Background: Aberrations in the timing of puberty may result in significant adverse health outcomes, including cancers, cardiovascular and neurological pathologies. Self-limited delayed puberty (DP) (i.e. constitutional delay of puberty) runs in families with either autosomal dominant or complex inheritance patterns in >70% of families, indicating a strong genetic basis of the trait. However, only a few genes have been identified underlying DP so far.
Objective and hypotheses: We hypothesize that genes causing DP are amenable to discovery through exome sequencing of our large cohort with familial DP.
Methods and results: Whole exome sequencing was performed on DNA from 111 individuals of 18 multi-generational families affected with DP. After filtering we identified three rare, potentially pathogenic missense variants in LGR4 (16 individuals in four families) and one in-frame deletion and one rare missense variant in EAP1 in two families (five affected individuals) that all segregated with the DP trait. In vitro analysis on LGR4 and EAP1 revealed specific expression in mice olfactory epithelium at different embryonic stages and in the peripubertal mice hypothalamus, respectively. The pathogenicity of each of variant is under investigation. LGR4 variants have been produced by site directed mutagenesis and expressed in eukaryotic cell through transfection. Intracellular trafficking, ligand binding and signal transduction through Wnt-signalling are being investigated.
Conclusion: The preliminary results suggest a causal role for LGR4 and EAP1 in delayed puberty. Embryonic expression points to a role for LGR4 in GnRH neuronal migration. EAP1 may act upstream of GnRH to influence pubertal timing.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology