Rezende Raíssa C, He Wen, Kaisinger Lena R, Lerario Antonio M, Schafer Evan C, Kentistou Katherine A, Barroso Priscila S, Andrade Nathalia L M, Dantas Naiara C B, Costa Elaine Maria F, Cellin Laurana P, P S Quedas Elisangela, Seminara Stephanie B, Rey Rodolfo A, Grinspon Romina P, Meriq Veronica, Ong Ken K, Latronico Ana Claudia, Perry John R B, Howard Sasha R, Chan Yee-Ming, Jorge Alexander A L
Unidade de Endocrinologia Genetica (LIM 25), Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP 0124690, Brazil.
Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, United States.
Eur J Endocrinol. 2025 Mar 27;192(4):481-490. doi: 10.1093/ejendo/lvaf061.
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.
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.
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.
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.
自限性青春期发育延迟（SLDP）是青春期发育延迟最常见的原因，具有较高的遗传度，尽管已鉴定出的致病基因很少。本研究旨在鉴定与SLDP相关的潜在候选基因。
对71例SLDP儿童进行全外显子测序，其中大多数表现为身材矮小。通过综合生物信息学分析对罕见编码变异进行优先级排序，并根据预测的功能效应将其分类为高影响或中等影响。候选基因的选择基于缺乏人类表型数据、在队列中的复发情况、对突变的不耐受性以及在全基因组关联研究中的先前鉴定。负荷检验比较了SLDP患者与gnomAD v2.0对照组中这些候选基因中罕见高影响变异的频率。使用英国生物银行数据进一步探索基因-表型关联。
在19个候选基因中鉴定出14个高影响变异和7个中等影响变异，提示其在SLDP中可能起作用。在负荷检验分析中，与对照组相比，8个候选基因（GPS1、INHBB、SP3、NAMPT、ARID3B、NASP、FNBP1、PRDM2）中的变异在病例中显著富集。在英国生物银行数据中，INHBB还与初潮延迟有关。此外，还鉴定出3个先前与人类生长或青春期疾病相关的致病变异（CDK13、GDF5、ANRKD11）和6个可能的致病变异（TYMP、DPF2、KMT2C、TP63、MC3R、GHSR）。
这些发现表明，SLDP涉及单基因和多基因机制，新的候选基因对其遗传基础有贡献。INHBB与青春期时间的关联突出了其在SLDP病理生理学中的潜在作用。
