Deleterious variants in intolerant genes reveal new candidates for self-limited delayed puberty
Year: 2025
Type: article
Study design: Observational Study
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.
Authors: Raíssa C Rezende, Wen He, Lena R Kaisinger, Antonio M Lerario, Evan C Schafer, Katherine A Kentistou, Priscila S Barroso, Nathalia L M Andrade, Naiara C B Dantas, Elaine Maria F Costa, Laurana P Cellin, Elisangela P S Quedas, Stephanie B Seminara, Rodolfo A Rey, Romina P Grinspon, Veronica Meriq, Ken K Ong, Ana Claudia Latronico, John R B Perry, Sasha R Howard, Yee-Ming Chan, Alexander A L Jorge, Leo Dunkel, Aristeides Giannakopoulos, Paulina Merino
Institutions: Universidade de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Boston Children's Hospital, University of Cambridge, MRC Epidemiology Unit, University of Michigan, Michigan Medicine, Harvard University, Massachusetts General Hospital, Consejo Nacional de Investigaciones Científicas y Técnicas, Hospital General de Niños Ricardo Gutierrez, University of Chile, Wellcome/MRC Institute of Metabolic Science, Queen Mary University of London, William Harvey Research Institute
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Wellcome Trust, Barts Charity, Fundação de Amparo à Pesquisa do Estado de São Paulo, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, U.S. Food and Drug Administration, Medical Research Council, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W4409229072