Balanced into array: genome-wide array analysis in 54 patients with an apparently balanced de novo chromosome rearrangement and a meta-analysis

Feenstra, Ilse; Hanemaaijer, Nicolien; Sikkema‐Raddatz, Birgit; Yntema, Helger G.; Dijkhuizen, Trijnie; Lugtenberg, Dorien; Verheij, Joanne; Green, Andrew J.; Hordijk, Roel; Reardon, William; Vries, Bert de; Brunner, Han G.; Bongers, Ernie M.H.F.; Leeuw, Nicole de; Ravenswaaij-Arts, Conny M. A. van

doi:10.1038/ejhg.2011.120

Cited by 44 publications

(52 citation statements)

References 33 publications

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“…However, apparently 'balanced' SVs, which represent a small but significant number of cases, will thus escape detection [De Gregori et al, 2007;Hochstenbach et al, 2009]. With improving resolution of the CNV detecting arrays, the number of truly 'balanced' cases of SVs decreases, since the breakpoint regions of these SVs are increasingly found to contain small CNVs [Gribble et al, 2005;Fauth et al, 2006;De Gregori et al, 2007;Baptista et al, 2008;Higgins et al, 2008;Sismani et al, 2008;Schluth-Bolard et al, 2009;Gijsbers et al, 2010;Kang et al, 2010;Feenstra et al, 2011;Kloosterman et al, 2011Kloosterman et al, , 2012Tabet et al, 2015]. Also cases with multiple de novo or transmitted CNVs raise the suspicion of a CCR [Houge et al, 2003;Lybaek et al, 2008;Ballarati et al, 2009;Poot et al, 2009Poot et al, , 2010aSchluth-Bolard et al, 2009;Tzschach et al, 2010].…”

Section: Multiple Possibly Pathogenic Mechanisms Provoked By Ccrs: Twmentioning

confidence: 99%

“…Classically, CCRs were extremely rare events detected by karyotyping [Madan et al, 1997;Park et al, 2001]. The implementation of genome-wide assays for segmental aneuploidy, such as BAC, oligonucleotide and SNP arrays, flow karyotyping, and nextgeneration sequencing techniques, has revealed an increasing complexity of CCRs [Gribble et al, 2005;Fauth et al, 2006;De Gregori et al, 2007;Baptista et al, 2008;Higgins et al, 2008;Sismani et al, 2008;Schluth-Bolard et al, 2009;Gijsbers et al, 2010;Kang et al, 2010;Feenstra et al, 2011;Kloosterman et al, 2011;Nazaryan et al, 2014;Tabet et al, 2015]. Not only the detection rate of CCRs increased, they were also more often associated with CNVs than reciprocal translocations were [Feenstra et al, 2011].…”

mentioning

confidence: 99%

“…The implementation of genome-wide assays for segmental aneuploidy, such as BAC, oligonucleotide and SNP arrays, flow karyotyping, and nextgeneration sequencing techniques, has revealed an increasing complexity of CCRs [Gribble et al, 2005;Fauth et al, 2006;De Gregori et al, 2007;Baptista et al, 2008;Higgins et al, 2008;Sismani et al, 2008;Schluth-Bolard et al, 2009;Gijsbers et al, 2010;Kang et al, 2010;Feenstra et al, 2011;Kloosterman et al, 2011;Nazaryan et al, 2014;Tabet et al, 2015]. Not only the detection rate of CCRs increased, they were also more often associated with CNVs than reciprocal translocations were [Feenstra et al, 2011]. An example of advancing insights into a CCR by progressively improving resolution is a case, which initially was reported as an 'interstitial loss 6q14 contained within a de novo pericentric inversion 6(p11.2q15)', but eventually became a 10-breakpoint CCR [Passarge, 2000;Poot et al, 2009;Kloosterman et al, 2012].…”

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Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Poot

Haaf

2015

Mol Syndromol

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Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C(JMJD2C) as a novel candidate gene for mental retardation.

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Section: Multiple Possibly Pathogenic Mechanisms Provoked By Ccrs: Twmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Poot

Haaf

2015

Mol Syndromol

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“…http://dx.doi.org/10.1101/257758 doi: bioRxiv preprint first posted online Feb. 1, 2018; We used a modified de Vries scoring system for quantifying the number and severity of phenotypic abnormalities in affected children, which allows for a uniform assessment of developmental phenotypes from clinical records (Table S1) 6,37-40 . Originally used for characterizing phenotypes associated with subtelomeric and balanced chromosomal rearrangements, this method, used reliably in several studies, allows for a uniform assessment of developmental phenotypes from clinical records [38][39][40] . Using keyword searches for more than 50…”

Section: Cc-by-nd 40 International License Peer-reviewed) Is the Autmentioning

confidence: 99%

Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

Pizzo

Jensen

Polyak

et al. 2018

Preprint

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Rare copy-number variants (CNVs) and gene-disruptive mutations associated with neurodevelopmental disease are characterized by phenotypic heterogeneity. When affected children inherit these mutations, they usually present more severe features than carrier parents, leading to challenges in diagnosis and management. To understand how the genetic background modulates phenotypes of these variants, we analyzed clinical and exome-sequencing data from 757 probands and 233 parents and siblings who carry disease-associated mutations. We found that the number of rare pathogenic secondary mutations in developmental genes (second-hits) modulates the expressivity of disease in probands with 16p12.1 deletion (n=26, p=0.014) and in autism probands with gene-disruptive mutations (n=184, p=0.031) when compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history of neuropsychiatric disease were more likely to manifest multiple and more severe clinical features (p=0.035) and carry a higher burden of second-hits compared to those with mild or no family history (p=0.001). The amount of secondary variants determined the severity of cognitive impairment in 432 probands carrying pathogenic rare CNVs or de novo mutations in disease genes and negatively correlated with head size in 84 probands with 16p11.2 deletion, suggesting an effect of the genetic background across multiple phenotypic domains. These second-hits involved known disease genes, such as SETD5, AUTS2, and NRXN1, and novel candidate modifiers, such as CDH23, RYR3, and DNAH3, affecting core developmental processes. Our findings suggest that in the era of personalized medicine, accurate diagnosis will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

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“…6 A patient with an apparently balanced de novo CCR and learning difficulties and/or multiple congenital abnormalities may have chromosome imbalance (cryptic or sub-microscopic) associated with the rearranged chromosomes or elsewhere in the genome. 7,8 A person with a normal phenotype who carries a CCR is unlikely to have clinically significant chromosome imbalance; however, the complexity of the CCR may be more extensive than can be seen using karyotyping alone and full characterization is important to assess the risk of progeny with chromosome imbalance; such characterization is essential for accurate prenatal diagnosis. 9 Male carriers of CCRs generally present with oligospermia.…”

Section: Introductionmentioning

confidence: 99%

Meiotic outcomes of three-way translocations ascertained in cleavage-stage embryos: refinement of reproductive risks and implications for PGD

et al. 2013

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Our study provides an analysis of the outcome of meiotic segregation of three-way translocations in cleavage-stage embryos and the accuracy and limitations of preimplantation genetic diagnosis (PGD) using the fluorescence in situ hybridization technique. We propose a general model for estimating reproductive risks for carriers of this class of complex chromosome rearrangement. The data presented describe six cycles for four couples where one partner has a three-way translocation. For male heterozygotes, 27.6% of embryos were consistent with 3:3 alternate segregation resulting in a normal or balanced translocation chromosome complement; 41.4% were consistent with 3:3 adjacent segregation of the translocations, comprising 6.9% reflecting adjacent-1 and 34.5% adjacent-2 segregation; 24.1% were consistent with 4:2 nondisjunction; none showed 5:1 or 6:0 segregation; the probable mode could not be ascertained for 6.9% of embryos due to complex mosaicism or nucleus fragmentation. The test accuracy for male heterozygotes was estimated to be 93.1% with 100% sensitivity and 75% specificity. With 72.4% prevalence, the predictive value was estimated to be 91.3% for an abnormal test result and 100% for a normal test result. Two of four couples had a healthy baby following PGD. The proportion of normal/balanced embryo could be significantly less for female heterozygotes, and our model indicates that this could be detrimental to the effectiveness of PGD. A 20% risk of live-born offspring with an unbalanced translocation is generally accepted, largely based on the obstetric history of female heterozygotes; we suggest that a 3% risk may be more appropriate for male carriers.

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Balanced into array: genome-wide array analysis in 54 patients with an apparently balanced de novo chromosome rearrangement and a meta-analysis

Cited by 44 publications

References 33 publications

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

Meiotic outcomes of three-way translocations ascertained in cleavage-stage embryos: refinement of reproductive risks and implications for PGD

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