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Published on: August 15, 2019
Genetic heterogeneity in pediatric short stature: insights from whole exome sequencing and snp- array analyses in a
Kubra Adanur Saglam1, Semiha Bekfilavioglu2, Aysel Yıldız Boyraz2
1Department of Medical Genetics, Faculty of Medicine, Karadeniz Technical University, Trabzon, Türkiye.
Insights
Genetic testing reveals new mutations causing short stature in children. This study highlights the importance of comprehensive genetic evaluation for accurate diagnosis and understanding of rare genetic conditions.
Area of Science:
- Pediatric Endocrinology
- Human Genetics
- Molecular Diagnostics
Background:
- Short stature is a common pediatric concern, often necessitating genetic investigation.
- Next-generation sequencing technologies have significantly improved the diagnostic accuracy for genetic causes of short stature.
Purpose of the Study:
- To identify genetic etiologies of short stature in a cohort of children from northeastern Türkiye.
- To evaluate the clinical and genetic data of children diagnosed with short stature using whole exome sequencing and SNP-array.
Main Methods:
- Retrospective screening of genetic laboratory results from patients aged 0-18 years evaluated for short stature.
- Whole exome sequencing (WES) with copy number variation (CNV) analysis and SNP-array testing were performed.
- Genetic variants were classified according to American College of Medical Genetics and Genomics (ACMG) criteria.
Main Results:
- The diagnostic yield was 24% for WES and 7.3% for SNP-array.
- Twenty-five variants in 20 known short stature-associated genes were identified, including 7 novel mutations.
- Syndromic short stature, skeletal dysplasia, and GH-IGF1 axis defects accounted for the majority of cases.
Conclusions:
- Comprehensive genetic evaluation is crucial for diagnosing syndromic and skeletal short stature.
- The study identified novel causative variants, emphasizing the broad genetic spectrum of short stature.
- Genetic testing aids in understanding the etiologies of short stature in pediatric populations.
Abstract:
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.
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