Background: Self-limited delayed puberty (DP) often segregates in an autosomal dominant pattern, suggesting that inheritance is conferred by a small number of genes. However, the underlying genetic background is mostly unknown. By comparison, many genes have been identified where loss-of-function mutations lead to hypogonadotropic hypogonadism (HH). Despite likely overlap between the pathophysiology of delayed puberty and conditions of GnRH deficiency, few studies have examined the contribution of mutations in HH genes to the phenotype of self-limited DP.
Methods: We performed whole exome sequencing in 52 members of seven families from our patient cohort with self-limited DP, and filtered the results for potentially pathogenic mutations in a list of 25 genes identified as causal in HH from the published literature. After follow-up targeted re-sequencing in a further 42 families (288 individuals), one candidate gene was identified. Developmental tissue expression studies and assessment of the enzymatic function of the mutant protein were carried out.
Results: A novel variant in heparan sulfate 6-O sulphotransferase 1 (HS6ST1) was identified, present in six affected members of one family and not present in 145 controls or unaffected family members. HS6ST1 codes for a member of the heparin sulfate biosynthetic family, and is involved in modification of extracellular matrix components critical for normal neural branching. It is thought to be required for the function of FGFR1 and KAL1 in vivo, both of which are vital for GnRH neuronal development and normal hypothalamicpituitarygonadal axis function. The mutated protein was shown to have reduced sulphotransferase activity in vitro.
Conclusions: Mutations in HS6ST1 contribute to the phenotype of self-limited DP. However, although mutations in genes controlling GnRH neuronal migration and differentiation may cause both HH and DP, the overlap between the genetic basis for the two conditions appears from our study to be limited to a small number of cases.
Funding: SRH: The Wellcome Trust (102745), Rosetrees Trust (M222) and the Barts and the London Charity (417/1551). LD: partly supported by the Academy of Finland (14135). MRB, HRW and CPC: the National Institutes for Health Research (NIHR).
01 - 03 Oct 2015
European Society for Paediatric Endocrinology