Identification of novel genetic variants associated with short stature using whole exome sequencing: insights from a pediatric cohort

Ting Chen; Bingyu Yang

doi:10.1530/endoabs.110.RC14.6

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Endocrine Abstracts (2025) 110 RC14.6 | DOI: 10.1530/endoabs.110.RC14.6

ECEESPE2025 Rapid Communications Rapid Communications 14: Growth Axis and Syndromes (6 abstracts)

Identification of novel genetic variants associated with short stature using whole exome sequencing: insights from a pediatric cohort

Ting Chen ^1,2 & Bingyu Yang ^1,2

Author affiliations

¹Suzhou Clinical Center for Rare Diseases in Children, Children’s Hospital of Soochow University, Suzhou, Jiangsu, China; ²Department of Endocrinology, Genetics and Metabolism, Children’s Hospital of Soochow University, Suzhou, Jiangsu, China

JOINT1680

Background: Short stature is a common pediatric condition with diverse etiologies, including genetic factors, endocrine disorders, and malnutrition. However, up to 70% of cases remain undiagnosed despite extensive clinical evaluation. Recent advances in genomic technologies, such as whole exome sequencing (WES), offer new insights into the genetic causes of unexplained short stature. This study aims to identify novel genetic mutations associated with short stature, particularly those not detectable by traditional diagnostic methods.

Methods: We analyzed 212 pediatric patients with short stature, 352 healthy controls, and 4327 East Asian samples from the ExAC database. WES was performed on all patients and their parents, with variants filtered for quality and rarity (gnomAD_MAF<0.001). Gene-based burden testing was conducted using the TRAPD method, and gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were applied to identify biological processes and pathways associated with the identified genetic variants.

Results: Our analysis identified 263 genes with significant associations to short stature under a dominant inheritance model (P<1×10^{^-5}), and 63 genes with strong associations in both dominant and recessive models. Notably, genes such as FCGBP, FRAS1, MPDZ, and OBSCN, which were previously not associated with short stature, were identified as potential genetic contributors. The top 10 genes with the strongest associations included FCGBP (P=5.06×10^{^-14}), FRAS1 (P=1.97×10^{^-10}), and OBSCN (P=3.62×10^{^-10}). Pathway analysis revealed that these genes were involved in processes such as muscle development, steroid hormone biosynthesis, and sarcomere organization, with significant enrichment in Z discs, myosin filaments, and retinoic acid binding.

Conclusion: This study identifies several novel genetic variants that may contribute to short stature, underscoring the value of WES in identifying genetic causes in cases where traditional methods fail. The findings highlight the importance of expanding genetic testing in the diagnostic workup of short stature and provide new insights into the molecular mechanisms underlying this common pediatric condition.

Key words: short stature, whole exome sequencing, gene-based burden testing