Genes underlying delayed puberty

Abstract

The genetic control of pubertal timing has been a field of active investigation for the last decade, but remains a fascinating and mysterious conundrum. Self-limited delayed puberty (DP), also known as constitutional delay of growth and puberty, represents the extreme end of normal pubertal timing, and is the commonest cause of DP in both boys and girls. Familial self-limited DP has a clear genetic basis. It is a highly heritable condition, which often segregates in an autosomal dominant pattern (with or without complete penetrance) in the majority of families. However, the underlying neuroendocrine pathophysiology and genetic regulation has been largely unknown. Very recently novel gene discoveries from next generation sequencing studies have provided insights into the genetic mutations that lead to familial DP. Further understanding has come from sequencing genes known to cause GnRH deficiency, next generation sequencing studies in patients with early puberty, and from large-scale genome wide association studies in the general population. Results of these studies suggest that the genetic basis of DP is likely to be highly heterogeneous. Abnormalities of GnRH neuronal development, function, and its downstream pathways, metabolic and energy homeostatic derangements, and transcriptional regulation of the hypothalamic-pituitary-gonadal axis may all lead to DP. This variety of different pathogenic mechanisms affecting the release of the puberty 'brake' may take place in several age windows between fetal life and puberty.

Keywords: Constitutional delay; Delayed puberty; IGSF10; Pubertal timing; Puberty; Puberty genetics; Self-limited delayed puberty.

Fig. 1

– The Genetics of Pubertal Timing. In the general population there is a near-normal distribution of the timing of pubertal onset, with the definitions of precocious and delayed being statistically determined ( ±2 standard deviations, SD). Cut-off ages for Tanner genital stage G2 (boys) and B2 (girls) defining precocious and delayed puberty are given (thick black lines represent 3rd and 97th centiles and dotted lines represent 1st and 99th centiles). Strategies to determine key genetic determinants in the timing of puberty include large genome wide association studies (GWAS) of age-at-menarche and voice breaking in the general population (common variants box), and identification of rare high-impact variants causing early, late or absent puberty in patients and their families. Patients with familial self-limited DP often display an autosomal dominant mode of inheritance, likely with a mono- or oligogenetic basis.

Fig. 2

– Schematic of the mechanism by which IGSF10 mutations lead to DP. Reduced levels of IGSF10 expression during embryogenesis (represented by green triangle) in the corridor of nasal mesenchyme from the vomeronasal organ (VNO) to the olfactory bulbs (in a murine model) result in delayed migration of GnRH neurons (represented by red ovals) to the hypothalamus. This presents for the first time in adolescence as a phenotype of DP due to abnormalities of the GnRH neuronal network (grey arrows linking fetal pathogenesis to adolescent phenotype). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

– Mutations in single genes at many levels of the HPG axis can cause hypogonadotropic hypogonadism (adapted from (Beate et al., 2012)).

Fig. 4

Overlap between genetic regulation in the general population and extreme phenotypes. Examples of genes implicated in timing of puberty from genome wide association studies in the general population (GWAS), conditions of GnRH deficiency such as idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann Syndrome (KS), and self-limited delayed puberty. Pale blue unfilled circles represent as yet undiscovered genes. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 5

Genetic regulators in the trans-synaptic and glial control of GnRH neurons during puberty, adapted from (Ojeda et al., 2006). This schematic represents a model whereby key transcriptional regulators govern a plethora of other genes (termed “subordinate genes” and “second tier genes”, controlling cell-cell communications and cell functions respectively). This hierarchy, itself controlled by as yet unknown upstream controlling genes, integrates the neuronal and glial networks influencing GnRH neuronal function. Inhibitory inputs are primarily from GABAergic (GABA Neuron) and opiatergic neurons (preproenkephalinergic neurons, Prepro ENK), whilst glutamate (Glu neurons) and kisspeptin (KISS Neuron) are the central excitatory neuronal signals. Glial cell inputs are primarily facilitatory.