Genomic Insights into Short Stature in Children Born Small for Gestational Age: A Korean Multicenter Exome Study

Context Most infants born small for gestational age (SGA) experience catch-up growth within two years, while 10‒15% remain short. The cause of this persistent growth failure remains unknown. Objective To investigate the genetic causes of SGA with short stature (SGA-SS) due to failure of catch-up growth. Methods A total of 191 children from multicenter SGA-SS cohorts across seven hospitals in South Korea underwent whole-exome sequencing. Identified copy number variants (CNVs) were confirmed via chromosomal microarray analysis. Results Genetic variants were identified in 34 children (17.8% diagnostic rate). CNVs accounted for 50% (17/34), including six children with 22q11.2 microdeletion syndrome, predominantly exhibiting mild dysmorphic features without severe intellectual disability (ID), developmental delay (DD) or severe anomalies. Single-nucleotide variants (SNVs) were identified in 17 children (17/34, 50%). One had compound heterozygous mutations in SLC26A2, one likely pathogenic mutation, and another of uncertain significance. The remaining children had heterozygous variants, including 5 pathogenic variants in COL2A1, ACAN, SALL1, TAOK1, ANKRD11 and 11 likely pathogenic variants in PIK3R1, PLAG1, SCUBE3, COL9A2 [in two patients], SMAD4, PTPN11 [in two patients], CDKN1C, ACAN, NF1. A novel familial Silver-Russell syndrome case was linked to a CDKN1C mutation. Genetic causes were identified in 14 (58.3%) of 24 patients with ID/DD: 9 with CNVs and 5 with SNVs. Conclusion SGA-SS has a heterogeneous genetic basis, with CNVs significantly contributing. The variable presentation of 22q11.2 microdeletion syndrome highlights its relevance. A genetic diagnosis is more likely in familial cases or those with ID/DD, supporting the utility of genetic testing.