Disease Models & Mechanisms · 19 authors, 11 centres
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This study used transcriptomic profiling of rodent GnRH neurons and exome sequencing from two human patients with gonadotropin-releasing hormone deficiency (GD) to identify candidate disease genes. The central result was the discovery that loss-of-function variants in the autism-linked gene *NLGN3* were found in two unrelated GD patients and that NLGN3 protein promotes neurite growth in GnRH cells, suggesting a shared genetic mechanism between GD and autism.
The researchers combined bioinformatic analysis of transcriptomes from immortalized and primary embryonic rodent GnRH neurons with exome sequencing from two human patients with gonadotropin-releasing hormone deficiency (GD) to identify novel genetic determinants. They identified loss-of-function variants in the *NLGN3* gene in two unrelated patients who presented with both GD and neurodevelopmental traits like autism spectrum disorder (ASD). *NLGN3* was found to be upregulated in developing GnRH neurons, and overexpression of the wild-type, but not mutant, protein promoted neuritogenesis in GnRH cells. The study provides proof-of-principle that integrating these omic approaches can identify new GD candidate genes and suggests a genotype-phenotype link between *NLGN3* variants and a combined phenotype of GD and ASD. Limitations include the very small patient sample size and the need for further studies to confirm the functional role of NLGN3 in GnRH neuron development in vivo.
