Emerging patterns of cryptic chromosomal imbalances in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of the literature

Björn Menten ¹, Nicole Maas ², Bernard Thienpont ², Karen Buysse ¹, Jo Vandesompele ¹, Cindy Melotte ², Thomy de Ravel ², Steven Van Vooren ³, Irina Balikova ², Liesbeth Backx ², Sandra Janssens ¹, Anne De Paepe ¹, Bart De Moor ³, Yves Moreau ³, Peter Marynen ⁴, Jean-Pierre Fryns ², Geert Mortier ¹, Koen Devriendt ², Frank Speleman ¹ and Joris R Vermeesch ^2*

¹ Center for Medical Genetics, Ghent University, Ghent, Belgium
² Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium
³ ESAT-SISTA, University of Leuven, Leuven, Belgium
⁴ Flanders Interuniversity Institute for Biotechnology (VIB4), Department of Human Genetics, Universi, Belgium

^* To whom correspondence should be addressed. E-mail: joris.vermeesch{at}med.kuleuven.be.

Accepted 12 January 2006

Abstract

Background: Chromosomal abnormalities are a major cause of mental retardation and multiple congenital anomalies (MCA/MR). Screening for these chromosomal imbalances has mainly been performed by standard karyotyping. Previous array CGH studies on selected patients with chromosomal phenotypes and normal karyotypes suggested an incidence of 10-15% previously unnoticed de novo chromosomal imbalances.

Methods: Here we report on array CGH screening of a series of 140 patients (the largest series published thus far) with idiopathic mental retardation and multiple congenital anomalies (MCA/MR) but normal karyotypes.

Results: Submicroscopic chromosomal imbalances were detected in 20% (28/140) patients and included 18 deletions, 7 duplications and 3 unbalanced translocations. Seventeen from twenty four imbalances were confirmed de novo and 19 were assumed to be causal. Excluding subtelomeric imbalances, our study identified 11 (8%) clinically relevant interstitial submicroscopic imbalances. Taking into consideration this and previously reported studies, array CGH screening with a resolution of at least 1 Mb, has been performed on 432 patients with MCA/MR. Most imbalances are non-recurrent and spread across the genome.

Conclusions: In at least 8.8% (38/432) of these patients de novo intrachromosomal alterations have been identified. Hence, array CGH should be considered as an essential aspect of the genetic analysis of patients with MCA/MR. In addition, in our study 3 patients were mosaic for a structural chromosome rearrangement. One of these patients had monosomy 7 in as little as 7% of the cells, illustrating that array CGH allows the detection of low grade mosaicisims.

Keywords: Array CGH, chromosomal mosaicism, mental retardation

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