biostudies-literatureRezende RCSão Paulo Research FoundationEunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of HealthCoordination for the Improvement of Higher Education PersonnelA.A.L.JNICHD NIH HHSNational Center for Translational Research in Reproduction and InfertilityBarts CharityMedical Research CouncilFDA HHSS.B.SNational Council for Scientific and Technological DevelopmentWellcome Trust481-490https://www.ebi.ac.uk/biostudies/studies/S-EPMC12013340biostudies-literatureUnknown192(4)<h4>Objective</h4>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.<h4>Methods</h4>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 variaEuropean journal of endocrinologyDeleterious variants in intolerant genes reveal new candidates for self-limited delayed puberty.PMC12013340222049/Z/20/Z303294/2020-5P50HD104224R01FD007843MGU05522022/10107-6R37 HD043341R37HD043341P50 HD104224MC_UU_00006/2R01 FD007843R01 HD090071Chan YMCosta EMFJorge AALMeriq VBarroso PSDantas NCBRezende RCP S Quedas EDunkel LHoward SRPerry JRBKentistou KAGiannakopoulos ALerario AMMerino POng KKHe WKaisinger LRAndrade NLMLatronico ACDelayed Puberty Genetics ConsortiumSchafer ECCellin LPSeminara SBGrinspon RPRey RAfalseDeleterious variants in intolerant genes reveal new candidates for self-limited delayed puberty.<h4>Objective</h4>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.<h4>Methods</h4>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 varia2025-01-01T00:00:00Z2025 Mar2026-06-19T04:59:22.12Z2026-06-19T03:07:16.622ZS-EPMC120133404019357510.1093/ejendo/lvaf061