Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes

Abstract

Purpose: Genomic rearrangements of chromosome 22q11.2, including the microdeletion associated with DiGeorge/velocardiofacial syndrome, are mediated by nonallelic homologous recombination between region-specific low-copy repeats. To date, only a small number of patients with 22q11.2 microduplication have been identified. Methods:We report the identification by array-comparative genomic hybridization of 14 individuals from eight families who harbor microduplications within the 22q11.2 region. Results: We have now observed a variety of microduplications, including the typical common ϳ3-Mb microduplication, ϳ1.5-Mb nested duplication, and smaller microduplications within and distal to the DiGeorge/velocardiofacial syndrome region, consistent with nonallelic homologous recombination using distinct low-copy repeats in the 22q11.2 DiGeorge/velocardiofacial syndrome region. These microduplications likely represent the predicted reciprocal rearrangements to the microdeletions characterized in the 22q11.2 region. The phenotypes seen in these individuals are generally mild and highly variable; familial transmission is frequently observed. Conclusions: These findings highlight the unbiased ability of array-comparative genomic hybridization to identify genomic imbalances and further define the molecular etiology and clinical phenotypes seen in microduplication 22q11.2 syndrome. Our findings also further support that the 22q11.2 region is highly dynamic with frequent rearrangements using alternative low-copy repeats as recombination substrates. Genet Med 2008:10(4):267-277.

Genome-wide arrays: Quality criteria and platforms to be used in routine diagnostics

“…However, caution should be taken not to automatically regard an inherited CNV as benign [Buysse et al, 2009]. There are numerous reports of inherited pathogenic deletions/duplications that display reduced penetrance and/or variable expression [Cooper et al, 2011;Fernandez et al, 2009;Kaminsky et al, 2011;Ou et al, 2008]. In addition, a deletion inherited from an apparently normal parent may in fact reveal a recessive disorder in the proband due to a mutation on the remaining allele that is not detectable by the array.…”

Duplicação 22q11.2 e defeitos cardíacos congênitos

“…In theory, these events should occur with equal frequency. However, reports of the 22q11.2 duplication syndrome have been quite rare in comparison with the del22q11 syndrome [4][5][6] .…”

“…With an estimated prevalence of 1:2,000-6,000 live births, this syndrome currently represents one of the main known causes of congenital cardiopathy 1 . It is known that the region q11.2 of chromosome 22 presents a non-usual rearrangement, with regions of low-copy number repeats which, during meiosis, predispose to a pairing error between the chromosomes and, consequently, to an unequal crossing-over, which can lead to a deletion (del22q11) or a duplication of the q11.2 rgion [2][3][4] . The latter condition was recently identified and has been characterized by an extremely variable phenotypic spectrum, which includes the presence, among many abnormalities, of congenital cardiac defects [4][5][6] .…”

“…It is known that the region q11.2 of chromosome 22 presents a non-usual rearrangement, with regions of low-copy number repeats which, during meiosis, predispose to a pairing error between the chromosomes and, consequently, to an unequal crossing-over, which can lead to a deletion (del22q11) or a duplication of the q11.2 rgion [2][3][4] . The latter condition was recently identified and has been characterized by an extremely variable phenotypic spectrum, which includes the presence, among many abnormalities, of congenital cardiac defects [4][5][6] . However, the actual frequency of these malformations is still unknown in individuals with the 22q11.2 duplication, as well as the frequency of this duplication in patients with congenital cardiopathy 3 …”

Practical guidelines for interpreting copy number gains detected by high-resolution array in routine diagnostics

“…Microduplication syndromes show a highly variable penetrance between generations and they are often found to be inherited from an asymptomatic or very mildly affected parent. 19,20 If we exclude the known microduplication syndromes, still 7 of the 14 remaining clinically relevant gains with known segregation were inherited. None of these were located in a region that is known to be parentally imprinted.…”