Cryptic deletions are a common finding in "balanced" reciprocal and complex chromosome rearrangements: a study of 59 patients

Abstract

Using array comparative genome hybridisation (CGH) 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) were screened. All cases had been interpreted as ''balanced'' by conventional cytogenetics. In all, 27 cases of reciprocal translocations were detected in patients with an abnormal phenotype, and after array CGH analysis, 11 were found to be unbalanced. Thus 40% (11 of 27) of patients with a ''chromosomal phenotype'' and an apparently balanced translocation were in fact unbalanced, and 18% (5 of 27) of the reciprocal translocations were instead complex rearrangements with .3 breakpoints. Fourteen fetuses with de novo, apparently balanced translocations, all but two with normal ultrasound findings, were also analysed and all were found to be normal using array CGH. Thirteen CCRs were detected in patients with abnormal phenotypes, two in women who had experienced repeated spontaneous abortions and three in fetuses. Sixteen patients were found to have unbalanced mutations, with up to 4 deletions. These results suggest that genome-wide array CGH may be advisable in all carriers of ''balanced'' CCRs. The parental origin of the deletions was investigated in 5 reciprocal translocations and 11 CCRs; all were found to be paternal. Using customised platforms in seven cases of CCRs, the deletion breakpoints were narrowed down to regions of a few hundred base pairs in length. No susceptibility motifs were associated with the imbalances. These results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.

The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype

“…16,17 Except for patient 10 who had a de novo apparently balanced translocation (46,XY,t(2;7)(q31q32), all patients showed a normal karyotype in G-banded chromosome studies. Clinical information was obtained from the respective physicians.…”

“…10,11 In recent years, six submicroscopic deletions comprising chromosome band 2q23.1 have been reported. [12][13][14][15][16][17] Unlike deletions mediated by a nonallelic homologous recombination, these deletions did not have common break points. Nevertheless, except for one case, all deletions did show a common region of overlap in the 2q23.1 region, including two candidate genes, EPC2 and MBD5.…”

“…14 In this study, we report on the molecular and clinical characterisation of nine new 2q23.1 microdeletion patients and on the clinical follow-up and further molecular characterisation of two patients who were previously reported only concisely. 16,17 This report provides a review on a total of 15 2q23.1 microdeletion patients.…”

Comparison of chromosome analysis and chromosomal microarray analysis: what is the value of chromosome analysis in today’s genomic array era?

“…It has been reported that ~40% of patients with multiple congenital anomalies/mental retardation and a de novo apparently balanced translocation have cryptic abnormalities near the breakpoints, or unrelated to the breakpoints, which can be easily detected by CMA. 19,20 However, CMA did not detect any copy number changes near the breakpoints in these 30 cases. Several factors may contribute to this observation.…”

Clinical Severity of PGK1 Deficiency Due To a Novel p.E120K Substitution Is Exacerbated by Co-inheritance of a Subclinical Translocation t(3;14)(q26.33;q12), Disrupting NUBPL Gene

“…On the contrary, genomic imbalance at breakpoint regions is the most plausible explanation of such phenotypic inconsistency observed among carriers of similar chromosomal translocations (De Gregori et al 2007).…”