Implications of copy number variation in people with chromosomal abnormalities: potential for greater variation in copy number state may contribute to variability of phenotype

Smith, Adam J. de; Trewick, Anne L.; Blakemore, Alexandra I. F.

doi:10.1007/s11568-010-9144-z

Cited by 11 publications

(11 citation statements)

References 65 publications

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“…Since CNVs embedded within the regions of chromosome may create imbalance and affect the clinical outcomes by altering the local copy number of important genes or regulatory regions, this could alleviate or exacerbate certain phenotypes. Thus, CNVs contribute to the clinical variability seen in many disorders caused by chromosomal abnormalities21. Therefore, this study was taken up to address the issue of CNV burden on genes causing NDJ in normal population.…”

Section: Discussionmentioning

confidence: 99%

Identifying the risk of producing aneuploids using meiotic recombination genes as biomarkers: A copy number variation approach

Suresh¹,

Lingaiah²,

Veerappa³

et al. 2017

Indian J Med Res

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Background & objectives:Aneuploids are the most common chromosomal abnormality in liveborns and are usually the result of non-disjunction (NDJ) in meiosis. Copy number variations (CNVs) are large structural variations affecting the human genome. CNVs influence critical genes involved in causing NDJ by altering their copy number which affects the clinical outcome. In this study influence of CNVs on critical meiotic recombination was examined using new computational technologies to assess their role in causing aneuploidy.Methods:This investigation was based on the analysis of 12 random normal populations consisting of 1714 individuals for aneuploid causing genes under CNV effect. To examine the effect of CNVs on genes causing aneuploidy, meiotic recombination genes were analyzed using EnrichR, WebGestalt and Ingenuity Pathway Analysis (IPA).Results:Forty three NDJ genes were found under CNV burden; IPA (Ingenuity Pathway Analysis) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis of CNV in meiotic recombination genes revealed a significant role of breast cancer gene 1, amyloid protein precursor, mitogen-activated protein kinase and nerve growth factor as key molecular players involved in causing aneuploidy. Interaction between these genes with other CNV-overlapping genes involved in cell cycle, recombination and meiosis might lead to increased incidences of aneuploidy.Interpretation & conclusions:The findings of this study implied that the effect of CNVs on normal genome contributed in amplifying the occurrences of chromosomal aneuploidies. The normal individuals consisting of variations in the susceptible genes causing aneuploids in the population remain undetected until the disorder genes express in the succeeding generations.

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Section: Discussionmentioning

confidence: 99%

Identifying the risk of producing aneuploids using meiotic recombination genes as biomarkers: A copy number variation approach

Suresh¹,

Lingaiah²,

Veerappa³

et al. 2017

Indian J Med Res

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“…Copy number variation on the trisomic chromosome 21 could also contribute to the CHD risk in DS and particularly for the AVSD risk (Beckmann et al 2007;de Smith et al 2010). After calling CNVs on chromosome 21 (see Methods), association tests using 55 DS-AVSD as cases and 53 DS-without CHD as controls were performed on 4401 CNV tests obtained after performing intersection across all the samples.…”

Section: Chromosome 21 Cnv Association Analysesmentioning

confidence: 99%

The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome

et al. 2013

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Congenital heart defect (CHD) occurs in 40% of Down syndrome (DS) cases. While carrying three copies of chromosome 21 increases the risk for CHD, trisomy 21 itself is not sufficient to cause CHD. Thus, additional genetic variation and/or environmental factors could contribute to the CHD risk. Here we report genomic variations that in concert with trisomy 21, determine the risk for CHD in DS. This case-control GWAS includes 187 DS with CHD (AVSD = 69, ASD = 53, VSD = 65) as cases, and 151 DS without CHD as controls. Chromosome 21-specific association studies revealed rs2832616 and rs1943950 as CHD risk alleles (adjusted genotypic P-values <0.05). These signals were confirmed in a replication cohort of 92 DS-CHD cases and 80 DS-without CHD (nominal P-value 0.0022). Furthermore, CNV analyses using a customized chromosome 21 aCGH of 135K probes in 55 DS-AVSD and 53 DS-without CHD revealed three CNV regions associated with AVSD risk (FDR £ 0.05). Two of these regions that are located within the previously identified CHD region on chromosome 21 were further confirmed in a replication study of 49 DS-AVSD and 45 DS-without CHD (FDR £ 0.05). One of these CNVs maps near the RIPK4 gene, and the second includes the ZBTB21 (previously ZNF295 ) gene, highlighting the potential role of these genes in the pathogenesis of CHD in DS. We propose that the genetic architecture of the CHD risk of DS is complex and includes trisomy 21, and SNP and CNV variations in chromosome 21. In addition, a yetunidentified genetic variation in the rest of the genome may contribute to this complex genetic architecture.

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“…The phenotypes seen in each affected individual with chromosomal syndromes clearly depend on the particular chromosomal region with a variability in the clinical presentations [2]. Chromosome 5p deletion or Cri-du-chat syndrome (CDCs, MIM 123450) was first described by Lejeune in 1963 [3] and it is the one of most common chromosomal deletion syndrome in humans [4].…”

Section: Introductionmentioning

confidence: 99%

A Familial Cri-du-Chat/5p Deletion Syndrome Resulted from Rare Maternal Complex Chromosomal Rearrangements (CCRs) and/or Possible Chromosome 5p Chromothripsis

Jiang

et al. 2013

PLoS ONE

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Cri-du-Chat syndrome (MIM 123450) is a chromosomal syndrome characterized by the characteristic features, including cat-like cry and chromosome 5p deletions. We report a family with five individuals showing chromosomal rearrangements involving 5p, resulting from rare maternal complex chromosomal rearrangements (CCRs), diagnosed post- and pre-natally by comprehensive molecular and cytogenetic analyses. Two probands, including a 4½-year-old brother and his 2½-year- old sister, showed no diagnostic cat cry during infancy, but presented with developmental delay, dysmorphic and autistic features. Both patients had an interstitial deletion del(5)(p13.3p15.33) spanning ∼26.22 Mb. The phenotypically normal mother had de novo CCRs involving 11 breakpoints and three chromosomes: ins(11;5) (q23;p14.1p15.31),ins(21;5)(q21;p13.3p14.1),ins(21;5)(q21;p15.31p15.33),inv(7)(p22q32)dn. In addition to these two children, she had three first-trimester miscarriages, two terminations due to the identification of the 5p deletion and one delivery of a phenotypically normal daughter. The unaffected daughter had the maternal ins(11;5) identified prenatally and an identical maternal allele haplotype of 5p. Array CGH did not detect any copy number changes in the mother, and revealed three interstitial deletions within 5p15.33-p13.3, in the unaffected daughter, likely products of the maternal insertions ins(21;5). Chromothripsis has been recently reported as a mechanism drives germline CCRs in pediatric patients with congenital defects. We postulate that the unique CCRs in the phenotypically normal mother could resulted from chromosome 5p chromothripsis, that further resulted in the interstitial 5p deletions in the unaffected daughter. Further high resolution sequencing based analysis is needed to determine whether chromothripsis is also present as a germline structural variation in phenotypically normal individuals in this family.

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Implications of copy number variation in people with chromosomal abnormalities: potential for greater variation in copy number state may contribute to variability of phenotype

Cited by 11 publications

References 65 publications

Identifying the risk of producing aneuploids using meiotic recombination genes as biomarkers: A copy number variation approach

Identifying the risk of producing aneuploids using meiotic recombination genes as biomarkers: A copy number variation approach

The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome

A Familial Cri-du-Chat/5p Deletion Syndrome Resulted from Rare Maternal Complex Chromosomal Rearrangements (CCRs) and/or Possible Chromosome 5p Chromothripsis

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