Genotype-phenotype correlations in children with short stature: results of targeted next-generation sequencing

Short stature is a frequent reason for referral to pediatric endocrinology clinics, and its underlying cause often remains unclear. This study aimed to determine the diagnostic yield of targeted next-generation sequencing (NGS) and to evaluate genotype-phenotype correlations in children with short stature.

This retrospective observational study included 64 children (37 males, 27 females) with short stature (height < -2 SDS) who underwent targeted NGS using a 185-gene panel. Patients were divided into two groups: those with pathogenic or likely pathogenic variants and all remaining patients. Clinical and anthropometric characteristics were compared between groups.

Genetic variants were identified in 31 patients (48.4 %), and pathogenic or likely pathogenic variants in 18, corresponding to a diagnostic yield of 28.1 %. Variants were distributed across 25 genes, most frequently FLNB (n=3) and OBSL1 (n=2). Compared with others, patients with pathogenic or likely pathogenic variants had lower birth weight SDS (-1.69 ± 1.73 vs. -0.56 ± 1.08, p=0.046), higher consanguinity (50 % vs. 13 %, p=0.007), and a smaller difference between bone age and chronological age (p=0.031). No differences were found in height SDS, parental height, or target height.

Targeted NGS provides a substantial diagnostic yield in children with short stature and reveals marked genetic heterogeneity. Clinical features such as consanguinity and lower birth weight may help identify patients with a higher likelihood of a genetic etiology. These findings support the integration of genetic testing into the diagnostic evaluation of selected patients with short stature.