Defensins and the dynamic genome: What we can learn from structural variation at human chromosome band 8p23.1

Hollox, Edward J.; Barber, John; Brookes, Anthony J.; Armour, John A.L.

doi:10.1101/gr.080945.108

Cited by 86 publications

(85 citation statements)

References 110 publications

(133 reference statements)

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“…[6][7][8][9]43,44 The copy numbers of different types of defensin and olfactory receptor genes in the REPD and REPP regions are highly variable, leading to cytogenetically visible euchromatic variants if the copies are sufficiently high. 4,45,46 However, these euchromatic variants are indistinguishable from the genuine 8p23.1 duplication under a light microscope. For example, two of the three patients with 8p23.1 duplication in this study were initially reported as euchromatic variants to the referring physicians.…”

Section: P231 Duplicationmentioning

confidence: 85%

“…Three mechanisms may explain the origin of inv dup del(8p) (Figure 3) with detailed explanations referred to the recent reports. 4,8,24,34 In brief, all three mechanisms involve the formation of a dicentric chromosome 8 (dic(8)) in meiosis I followed by breakage of the dic(8) either during meiotic division or during early stages of embryonic development leading to the production of an inv dup del(8p). However, the events causing the formation of a dic (8) differ among the three mechanisms.…”

Section: Repd and Repp-mediated Inv Dup Del(8p)mentioning

confidence: 99%

“…This B5.0 Mb duplication of 8p23.1 is flanked by REPD and REPP, which share a high level of identity of complex genomic repeats involving retroviral elements, olfactory repeat regions, and variable copy numbers of defensin genes. 4,7,8,42 The 8p23.1 duplication is likely caused by intrachromosomal recombination between REPD and REPP within the 8p23.1 region through LCR-mediated nonallelic homologous misalignment and unequal recombination (NAHR) during meiosis. [6][7][8][9]43,44 The copy numbers of different types of defensin and olfactory receptor genes in the REPD and REPP regions are highly variable, leading to cytogenetically visible euchromatic variants if the copies are sufficiently high.…”

Section: P231 Duplicationmentioning

confidence: 99%

“…These results are concordant to the data documented in the Database of Genomic Variants (http://projects.tcag.ca/variation/), reflecting the extreme instability of these three regions. Variable copy numbers of defensin and olfactory receptor genes within the REPD and REPP regions, 4 and the large numbers of simple tandem repeats within the 8p11.23 region should be the structural basis leading to the formation of these benign copy variations.…”

Section: Mechanisms Leading To the Formation Of Benign Cnvs On 8pmentioning

confidence: 99%

“…[2][3][4][5][6] These REPD-and/or REPP-related 8p genomic rearrangements include (1) the 8p23.1 deletion or duplication between REPD and REPP, [6][7][8][9] (2) the 8p23.1 paracentric inversion between REPD and REPP, 8,10 (3) the pericentric inversion (inv(8)(p23.1q22.1)) and recombinant chromosome 8 (rec (8)dup(8q)inv(8)(p23.1q22.1)), 11 (4) the 8p interstitial inverted duplication with associated terminal deletion (inv dup del(8p)), 5,6,8,10,[12][13][14][15][16][17][18][19][20][21][22][23][24] (5) the 8p translocations involving the 8p23.1, 25,26 and (6) different types of supernumerary chromosome 8 (SMC (8)) involving the breakpoints within 8p23.1. 4,27 In addition to these defined 8p genomic abnormalities, other pathogenic genomic changes have been identified, [28][29][30] whereas numerous genomic imbalances on 8p are still described as copy number variants (CNVs) of unknown clinical significance or CNVs without apparent clinical significance (benign CNVs) (http://projects.tcag.ca/variation).…”

Section: Introductionmentioning

confidence: 99%

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Genomic profile of copy number variants on the short arm of human chromosome 8

Fiedler

Stegner

et al. 2010

Eur J Hum Genet

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We evaluated 966 consecutive pediatric patients with various developmental disorders by high-resolution microarray-based comparative genomic hybridization and found 10 individuals with pathogenic copy number variants (CNVs) on the short arm of chromosome 8 (8p), representing approximately 1% of the patients analyzed. Two patients with 8p terminal deletion associated with interstitial inverted duplication (inv dup del(8p)) had different mechanisms leading to the formation of a dicentric intermediate during meiosis. Three probands carried an identical B5.0 Mb interstitial duplication of chromosome 8p23.1. Four possible hotspots within 8p were observed at nucleotide coordinates of B10. 45, 24.32-24.82, 32.19-32.77, and 38.94-39.72 Mb involving the formation of recurrent genomic rearrangements. Other CNVs with deletion-or duplicationspecific start or stop coordinates on the 8p provide useful information for exploring the basic mechanisms of complex structural rearrangements in the human genome.

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Section: P231 Duplicationmentioning

confidence: 85%

Section: Repd and Repp-mediated Inv Dup Del(8p)mentioning

confidence: 99%

Section: P231 Duplicationmentioning

confidence: 99%

Section: Mechanisms Leading To the Formation Of Benign Cnvs On 8pmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Genomic profile of copy number variants on the short arm of human chromosome 8

Fiedler

Stegner

et al. 2010

Eur J Hum Genet

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Three cases of isolated terminal deletion of chromosome 8p without heart defects presenting with a mild phenotype

Burnside

Pappas

Sacharow

et al. 2013

American J of Med Genetics Pt A

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Individuals with isolated terminal deletions of 8p have been well described in the literature, however, molecular characterization, particularly by microarray, of the deletion in most instances is lacking. The phenotype of such individuals falls primarily into two categories: those with cardiac defects, and those without. The architecture of 8p has been demonstrated to contain two inversely oriented segmental duplications at 8p23.1, flanking the gene, GATA4. Haploinsufficiency of this gene has been implicated in cardiac defects seen in numerous individuals with terminal 8p deletion. Current microarray technologies allow for the precise elucidation of the size and gene content of the deleted region. We present three individuals with isolated terminal deletion of 8p distal to the segmental duplication telomeric to GATA4. These individuals present with a relatively mild and nonspecific phenotype including mildly dysmorphic features, developmental delay, speech delay, and early behavior issues.

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8p23.1 duplication syndrome; common, confirmed, and novel features in six further patients

Barber

Rosenfeld

Foulds

et al. 2013

American J of Med Genetics Pt A

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The 8p23.1 duplication syndrome is a relatively rare genomic condition that has been confirmed with molecular cytogenetic methods in only 11 probands and five family members. Here, we describe another prenatal and five postnatal patients with de novo 8p23.1 duplications analyzed with oligonucleotide array comparative genomic hybridization (oaCGH). Of the common features, mild or moderate developmental delays and/or learning difficulties have been found in 11/12 postnatal probands, a variable degree of mild dysmorphism in 8/12 and congenital heart disease (CHD) in 4/5 prenatal and 3/12 postnatal probands. Behavioral problems, cleft lip and/or palate, macrocephaly, and seizures were confirmed as additional features among the new patients, and novel features included neonatal respiratory distress, attention deficit hyperactivity disorder (ADHD), ocular anomalies, balance problems, hypotonia, and hydrocele. The core duplication of 3.68 Mb contains 31 genes and microRNAs of which only GATA4, TNKS, SOX7, and XKR6 are likely to be dosage sensitive genes and MIR124-1 and MIR598 have been implicated in neurocognitive phenotypes. A combination of the duplication of GATA4, SOX7, and related genes may account for the variable penetrance of CHD. Two of the duplications were maternal and intrachromosomal in origin with maternal heterozygosity for the common inversion between the repeats in 8p23.1. These additional patients and the absence of the 8p23.1 duplications in published controls, indicate that the 8p23.1 duplication syndrome may now be considered a pathogenic copy number variation (pCNV) with an estimated population prevalence of 1 in 58,000.

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Defensins and the dynamic genome: What we can learn from structural variation at human chromosome band 8p23.1

Cited by 86 publications

References 110 publications

Genomic profile of copy number variants on the short arm of human chromosome 8

Genomic profile of copy number variants on the short arm of human chromosome 8

Three cases of isolated terminal deletion of chromosome 8p without heart defects presenting with a mild phenotype

8p23.1 duplication syndrome; common, confirmed, and novel features in six further patients

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