Genetic heterogeneity in pediatric short stature: insights from whole exome sequencing and snp- array analyses in a Turkish cohort.

UNLABELLED: This study presents the genetic etiologies other than chromosomal and methylation anomalies and comprehensive clinical evaluation and genetic data of a selected cohort of children diagnosed with short stature in the northeastern region of Türkiye. Patients aged 0-18 years who were evaluated by a pediatric endocrinologist for short stature (height less than - 2 standard deviation score or less than 3 percentile at the time of initial presentation or at follow-up) between January 2021 and January 2024 and who underwent whole exome sequencing (WES) and/or SNP- array were retrospectively screened from the genetic laboratory result data. A copy number variation (CNV) analysis was simultaneously performed in all patients who underwent WES. In this study, 57% [16/28], 36% [10/28], and 7% [2/28] cases were due to syndromic short stature, skeletal dysplasia, and defects in the GH-IGF1 axis, respectively. Twenty-five variants affecting 23 families were identified across 20 known short stature-associated genes, including 7 novel variants. According to the American College of Medical Genetics and Genomics (ACMG) criteria, 5 of 25 variations were variants of uncertain significance and 20 were likely pathogenic/pathogenic. The diagnostic yield was 24% [18/75] and 7.3% [3/41] in patients who underwent WES and SNP- array testing, respectively. In SNP array analysis, deletions of chromosome 4p16, chromosome 15q26 and SHOX gene were found in three patients from three different families.

CONCLUSIONS

This study underscores the importance of comprehensive genetic evaluation in children with syndromic and skeletal forms of short stature by identifying causative variants, including several novel mutations, across a broad range of genes.

WHAT IS KNOWN: • Short stature is one of the most common reasons for pediatrician visits. The widespread use of next-generation sequencing technology has increased the diagnostic accuracy of short stature-associated genetic causes.

WHAT IS NEW: • This study emphasizes the significance of thorough genetic assessment in children with syndromic and skeletal short stature by revealing causal variations, including numerous new mutations, across a broad spectrum of genes.