Co-occurrence of recurrent duplications of the DiGeorge syndrome region on both chromosome 22 homologues due to inherited and de novo events

Bi, Weimin; Probst, Frank J.; Wiszniewska, Joanna; Plunkett, Katie; Roney, Erin K.; Carter, Brian S.; Williams, Misti; Stankiewicz, Paweł; Patel, Ankita; Stevens, Cathy A.; Lupski, James R.; Cheung, Sau Wai

doi:10.1136/jmedgenet-2012-101002

Cited by 12 publications

(13 citation statements)

References 28 publications

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“…There are several possible explanations for the incomplete penetrance and variable expressivity observed in this syndrome: (1) the variable size of the imbalance (as we saw above); (2) the influence of several interfering genes or epigenetic factors; and (3) the co‐existence of additional CNVs …”

Section: Discussionmentioning

confidence: 90%

“…Transgenic mice overexpressing human TBX1 with a gain‐of‐function mutation had the same phenotype as with 22q11.2 deletion . Genetic studies in mice have suggested the presence of modifier genes both in the critical region and elsewhere in the genome . Most of these candidate genes are likely be involved in TBX1 –related pathways in the development of the pharyngeal germ layers.…”

Section: Discussionmentioning

confidence: 91%

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Prenatal diagnosis of 24 cases of microduplication 22q11.2: an investigation of phenotype-genotype correlations

Dupont

Grati²,

Choy

et al. 2014

Prenat Diagn

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 91%

Prenatal diagnosis of 24 cases of microduplication 22q11.2: an investigation of phenotype-genotype correlations

Dupont

Grati²,

Choy

et al. 2014

Prenat Diagn

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“…Biallelic CNVs can cause disease either as homozygous deletions in consanguineous populations or as compound heterozygous deletions (Figure A‐B). Rarely, common DNA rearrangements, each of which independently leads to disease, can aggregate in trans at a single locus or can be seen in homozygous state due to inherited and/or de novo events …”

Section: Downstream Mechanisms: From Cnv To Phenotype and Beyondmentioning

confidence: 99%

Genomic disorders 20 years on—mechanisms for clinical manifestations

2017

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Genomic disorders result from copy-number variants (CNVs) or submicroscopic rearrangements of the genome rather than from single nucleotide variants (SNVs). Diverse technologies, including array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) microarrays, and more recently, whole genome sequencing and whole-exome sequencing, have enabled robust genome-wide unbiased detection of CNVs in affected individuals and in reportedly healthy controls. Sequencing of breakpoint junctions has allowed for elucidation of upstream mechanisms leading to genomic instability and resultant structural variation, whereas studies of the association between CNVs and specific diseases or susceptibility to morbid traits have enhanced our understanding of the downstream effects. In this review, we discuss the hallmarks of genomic disorders as they were defined during the first decade of the field, including genomic instability and the mechanism for rearrangement defined as nonallelic homologous recombination (NAHR); recurrent vs nonrecurrent rearrangements; and gene dosage sensitivity. Moreover, we highlight the exciting advances of the second decade of this field, including a deeper understanding of genomic instability and the mechanisms underlying complex rearrangements, mechanisms for constitutional and somatic chromosomal rearrangements, structural intra-species polymorphisms and susceptibility to NAHR, the role of CNVs in the context of genome-wide copy number and single nucleotide variation, and the contribution of noncoding CNVs to human disease.

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“…We also identified one homozygous deletion of CHRNA7 in 15q13.3, one homozygous deletion of NPHP1 in 2q13, 24 hemizygous deletions of STS in Xp22.31, four homozygous duplications (or triplications) of NPHP1 in 2q13, one homozygous duplication (or triplication) of BP1/BP2 in 15q11.2, two homozygous duplications (or triplications) of CHRNA7 in 15q13.3, three homozygous duplications of the DiGeorge/velocardiofacial syndrome (DGS/VCFS) region in 22q11.21 (Bi et al 2012), and one Prader-Willi/Angelman syndromes (PWS/AS) interstitial triplication in 15q11.2q13.…”

Section: Prevalence Of the Known Pathogenic Recurrent Regionsmentioning

confidence: 99%

NAHR-mediated copy-number variants in a clinical population: Mechanistic insights into both genomic disorders and Mendelizing traits

et al. 2013

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We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our chromosomal microarray analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically derived large data set allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/velocardiofacial syndrome, 166). In the~25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 59-CCNCCNTNNCCNC-39, correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13, were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR-mediated genomic instability and further elucidates the role of NAHR in human disease.

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Co-occurrence of recurrent duplications of the DiGeorge syndrome region on both chromosome 22 homologues due to inherited and de novo events

Cited by 12 publications

References 28 publications

Prenatal diagnosis of 24 cases of microduplication 22q11.2: an investigation of phenotype-genotype correlations

Prenatal diagnosis of 24 cases of microduplication 22q11.2: an investigation of phenotype-genotype correlations

Genomic disorders 20 years on—mechanisms for clinical manifestations

NAHR-mediated copy-number variants in a clinical population: Mechanistic insights into both genomic disorders and Mendelizing traits

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