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. 2025 Mar 27;192(4):481-490.
doi: 10.1093/ejendo/lvaf061.

Deleterious variants in intolerant genes reveal new candidates for self-limited delayed puberty

Raíssa C Rezende  1 , Wen He  2 , Lena R Kaisinger  3 , Antonio M Lerario  4 , Evan C Schafer  2 , Katherine A Kentistou  3 , Priscila S Barroso  1 , Nathalia L M Andrade  1 , Naiara C B Dantas  1 , Elaine Maria F Costa  1 , Laurana P Cellin  1 , Elisangela P S Quedas  1 , Stephanie B Seminara  5 , Rodolfo A Rey  6 , Romina P Grinspon  6 , Veronica Meriq  7 , Ken K Ong  3 , Ana Claudia Latronico  1 , John R B Perry  3   8 , Sasha R Howard  9 , Yee-Ming Chan  2   10 , Alexander A L Jorge  1 ; Delayed Puberty Genetics Consortium
Collaborators, Affiliations

Deleterious variants in intolerant genes reveal new candidates for self-limited delayed puberty

Raíssa C Rezende et al. Eur J Endocrinol. .

Abstract

Objective: Self-limited delayed puberty (SLDP) is the most common cause of delayed puberty and exhibits high heritability, although few causal genes have been identified. This study aims to identify potential candidate genes associated with SLDP.

Methods: Whole-exome sequencing was conducted in 71 children with SLDP, most of whom presented with short stature. Rare coding variants were prioritized through comprehensive bioinformatics analyses and classified as high-impact or moderate-impact based on predicted functional effects. Candidate genes were selected based on the absence of human phenotype data, recurrence within the cohort, intolerance to mutation, and prior identification in genome-wide association studies. Burden tests compared the frequency of rare high-impact variants in these candidate genes between SLDP patients and the gnomAD v2.0 control group. Gene-phenotype associations were further explored using UK Biobank data.

Results: Fourteen high-impact and 7 moderate-impact variants were identified in 19 candidate genes, suggesting a potential role in SLDP. Variants in 8 candidate genes (GPS1, INHBB, SP3, NAMPT, ARID3B, NASP, FNBP1, PRDM2) were significantly enriched in cases compared to controls in the burden test analysis. INHBB was additionally linked to delayed menarche in UK Biobank data. Furthermore, 3 pathogenic variants (CDK13, GDF5, ANRKD11) and 6 likely pathogenic variants (TYMP, DPF2, KMT2C, TP63, MC3R, GHSR) previously associated with growth or pubertal human disorders were identified.

Conclusion: These findings suggest that SLDP involves both monogenic and polygenic mechanisms, with novel candidate genes contributing to its genetic basis. The association of INHBB with pubertal timing underscores its potential role in SLDP pathophysiology.

Keywords: delayed puberty; exome sequencing; genetic association studies; self-limited delayed puberty.

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Conflict of interest statement

Conflict of interest: A.A.L.J. has received consulting fees from Novo Nordisk and an independent research grant from BioMarin. P.S.B is employe and shareholder of Eli Lilly and Company. J.R.B.P. is an employe of Insmed Innovation UK and holds stock/stock options in Insmed Inc. J.R.B.P. also receives research funding from GSK and engages in paid consultancy for WW International Inc. S.B.S. holds stock in SeNa Therapeutics and receives consulting fees. The other authors declare no competing financial interests.

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