Background: Self-limited delayed puberty (DP) is an extreme variant of normal pubertal timing and it often clusters in families. Although it is highly heritable and is the most common cause of delayed puberty, little is known about the genetic control. GnRH neuronal biology has been implicated as a key element in the pathogenesis of DP. By focusing on genes involved in GnRH neuron development, migration and function we may understand more about the genetic basis of this condition.
Objective: To investigate novel genetic pathways in the pathogenesis of DP via analysis of whole exome sequencing (WES) data from our large cohort with familial self-limited DP, particularly with respect to GnRH neuronal biology.
Method: WES data from our large Finnish cohort consisting of 104 DP families have been analysed with a total of 197 individuals: 104 probands, 58 affected and 35 unaffected family members. Initially, variants were filtered for rare, predicted deleterious variants that segregated with trait, and were significantly enriched for pathogenic variants in our cohort by burden testing. Additionally, genes involved in GnRH neuronal development and function have been identified by pathway analysis. Sanger sequencing was performed to validate the findings and to evaluate the correlation between genotype and phenotype, to see whether the variants segregate well with the DP trait within each pedigree.
Results: We have identified 2 candidate genes of interest. Firstly, CCDC141, in which we have identified 5 rare, potentially pathogenic missense variants in 20 individuals from 6 families. Homozygous mutation of CCDC141 have been reported as causal in cases of hypogonadotropic hypogonadism (HH) and Kallmann Syndrome, due to impaired GnRH migration. The second candidate is NOS1AP, in which an in-frame deletion located in the region that interacts with carboxypeptidase E (CPE) was present in 2 families (7 individuals). Although there is no known link between NOS1AP and pubertal timing, abnormalities in CPE have been reported to cause HH by abnormal GnRH secretion or impaired dendritic development. Our preliminary work with this variant in NOS1AP show that it has increased interaction with CPE via co-immunoprecipitation experiments when compared to wild type in vitro. The pathogenicity of each of variant is under investigation.
Conclusion: The preliminary results suggest a causal role for CCDC141 and NOS1AP in self-limited DP. Heterozygous mutations in CCDC141 lead to impaired GnRH neuron migration, whilst NOS1AP may have a role in GnRH secretion via interaction with CPE.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology