Parental and chromosomal origins of microdeletion and duplication syndromes involving 7q11.23, 15q11-q13 and 22q11

Abstract

Non-allelic homologous recombination between chromosome-specific LCRs is the most common mechanism leading to recurrent microdeletions and duplications. To look for locus-specific differences, we have used microsatellites to determine the parental and chromosomal origins of a large series of patients with de novo deletions of chromosome 7q11.23 (Williams syndrome), 15q11-q13 (Angelman syndrome, Prader -Willi syndrome) and 22q11 (Di George syndrome) and duplications of 15q11-q13. Overall the majority of rearrangements were interchromosomal, so arising from unequal meiotic exchange, and there were approximately equal numbers of maternal and paternal deletions. Duplications and deletions of 15q11-q13 appear to be reciprocal products that arise by the same mechanisms. The proportion arising from interchromosomal exchanges varied among deletions with 22q11 the highest and 15q11 -q13 the lowest. However, parental and chromosomal origins were not always independent. For 15q11 -q13, maternal deletions tended to be interchromosomal while paternal deletions tended to be intrachromosomal; for 22q11 there was a possible excess of maternal cases among intrachromosomal deletions. Several factors are likely to be involved in the formation of recurrent rearrangements and the relative importance of these appear to be locus-specific.

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

“…5 At most loci studied in detail, the number of maternally and paternally derived cases is approximately equal. 2,3 Array CGH has defined many new microdeletion syndromes, and although these generally involve relatively small numbers of cases with little or no information on parental origin, the data presented in this paper suggest that these are also equally likely to be paternal or maternal in origin.…”

“…Using the same statistical approach, we have also re-analysed the parental age data of all categories of structural abnormalities from our two papers published in 2006: 122 patients with a de novo microdeletion 3 and 115 patients with a non-recurrent cytogenetic rearrangement. 4 This analysis showed no significant effect of increased parental age in any of the classes of abnormality (Morris, Thomas and Jacobs, unpublished data).…”

“…2,3 In contrast, among cytogenetically visible non-recurrent de novo imbalances, there is a clear paternal bias and in a study of 115 such abnormalities we showed that the overall proportion of paternally derived cases was 72%. 4 For recurrent rearrangements, the predominant mechanism is nonallelic homologous recombination (NAHR) mediated by low copy repeats (LCRs, also called segmental duplications or SDs).…”

“…An interchromosomal origin is likely to indicate a meiotic event while an intrachromosomal origin may be either meiotic or mitotic. 2,3,5 Recurrent microdeletions and microduplications are mainly interchromosomal and are assumed to arise at meiosis. 2,3 Although more frequent, the formation of non-recurrent rearrangements is less well understood.…”

“…2,3,5 Recurrent microdeletions and microduplications are mainly interchromosomal and are assumed to arise at meiosis. 2,3 Although more frequent, the formation of non-recurrent rearrangements is less well understood. Among cytogenetically visible deletions and duplications, there appear to be approximately equal numbers of interchromosomal and intrachromsomal abnormalities, 4 although only relatively small numbers have been investigated.…”