Delayed puberty (DP) is common in the developed world, affecting over 2% of adolescents, and is associated with adverse health outcomes including short stature, reduced bone mineral density and compromised psychosocial health. The majority of patients have constitutional or self-limited DP, which is often familial, most commonly segregating in an autosomal dominant pattern. However, the key genetic regulators in self-limited DP are largely unknown , Figure 1.
Insights into the genetic mutations that lead to familial DP have come from sequencing genes within the gonadotropin-releasing hormone (GnRH) pathway known to cause pubertal failure. Recently, via next generation sequencing, mutations in HS6ST1, GNRHR, IL17RD, SEMA3A, TACR3 and TAC3  have been found in patients with DP and spontaneous onset of puberty. One persuasive hypothesis is that a single deleterious mutation may lead to a phenotype of DP, whilst two or more mutations may be required to cause absent puberty, for example in congenital hypogonadotropic hypogonadism (cHH).
Upstream transcriptional regulators of GnRH signalling, such as KISS1, OCT2, TTF1, YY1 and EAP1, which act as a pubertal “brake” through a balance of activating and repressive inputs, have been proposed as attractive candidates for the pathogenesis of DP. EAP1 is known to contribute to the initiation of female puberty through transactivation of the GnRH promoter, and mutations in EAP1 have very recently been found in families with self-limited DP . New evidence has also identified small non-coding RNAs important for the murine critical period (or mini-puberty). The microRNA (miR)-200/429 family and miR-155 both act as epigenetic up-regulators of GnRH transcription , whilst miR-7a2 has been demonstrated to be essential for normal hypothalamic–pituitary–gonadal function, with deletion in mice leading to cHH.
Large-scale genome-wide association studies in the general population have highlighted hundreds of potential loci associated with the timing of puberty. Few genes at these loci have been shown to be causal in DP, although several loci are in or near to genes implicated in rare disorders of puberty (LEPR, GNRH1, KISS1 and TACR3) and pituitary function (POU1F1, TENM2 and LGR4), and two imprinted central precocious puberty genes (MKRN3 and DLK1). Genes involved in BMI control including FTO were also seen, and rare heterozygous variants in FTO have been identified in families with self-limited DP with extreme low BMI and maturational delay in growth.
Thus, the genetic basis of DP is highly heterogeneous, with gene defects producing pathogenic mechanisms that act from early foetal life into adolescence, all converging on a common pathway of pubertal delay.