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

Rezende RC; He W; Kaisinger LR; Lerario AM; Schafer EC; Kentistou KA; Barroso PS; Andrade NLM; Dantas NCB; Costa EMF; Cellin LP; E P S Quedas; Seminara SB; Rey RA; Grinspon RP; Meriq V; Ong KK; Latronico AC; Perry JRB; Howard SR; Chan YM; Jorge AAL

doi:10.1530/ey.22.7.5

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 7.5 | DOI: 10.1530/ey.22.7.5

ESPEYB25 7. Puberty Clinical Guidance and Studies (8 abstracts)

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

Rezende RC , He W , Kaisinger LR , Lerario AM , Schafer EC , Kentistou KA , Barroso PS , Andrade NLM , Dantas NCB , Costa EMF , Cellin LP , P S Quedas E , Seminara SB , Rey RA , Grinspon RP , Meriq V , Ong KK , Latronico AC , Perry JRB , Howard SR , Chan YM & Jorge AAL

Eur J Endocrinol. 2025 Mar 27;192(4):481-490. doi: 10.1093/ejendo/lvaf061. PMID: 40193575.

Brief summary: Using whole-exome sequencing in 71 patients, this study identified 19 novel candidate genes potentially involved in self-limited delayed puberty. Self-limited delayed puberty (SLDP) is the most common cause of pubertal delay and is highly heritable, yet its genetic basis remains poorly understood (1). While genome-wide association studies have identified common variants influencing pubertal timing (2), few rare coding variants have been linked to SLDP. This study aimed to uncover novel candidate genes by performing whole-exome sequencing (WES) in a cohort of children with SLDP, most of whom also presented with short stature.

WES in 71 SLDP patients identified 21 rare high- or moderate-impact variants across 19 candidate genes intolerant to mutation. Eight genes (GPS1, INHBB, SP3, NAMPT, ARID3B, NASP, FNBP1, and PRDM2) were enriched in SLDP cases compared to gnomAD controls. Notably, INHBB was also associated with delayed menarche based on the UK Biobank data. Several variants were found in genes previously linked to growth or pubertal disorders, including CDK13, GDF5, ANRKD11, and GHSR. Pathway analysis revealed enrichment in TGF-β and GnRH receptor signalling, both central to reproductive maturation.

This study expands the genetic landscape of SLDP, suggesting contributions from oligogenic/polygenic mechanisms. The identification of novel candidate genes, particularly INHBB, provides new insights into the biology of pubertal timing and highlights the importance of integrating rare variant analysis with functional and population-level data. These findings may inform future diagnostic and therapeutic strategies for pubertal disorders.

References: 1. Saengkaew T, Howard SR. Genetics of pubertal delay. Clin Endocrinol (Oxf). 2022 Oct;97(4):473-482. doi: 10.1111/cen.14606. Epub 2021 Oct 13. PMID: 34617615.2. Kentistou KA et al. Understanding the genetic complexity of puberty timing across the allele frequency spectrum. Nat Genet. 2024 Jul;56(7):1397-1411. doi: 10.1038/s41588-024-01798-4. Epub 2024 Jul 1. Erratum in: Nat Genet. 2024 Aug;56(8):1763-1764. doi: 10.1038/s41588-024-01857-w. PMID: 38951643;.