Endocrine Abstracts (2017) 51 OC4.1 | DOI: 10.1530/endoabs.51.OC4.1

Patients with self-limited delayed puberty harbour mutations in multiple genes controlling GnRH neuronal development

Sasha Howard1, Valentina Andre2, Leo Guasti1, Claudia Cabrera3, Michael Barnes3, Anna Cariboni2 & Leo Dunkel4


1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 2Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; 3Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 4Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.


Objectives: Abnormal pubertal timing affects >4% of adolescents and is associated with adverse health outcomes. Up to 80% of variation in the timing of pubertal onset is genetically determined. Self-limited delayed puberty (DP) segregates in an autosomal dominant pattern, but in the majority the neuroendocrine pathophysiology and genetic regulation remain unclear. Mis-regulation of the embryonic migration of GnRH neurons has been implicated in the pathogenesis of DP (Howard et al 2016). We hypothesised that new candidates for the genetic basis of DP could be identified using expression data on genes up- or down-regulated during GnRH neuronal migration.

Methods: We performed whole exome sequencing (WES) in 160 members of 67 families from our self-limited DP patient cohort, and filtered the data for genes with rare, predicted deleterious variants that segregated with trait within families. These data were firstly examined for overlap with gene expression data from microarray analysis of GnRH:GFP primary rat neurons at E14, E17 and E20. Secondly the data were compared to a microarray analysis of genes differentially expressed in GN11 (immature and migratory) and GT1-7 (mature and non-migratory) immortalised GnRH neurons.

Results: After WES, 7350 genes contained rare, predicted deleterious variants that passed quality control. Microarray analysis identified 677 genes with significant (fold change > 2) up- or down-regulation during the time period of embryonic GnRH neuronal migration, and 102 differently expressed between GN11 and GT1-7 cells. 265 genes identified as significantly up- or down-regulated between GnRH:GFP primary rat neurons at E14 and at E20, and 33 genes reaching statistical significance for differential expression between GN11 and GT1-7 cells, were also identified as potentially pathogenic in self-limited DP patients. These include the G-protein coupled receptor LGR4, the neuronal growth regulator NEGR1 and several other neuronal chemokines or axonal growth guidance molecules.

Conclusions: This analysis has yielded several interesting new rare, potentially pathogenic variants in genes implicated in GnRH neuronal migration and development in 12 families from our cohort. Whilst these candidates need to be functionally validated, these data provides further evidence for the importance of GnRH neuronal migration in the timing of puberty onset.

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