Molecular and clinical characterization of de novo and familial cases with microduplication 3q29: Guidelines for copy number variation case reporting

Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ont., Canada.
Cytogenetic and Genome Research (Impact Factor: 1.56). 02/2008; 123(1-4):65-78. DOI: 10.1159/000184693
Source: PubMed


Microdeletions of 3q29 have previously been reported, but the postulated reciprocal microduplication has only recently been observed. Here, cases from four families, two ascertained in Toronto (Canada) and one each from Edinburgh (UK) and Leiden (Netherlands), carrying microduplications of 3q29 are presented. These families have been characterized by cytogenetic and molecular techniques, and all individuals have been further characterized with genome-wide, high density single nucleotide polymorphism (SNP) arrays run at a single centre (The Centre for Applied Genomics, Toronto). In addition to polymorphic copy-number variants (CNV), all carry duplications of 3q29 ranging in size from 1.9 to 2.4 Mb, encompassing multiple genes and defining a minimum region of overlap of about 1.6 Mb bounded by clusters of segmental duplications that is remarkably similar in location to previously reported 3q29 microdeletions. Consistent with other reports, the phenotype is variable, although developmental delay and significant ophthalmological findings were recurrent, suggesting that dosage sensitivity of genes located within 3q29 is important for eye and CNS development. We also consider CNVs found elsewhere in the genome for their contribution to the phenotype. We conclude by providing preliminary guidelines for management and anticipatory care of families with this microduplication, thereby establishing a standard for CNV reporting.

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    • "The presence of low copy repeats (LCRs) flanking this chromosomal region suggests that both 1.63 Mb deletions and duplications of 3q29 arise via non-allelic homologous recombination between LCRs on either side of the breakpoint [Willatt et al., 2005]. In addition to the typical 1.63 Mb rearrangements a few individuals with both atypical deletions and reciprocal 3q29 duplications have been described [Ballif et al., 2008; Goobie et al., 2008]. "
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    ABSTRACT: Oculo auriculo vertebral spectrum (OAVS; OMIM 164210) is a clinically and genetically heterogeneous disorder originating from an abnormal development of the first and second branchial arches. Main clinical characteristics include defects of the aural, oral, mandibular, and vertebral development. Anomalies of the cardiac, pulmonary, renal, skeletal, and central nervous systems have also been described. We report on a 25-year-old male showing a spectrum of clinical manifestations fitting the OAVS diagnosis: hemifacial microsomia, asymmetric mandibular hypoplasia, preauricular pits and tags, unilateral absence of the auditory meatus, dysgenesis of the inner ear and unilateral microphthalmia. A SNP-array analysis identified a de novo previously unreported microduplication spanning 723 Kb on chromosome 3q29. This rearrangement was proximal to the 3q29 microdeletion/microduplication syndrome region, and encompassed nine genes including ATP13A3 and XXYLT1, which are involved in the organogenesis and regulation of the Notch pathway, respectively. The present observation further expands the spectrum of genomic rearrangements associated to OAVS, underlying the value of array-based studies in patients manifesting OAVS features. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
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    • "These cases were not included in our overview. Reported cases with more extensive overlapping microduplications have also been excluded [Goobie et al., 2008]. Other international databases collect cases, but with incomplete feature description [Firth et al., 2009]. "
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    Full-text · Article · Aug 2014 · American Journal of Medical Genetics Part A
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    • "In theory, partial gene duplication may result in a similar non-sense transcript, however, in our study none of the investigated genomic regions showed duplication of the EXT1/2 genes or in other genes. Based on this observation, it is unlikely that copy number neutral inversions could play a role in the other cases, especially as genomic inversions are often found to be associated with both by deletions and duplications (Goobie et al., 2008; Male et al., 2002). For the remaining deletion-and mutation-negative cases there are several possible explanations why pathogenic alterations could not be detected. "
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