Elsevier

The Journal of Pediatrics

Volume 161, Issue 5, November 2012, Pages 933-942.e1
The Journal of Pediatrics

Original Article
Molecular Karyotyping as a Relevant Diagnostic Tool in Children with Growth Retardation with Silver-Russell Features

https://doi.org/10.1016/j.jpeds.2012.04.045Get rights and content

Objective

To determine the contribution of submicroscopic chromosomal imbalances to the etiology of Silver-Russell syndrome (SRS) and SRS-like phenotypes.

Study design

We performed molecular karyotyping in 41 patients with SRS or SRS-like features without known chromosome 7 and 11 defects using the Affymetrix SNP Array 6.0 system (Affymetrix, High Wycombe, United Kingdom).

Results

In 8 patients, pathogenic copy number variations with sizes ranging from 672 kb to 9.158 Mb were identified. The deletions in 1q21, 15q26, 17p13, and 22q11 were associated with known microdeletion syndromes with overlapping features with SRS. The duplications in 22q13 and Xq25q27 represent unique novel copy number variations but have an obvious influence on the phenotype. In 5 additional patients, the pathogenetic relevance of the detected variants remained unclear.

Conclusion

Pathogenic submicroscopic imbalances were detectable in a significant proportion of patients with short stature and features reminiscent of SRS. Therefore, molecular karyotyping should be implemented in routine diagnostics for growth-retarded patients with even slight dysmorphisms suggestive for SRS.

Section snippets

Methods

The study population consisted of 41 patients with SRS features [without ICR1 (epi)mutations and upd(7)mat] and their parents. All patients were initially referred as SRS for routine diagnostic testing because they had intrauterine and/or postnatal growth retardation and suggestive clinical features. Genomic DNA was isolated from peripheral lymphocyte cells by salting-out.11 The study was approved by the ethical committee of the University Hospital Aachen. Appropriate informed consent was

Results

We detected an average of 8 common CNVs per patient, which were either registered in the Database of Genomic Variants database or had been observed in our own control cohort.

So far, unknown CNVs were detected in 24 of the 41 patients with SRS (Figure 1). Eleven of the so far novel CNVs were inherited from an unaffected parent and therefore were more likely to represent nonpathogenic changes. This group included a patient with a maternally inherited 15q13 microdeletion, which has recently been

Discussion

As a uniform and standardized classification system for SRS is lacking, and the clinical spectrum comprises many unspecific features overlapping with other congenital disorders, our cohort consists of a clinically as well as genetically heterogeneous group. Indeed, we have to consider that a significant fraction of our patients was referred with the clinical diagnosis of SRS but showed only slight compatible features. To compare these heterogeneous phenotypes of our patients, we therefore

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    Supported by Bundesministerium für Bildung und Forschung (Network “Imprinting Diseases”: 01GM0884) and an investigator-initiated, unrestricted research grant from Merck-Serono GmbH. M.G. has a scholarship of the German exchange service. The authors declare no conflicts of interest.

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