Original articleIdentification of gene copy number variations in patients with mental retardation using array-CGH: Novel syndromes in a large French series
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.
References (67)
- et al.
A locus for isolated cleft palate, located on human chromosome 2q32
Am. J. Hum. Genet.
(1999) - et al.
Satb2 haploinsufficiency phenocopies 2q32-q33 deletions, whereas loss suggests a fundamental role in the coordination of jaw development
Am. J. Hum. Genet.
(2006) - et al.
Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller–Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3
Am. J. Hum. Genet.
(2003) - et al.
Diagnostic genome profiling in mental retardation
Am. J. Hum. Genet.
(2005) - et al.
The use of telomere probes to investigate submicroscopic rearrangements associated with mental retardation
Curr. Opin. Genet. Dev.
(2003) - et al.
Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation
Am. J. Hum. Genet.
(2006) - et al.
Mutational survey of the PHEX gene in patients with X-linked hypophosphatemic rickets
Bone
(2008) - et al.
Genomic disorders on 22q11
Am. J. Hum. Genet.
(2002) - et al.
Private inherited microdeletion/microduplications: implications in clinical practice
Eur. J. Med. Genet.
(2008) - et al.
Genomic analysis of five chromosome 7p deletion patients with Greig cephalopolysyndactyly syndrome (GCPS)
Eur. J. Med. Genet.
(2006)