Molecular cytogenetic analysis of complex chromosomal rearrangements in patients with mental retardation and congenital malformations: Delineation of 7q21.11 breakpoints

Abstract

Constitutional de novo complex chromosomal rearrangements (CCRs) are a rare finding in patients with mild to severe mental retardation. CCRs pose a challenge to the clinical cytogeneticist: generally CCRs are assumed to be the cause of the observed phenotypic abnormalities, but the complex nature of these chromosomal changes often hamper the accurate delineation of the chromosomal breakpoints and the identification of possible imbalances. In a first step towards a more detailed molecular cytogenetic characterization of CCRs, we studied four de novo CCRs using multicolor fluorescent in situ hybridization (M‐FISH), comparative genomic hybridization (CGH), and FISH with region specific probes. These methods allowed a more refined characterization of the breakpoints in three of the four CCRs. The occurrence of 7q breakpoints in three out of these four CCRs and in 30% of reported CCRs suggested preferential involvement of this chromosomal region in the formation of CCRs. Further analysis of these 7q breakpoints revealed a 2 Mb deletion at 7q21.11 in one patient and involvement of the same region in a cryptic insertion in a second patient. This particular region contains at least 5 candidate genes for mental retardation. The other patient had a breakpoint more proximal to this region. The present data together with these from the literature provide evidence that a region within 7q21.11 may be prone to breakage and formation of CCRs. © 2003 Wiley‐Liss, Inc.

A highly complex rea(2;3;11) and aniridia by position effect

“…4 . otic multivalent confi guration whose resolution resulted in this highly chaotic CCR (Houge et al, 2003). Indeed, the remarkable complexity of the present case agrees with the observation by other authors (Astbury et al, 2004;Lespinasse et al, 2004;Vermeulen et al, 2004;Borg et al, 2005;Gribble et al, 2005) that CCRs may actually be more complex than they seem when further characterized by sophisticated molecular cytogenetic techniques such as array-painting and micro-array CGH. That the 2q32 and 3q13 partial insertions were overlooked after hybridization with the chromosome 11 WCP can mainly be attributed to an excess of signal that obscured these relatively small insertions.…”

Untitled

“…The human ADAM22 gene is relatively large, at 300 kb in length, and is comprised of more than 30 exons. It is assigned on 7q21, where several chromosomal aberrations that are accompanied by neurological disorders have been identified [29,30]. Further detailed molecular function analysis of ADAM22 may lead to progress in uncovering the mechanisms that underlie certain human neurological diseases.…”

Complex chromosome 17p rearrangements associated with low-copy repeats in two patients with congenital anomalies

“…In standard clinical practice, this characterization is usually achieved by conventional cytogenetic approaches only, thus submicroscopic imbalances at the breakpoints will remain undetected because of the low resolution of such approaches. Recently, the use of high-resolution molecular techniques such as array-based comparative genomic hybridization (array CGH) have contributed to a growing awareness of the presence of CCRs and cryptic imbalances in patients with MR and/or congenital anomalies (Vissers et al 2003; Weise et al 2003; Lespinasse et al 2004; Patsalis et al 2004; Shaw-Smith et al 2004; Vermeulen et al 2004; Borg et al 2005; de Vries et al 2005; Chen et al 2006; Gajecka et al 2006; Karmous-Benailly et al 2006). Although molecular mechanisms have been studied in recurrent, simple rearrangements, the role of genomic architecture underlying the occurrence of nonrecurrent CCRs, remains as yet poorly understood because until recently detailed identification of the exact breakpoints was lacking.…”