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.