Original article
Identification of gene copy number variations in patients with mental retardation using array-CGH: Novel syndromes in a large French series

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Abstract

Array-CGH has revealed a large number of copy number variations (CNVs) in patients with multiple congenital anomalies and/or mental retardation (MCA/MR). According to criteria recently listed, pathogenicity was clearly suspected for some CNVs but benign CNVs, considered as polymorphisms, have complicated the interpretation of the results. In this study, genomic DNAs from 132 French patients with unexplained mental retardation were analysed by genome wide high-resolution Agilent® 44K oligonucleotide arrays. The results were in accordance with those observed in previous studies: the detection rate of pathogenic CNVs was 14.4%. A non-random involvement of several chromosomal regions was observed. Some of the microimbalances recurrently involved regions (1q21.1, 2q23.1, 2q32q33, 7p13, 17p13.3, 17p11.2, 17q21.31) corresponding to known or novel syndromes. For all the pathogenic CNVs, further cases are needed to allow more accurate genotype–phenotype correlations underscoring the importance of databases to group patients with similar molecular data.

Introduction

From the observation that subtelomeric anomalies can be found in about 5% of MCA/MR patients [22], it was suspected that small interstitial imbalances may also be an important cause of MCA/MR [46], [65] that is underestimated by current cytogenetics methods (conventional and molecular cytogenetics). Whole-genome array-based technologies have became an essential tool for the detection of microimbalances and have identified such aberrations in 10–15% of MCA/MR patients with normal karyotype [17], [20], [21], [23], [24], [29], [40], [41], [45], [46], [54], [59], [65], [66]. The challenge now is to describe novel syndromes which can be achieved by comparing patients carrying the same subtle rearrangement. Array-CGH can give an accurate delineation of the imbalances which raises the possibility of making genotype–phenotype correlations, in order to identify minimal critical regions and candidate genes for a pattern of clinical features including learning disability. Fine mapping of genomic imbalances may indeed be useful to narrow down regions suspected to contain dosage sensitive genes critical for normal development [35].

Section snippets

Patients

Subjects with unexplained mental retardation were selected by clinical geneticists according to criteria derived from the checklist of de Vries et al. [18], which is linked with a higher likelihood of manifesting submicroscopic copy number changes, particularly, subtelomeric imbalances. Criteria for the present study corresponded to mental retardation with at least one associated criterion (familial history of mental retardation, growth abnormalities, facial dysmorphic features, congenital

Results

Criteria of pathogenicity established by Lee et al. [31] were used to determine clinical relevance of the CNVs observed. According to Lee et al. CNVs are more likely to be pathogenic if correspond to one of the following criteria i.e. they are de novo, they are inherited from an affected parent or observed in an affected relative, they do not overlap a polymorphism listed in a CNV database for healthy individuals but overlap a genomic imbalance in a CNV database for affected individuals, they

Discussion

Our study further demonstrates the efficiency of whole-genome high-resolution array in the detection of chromosomal microimbalances. Out of the 132 patients with MCA/MR of unknown aetiology studied using genomewide array-CGH, 19 imbalances interpreted as pathogenic were identified (detection rate: 14.4%). Several studies have previously used array-CGH to make genomewide screening of patients with MCA/MR and normal karyotype. This approach identified pathogenic imbalances in 10–15% of the

Acknowledgements

This work was supported by grants from the CHU of Rennes (concours post-internat), PHRC inter-régional 2006 and DHOS (Direction de l'Hospitalisation et de l'Organisation des soins) “Réseau de soutien pour le développement dans les CHU de plateaux techniques mutualisés de génétique constitutionnelle pour la détection de microremaniements chromosomiques”.

We are grateful to H. Beverley Osborne (UMR 6061, Rennes, France) for revising the English text.

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