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

Abstract

Background/Aims: 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. Methods: 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. Results: 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. Conclusion: 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.

Focused Revision: ACMG practice resource: Genetic evaluation of short stature

“…4 Multiple studies have reaffirmed use of microarray as first-line testing in patients with syndromic short stature with an average yield of 10-15%. [5][6][7][8] It is important to note that SNP-based chromosomal microarray can document uniparental isodisomy, but not uniparental heterodisomy or methylation patterns. 9,10 Therefore, further specific methylation or uniparental heterodisomy testing should be considered for any condition related to methylation defects (e.g., Silver-Russell syndrome, Temple syndrome).…”

Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders

“…Previous WES studies revealed a diagnosis rate of ∼25-30% in nonselective patients (Yang et al, 2013(Yang et al, , 2014Lee et al, 2014;Daoud et al, 2016;Retterer et al, 2016). Moreover, additional pathogenic and likely pathogenic CNVs were also identified in over 10% of patients (Sanmann et al, 2015;Homma et al, 2018;Jang et al, 2019). The development of NGS data based CNV calling algorithm makes it possible to identify SNVs and CNVs at same time.…”

“…Recently, multiple researches on clinical utility and cost of WES have provided evidence endorsing it as a first-tier test for children with suspected monogenic disorders (Nguyen and Charlebois, 2015;Monroe et al, 2016;Stark et al, 2016;Hu et al, 2018). CMA has been used as a first-tier clinical diagnostic test in patients with developmental delay (DD)/intellectual disability (ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA) since 2010 (Manning et al, 2010;Miller et al, 2010); and copy number variants (CNVs) detected by CMA explained the pathogenesis for over 10% of these cases (Sanmann et al, 2015;Homma et al, 2018;Jang et al, 2019).…”

Rare CNVs provide novel insights into the molecular basis of GH and IGF-1 insensitivity

“…Many have growth retardation in association with malformations and/or neurodevelopmental disorders ( 17 ). The incidence of pathogenic/likely pathogenic CNVs are reported as ~4–13% children with idiopathic SS, 16% born SGA with persistent SS and 14% with syndromic SS ( 15 , 17 , 18 , 19 , 20 ). Hence rare CNVs contribute to childhood SS and potential candidate genes and/or loci can potentially be identified ( 15 , 17 , 18 , 19 ).…”