Genetics of pubertal delay

Abstract

The timing of pubertal development is strongly influenced by the genetic background, and clinical presentations of delayed puberty are often found within families with clear patterns of inheritance. The discovery of the underlying genetic regulators of such conditions, in recent years through next generation sequencing, has advanced the understanding of the pathogenesis of disorders of pubertal timing and the potential for genetic testing to assist diagnosis for patients with these conditions. This review covers the significant advances in the understanding of the biological mechanisms of delayed puberty that have occurred in the last two decades.

SEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability

“…DP is a highly heritable condition affecting up to 2% of the population 8,67 . Yet, despite recent progress, the genetic determinants of DP remain largely unknown 10 . The analysis of exome sequencing from 100 probands from a self-limited DP cohort led to the identification of this novel missense variant in SEMA6A , segregating with the DP trait in 4 individuals from the same family and two further probands from unrelated families.…”

“…These are the hallmarks of reproductive disorders such as Congenital Hypogonadotropic Hypogonadism (HH), and also contribute to the etiology of familial Delayed Puberty (DP) 7,8 . The genetic determinants underlying these reproductive disorders remain unknown in many congenital cases, suggesting the existence of unexplored mechanisms controlling the development and function of the GnRH neuronal system relevant to these conditions 9,10 .…”

Assessing hypothalamic pituitary gonadal function in reproductive disorders

“…An important alternate cause of delayed puberty is CHH found in 10–20% of cases of delayed puberty, characterised by failure of GnRH secretion or action resulting in absent or incomplete puberty [ 18 ]. To date, more than 50 genes have been shown to contribute to the pathogenesis of CHH [ 19 ], the identification of which have furthered our understanding of key pathways in the HPG axis. CHH can result from variants in genes that regulate GnRH neuronal development, migration and maturation such as ANOS1 , PROK2, PROK2R, FGFR1 and CHD7 and those involved in GnRH function including KISS1, KISS1R, TAC3, TAC3R, GNRH1 / GNRHR , FSHB and LHB [ 19 ].…”

Editorial for Clinical Endocrinology special issue on “Genetics in Endocrinology”

“…7 Tansit Saengkaew and Sasha Howard describe recent advances in the understanding of biological mechanisms underpinning delayed puberty. 8 Paul Newey, Fadil Hannan, Abbie Wilson and Rajesh Thakker provide an overview of the genetic basis of monogenic metabolic bone and mineral disorders and provide expert advice on the implementation of clinical genetic testing for these conditions. 9 Finally, Carla Moran and colleagues outline the genetic disorders of thyroid development, hormone biosynthesis and signalling and provide a clear description of associated phenotypes and an update on confirmed pathogenic variants in key genes.…”

“…Tansit Saengkaew and Sasha Howard describe recent advances in the understanding of biological mechanisms underpinning delayed puberty 8 . Paul Newey, Fadil Hannan, Abbie Wilson and Rajesh Thakker provide an overview of the genetic basis of monogenic metabolic bone and mineral disorders and provide expert advice on the implementation of clinical genetic testing for these conditions 9 …”