered transcripts, we found loss-of-function (LoF) variants of the autism-linked Neuroligin 3 (NLGN3) gene in two unrelated patients co-presenting with GD and neurodevelopmental traits. We demonstrated that NLGN3 is upregulated in maturing GnRH neurons and that NLGN3 wild type, but not mutant proteins, promotes neuritogenesis when overexpressed in developing GnRH cells. Our data represent proof-of-principle that this complementary approach can identify novel candidate GD genes and demonstrate that LoF NLGN3 variants may contribute to GD. This novel genotype-phenotype correlation implies common genetic mechanisms underlying neurodevelopmental disorders, such as GD and autistic spectrum disorder.

The authors have declared no competing interest.

A.C. and V.V. were funded by the Italian Ministry of Health (GR-2016-02362389). S.R.H. is funded by the National Institute for Health Research [CL-2017-19-002], Wellcome Trust (222049/Z/20/Z), Barts charity [MGU0552] and the Rosetrees Trust [M222-F1]. Work in the laboratory of P.S. is supported by AIMS-2-TRIALS a Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. R.O. was supported by ESPE Early Career Scientific Development Grant and a postdoctoral fellowship sponsored by Fondazione Collegio Ghislieri. A.P. was partially sponsored by BSN.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee of London-Chelsea NRES (13/LO/0257), UK NHS Health Research Authority (IRAS 95781) and CHU de Caen and Dijon Bourgogne gave ethical approvals for this work.

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The exome sequencing datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.