Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause

Genetic imbalances are responsible for many cases of short stature of unknown etiology. This study aims to identify recurrent pathogenic copy number variants (CNVs) in patients with syndromic short stature of unknown cause.

We selected 229 children with short stature and dysmorphic features, developmental delay, and/or intellectual disability, but without a recognized syndrome. All patients were evaluated by chromosomal microarray (array-based comparative genomic hybridization/single nucleotide polymorphism array). Additionally, we searched databases and previous studies to recover recurrent pathogenic CNVs associated with short stature.

We identified 32 pathogenic/probably pathogenic CNVs in 229 patients. By reviewing the literature, we selected 4 previous studies which evaluated CNVs in cohorts of patients with short stature. Taken together, there were 671 patients with short stature of unknown cause evaluated by chromosomal microarray. Pathogenic/probably pathogenic CNVs were identified in 87 patients (13%). Seven recurrent CNVs, 22q11.21, 15q26, 1p36.33, Xp22.33, 17p13.3, 1q21.1, 2q24.2, were observed. They are responsible for about 40% of all pathogenic/probably pathogenic genomic imbalances found in short stature patients of unknown cause.

CNVs seem to play a significant role in patients with short stature. Chromosomal microarray should be used as a diagnostic tool for evaluation of growth disorders, especially for syndromic short stature of unknown cause.