World journal of pediatrics : WJP · 2026
Gene-based burden testing implicates four novel susceptibility genes associated with isolated short stature in pediatric patients.
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Xiao Fei, Cai Ming-Yue, Yang Bing-Yu, Gu Wu-Di, Wang Li-Li, Wu Hai-Ying, Xie Rong-Rong, Wang Feng-Yun, Chen Xiu-Li, Chen Lin-Qi, Zhang Dan-Dan, Wang Qing, Wang Hong-Ying, Jin Yu, Wang Xue-Qian, Chen Ting
Аннотация
BACKGROUND: Idiopathic short stature (ISS), a common cause of unexplained growth failure in children, remains poorly characterized at the genetic level. This study aimed to investigate the contribution of rare variant burdens in growth-related genes and pathways to the etiology of ISS using next-generation sequencing and gene-based burden testing, thereby identifying novel genetic contributors to the polygenic landscape of ISS.
METHODS: We analyzed 212 pediatric patients with short stature who remained undiagnosed following trio-based whole-exome sequencing. The comparison cohort included 352 healthy adults with normal stature and 4327 internal samples from the Exome Aggregation Consortium database. Gene-based burden testing was performed using an optimized TRAPD (testing rare variants using public data) framework. Functional enrichment analyses, including Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathway analyses, were conducted to delineate the biological processes associated with the identified candidate genes.
RESULTS: Under a dominant inheritance model, 3907 genes were significantly enriched in rare variants (P < 0.05), whereas 85 genes were significantly enriched under a recessive model (P < 0.05). The top 10 most significantly associated genes identified through primary modeling included FCGBP, FRAS1, MPDZ, and OBSCN, among which highly significant signals were identified (P < 1 × 10-⁹). Pathway analyses revealed enrichment in steroid hormone biosynthesis, ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and porphyrin metabolism. Key genes such as OBSCN, FRAS1, and MPDZ were involved in multiple enriched pathways.
CONCLUSIONS: This study implicates rare variant burdens in growth-related genes as contributors to ISS pathogenesis, highlighting key genes (OBSCN, FCGBP, FRAS1, and MPDZ) and pathways involved. These findings suggest that the dysregulation of hormonal signaling, the extracellular matrix, and muscle-skeletal interactions impairs linear growth, suggesting potential diagnostic and therapeutic targets for ISS.
METHODS: We analyzed 212 pediatric patients with short stature who remained undiagnosed following trio-based whole-exome sequencing. The comparison cohort included 352 healthy adults with normal stature and 4327 internal samples from the Exome Aggregation Consortium database. Gene-based burden testing was performed using an optimized TRAPD (testing rare variants using public data) framework. Functional enrichment analyses, including Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathway analyses, were conducted to delineate the biological processes associated with the identified candidate genes.
RESULTS: Under a dominant inheritance model, 3907 genes were significantly enriched in rare variants (P < 0.05), whereas 85 genes were significantly enriched under a recessive model (P < 0.05). The top 10 most significantly associated genes identified through primary modeling included FCGBP, FRAS1, MPDZ, and OBSCN, among which highly significant signals were identified (P < 1 × 10-⁹). Pathway analyses revealed enrichment in steroid hormone biosynthesis, ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and porphyrin metabolism. Key genes such as OBSCN, FRAS1, and MPDZ were involved in multiple enriched pathways.
CONCLUSIONS: This study implicates rare variant burdens in growth-related genes as contributors to ISS pathogenesis, highlighting key genes (OBSCN, FCGBP, FRAS1, and MPDZ) and pathways involved. These findings suggest that the dysregulation of hormonal signaling, the extracellular matrix, and muscle-skeletal interactions impairs linear growth, suggesting potential diagnostic and therapeutic targets for ISS.