Endocrine Abstracts

Background: Pubertal timing has importance both for the individual, but also for public health. Previous studies estimate that 60–80% of variation in pubertal onset is genetically determined. Recently, a large genome-wide association study (GWAS) meta-analysis identified 42 loci for age-at-menarche (AAM), which explained 3.6–6.1% of the variation in the general population, but causal genes have not been identified.

CDGP is defined as pubertal onset at more than 2.0 standard deviations later than mean population age. CDGP therefore represents an extreme variant of normal pubertal timing and has repeatedly been shown to cluster in families, but the genetic factors behind CDGP remain elusive.

Aims: We hypothesise that in CDGP only a few genetic variants have a strong impact on the timing of puberty, and we aim to identify these using whole exome sequencing (WES).

Methods/Results: We selected seven very informative CDGP families who have been accurately phenotyped through long-term growth data. Filtering and annotation of over 2 million variants returned from WES of 52 individuals produced an extensive list of potential causative variants that segregate with the trait. No common gene mutations were apparent across the seven families, and pathway analysis did not identify common pathways across the families.

To examine for genetic overlap between causal genes in CDGP, and AAM in the normal population, we identified all genes in linkage disequilibrium with the GWAS loci with inclusive limits (D′>0.8, r² no limit, altogether 297 genes). Nine variants were seen in these 297 genes in our CDGP patients, all known non-synonymous single nucleotide polymorphisms. Sequencing of the nine genes in a further 288 CDGP individuals is currently underway for validation.

Discussion: Our results highlight the significant genetic heterogeneity in CDGP, and suggest limited overlap between the genetic factors regulating pubertal timing in the normal population and CDGP.

Declaration of funding: This work was supported by the Barts and the London Charity (grant number 417/1551) and the Academy of Finland (grant number 14135).