De novo deletions and duplications detected by array CGH: a study of parental origin in relation to mechanisms of formation and size of imbalance

Abstract

We report a large series of 173 patients with physical and/or neurological abnormalities and a de novo imbalance identified by array CGH. Breakpoint intervals were screened for the presence of low copy repeats (LCRs) to distinguish between rearrangements formed by non-allelic homologous recombination (NAHR) and rearrangements formed by other mechanisms. We identified significant differences in size and parental origin between the LCR-mediated and non-LCR groups. Non-LCR imbalances were evenly distributed among the four size intervals we defined, whereas LCR-mediated rearrangements had a narrow size distribution, predominantly between 1 and 5 Mb (P¼0.001). Among the LCR-mediated rearrangements there were equal numbers of maternally and paternally derived cases. In contrast, for the non-LCR rearrangements there was a significant excess of paternal cases (P¼0.024) over a wide size range including below 1 Mb. Our results provide novel evidence that unbalanced chromosome rearrangements are not only more frequent in males, but may also arise through different mechanisms than those seen in females. Although the paternal imbalances identified in our study are evenly distributed throughout the four size groups, there are very few maternal imbalances either o1 Mb or 410 Mb. Furthermore, a lower proportion of paternal imbalances are LCR mediated (13/71) compared with the maternal imbalances (12/30). We hypothesise that imbalances of maternal origin arise predominantly through NAHR during meiosis, while the majority of imbalances of paternal origin arise through male-specific mechanisms other than NAHR. Our data suggest that mitotic mechanisms could be important for the formation of chromosome imbalances; however, we found no association with increased paternal age.

De novo dup p/del q or dup q/del p Rearranged Chromosomes: Review of 104 Cases of a Distinct Chromosomal Mutation

“…Such a predominant sporadic occurrence along with the seemingly exclusive paternal derivation of rea(X) chromosomes (see below) may predict an advanced paternal age at the patients' conception. Yet, the mean paternal age in 10 sporadic rea(X) cases (including 7 de novo but just 1 of proven paternal descent) was 32.50 years, a figure in agreement with the lack of a paternal age effect in large and submicroscopic de novo imbalances [Thomas et al, 2006;Lupski, 2007;Sibbons et al, 2012]. Of note, among 10 rea(X) chromosomes (including 4 with dup p, 6 with dup q; 8 of these proved to be de novo) whose parental origin was elucidated, 9 were paternal.…”

“…The parental and inter-or intrachromosomal derivation as well as the underlying mechanism in most recombinant-like autosomes is unknown; among 14 cases with identified parentage, paternal and maternal descent were equally frequent. In comparison, there were 8 interchromosomal and 15 intrachromosomal cases among 23 autosomal duplications (11 paternal, 12 maternal) not due to rec-like chromosomes [Sibbons et al, 2012]. Of note, 1 acquired [Hecht et al, 1984] dup q and 2 constitutional rea(1) chromosomes (cases 2 and 10) have been associated with cranial teratoma, acute leukemia, and Wilms tumor, respectively.…”

An Opportune Life: 50 Years in Human Cytogenetics

“…We found that they were equally likely to be maternal or paternal in origin and that they were not associated with any parental age effect. In both these respects, they are the same as the common conditions such as DiGeorge and Williams syndromes, which is hardly surprising as they all appear to result from the same mechanism (43).…”

“…These are detected using fluorescence in situ hybridization or, more recently, array comparative genomic hybridization (aCGH). We and others have shown that the origin of many of the more common microdeletion and microduplication syndromes-e.g., DiGeorge syndrome and Williams syndrome-is equally likely to be maternal or paternal, and there appears to be no effect of parental age (43).…”

Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

“…44 In another study, de novo imbalances not mediated by low copy repeats were significantly more often of paternal than of maternal origin. 45 Thus, to date, although there is no strong evidence supporting an imprinting mechanism in the 6q16 region, a parent-of-origin effect cannot be excluded, as none of the three maternally derived deletions, which were currently reported, (patient no. 11, 14, and case 4 from Bonaglia et al report) 13 was associated with PWS-like features.…”