Unexpected high frequency of de novo unbalanced translocations in patients with Wolf-Hirschhorn syndrome (WHS)

Wieczorek, Dagmar; Krause, Mario; Majewski, F.; Albrecht, Beate; Meinecke, Peter; Rieß, Olaf; Gillessen‐Kaesbach, Gabriele

doi:10.1136/jmg.37.10.798

Cited by 47 publications

(58 citation statements)

References 55 publications

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“…12,13 De novo 4p deletions are reasonably assumed to be single chromosome anomalies. However, unbalanced de novo translocations, above all t(4;8)(p16.1;p23) translocations, were detected recently with an unexpectedly high frequency in WHS 10,14,15 and, whenever investigated, they were of maternal origin. It was recently demonstrated that WHS-associated t(4p;8p) translocations occur within OR-gene clusters on both 4p and 8p, with the involvement of two distinct OR-gene clusters in 4p at a distance of about 5 and 14 Mb from the telomere and of a unique OR-gene cluster in 8p.…”

Section: Discussionmentioning

confidence: 99%

“…However, unbalanced de novo t(4p;8p) translocations have been detected with unexpected high frequency in WHS patients and, whenever tested, they were maternal in origin. 10,14,15 It was recently demonstrated that the breakpoints of t(4;8) translocations fall within 4p and 8p olfactory receptors (OR)-gene clusters, with the involvement of two different OR-gene clusters in 4p at an average distance of 5 and 14 Mb from the telomere. 16 Frequency, specificity and, more importantly, clinical relevance of unbalanced de novo translocations in WHS are currently unclear.…”

Section: Introductionmentioning

confidence: 99%

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A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf–Hirschhorn syndrome

Zollino¹,

Lecce²,

Selicorni

et al. 2004

Eur J Hum Genet

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A total of five Wolf-Hirschhorn syndrome (WHS) patient with a 4p16.3 de novo microdeletion was referred because of genotype -phenotype inconsistencies, first explained as phenotypic variability of the WHS. The actual deletion size was found to be about 12 Mb in three patients, 5 Mb in another one and 20 Mb in the last one, leading us to hypothesize the presence of an extrachromosome segment on the deleted 4p. A der(4)(4qter-p16.1::8p23-pter) chromosome, resulting from an unbalanced de novo translocation was, in fact, detected in four patients and a der(4)(4qter-q32::4p15.3-qter) in the last. Unbalanced t(4;8) translocations were maternal in origin, the rec(4p;4q) was paternal. With the purpose of verifying frequency and specificity of this phenomenon, we investigated yet another group of 20 WHS patients with de novo large deletions (n ¼ 13) or microdeletions (n ¼ 7) and with apparently straightforward genotypephenotype correlations. The rearrangement was paternal in origin, and occurred as a single anomaly in 19 out of 20 patients. In the remaining patient, the deleted chromosome 4 was maternally derived and consisted of a der(4)(4qter-4p16.3::8p23-8pter). In conclusions, we observed that 20% (5/25) of de novo WHS-associated rearrangements were maternal in origin and 80% (20/25) were paternal. All the maternally derived rearrangements were de novo unbalanced t(4;8) translocations and showed specific clinical phenotypes. Paternally derived rearrangements were usually isolated deletions. It can be inferred that a double, cryptic chromosome imbalance is an important factor for phenotypic variability in WHS. It acts either by masking the actual deletion size or by doubling a quantitative change of the genome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf–Hirschhorn syndrome

Zollino¹,

Lecce²,

Selicorni

et al. 2004

Eur J Hum Genet

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“…8,14 The initial large study was based primarily on cytogenetically visible translocations. Therefore, with the use of new techniques that improve the detection rate of cryptic alterations such as aCGH, perhaps it is not surprising that the true incidence is higher.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of Wolf–Hirschhorn syndrome using array CGH indicates a high prevalence of translocations

et al. 2007

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Wolf-Hirschhorn syndrome (WHS) is caused by deletions involving chromosome region 4p16.3. The minimal diagnostic criteria include mild-to-severe mental retardation, hypotonia, growth delay and a distinctive facial appearance. Variable manifestations include feeding difficulties, seizures and major congenital anomalies. Clinical variation may be explained by variation in the size of the deletion. However, in addition to having a deletion involving 4p16.3, previous studies indicate that approximately 15% of WHS patients are also duplicated for another chromosome region due to an unbalanced translocation. It is likely that the prevalence of unbalanced translocations resulting in WHS is underestimated since they can be missed using conventional chromosome analyses such as karyotyping and WHS-specific fluorescence in situ hybridization (FISH). Therefore, we hypothesized that some of the clinical variation may be due to an unrecognized and unbalanced translocation. Array comparative genomic hybridization (aCGH) is a new technology that can analyze the entire genome at a significantly higher resolution over conventional cytogenetics to characterize unbalanced rearrangements. We used aCGH to analyze 33 patients with WHS and found a much higher than expected frequency of unbalanced translocations (15/33, 45%). Seven of these 15 cases were cryptic translocations not detected by a previous karyotype combined with WHS-specific FISH. Three of these 15 cases had an unbalanced translocation involving the short arm of an acrocentric chromosome and were not detected by either aCGH or subtelomere FISH. Analysis of clinical manifestations of each patient also revealed that patients with an unbalanced translocation often presented with exceptions to some expected phenotypes.

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“…7 Translocations between chromosomes 4 and 8 occur more frequently than expected. [7][8][9][10][11] WHS is characterized by pre-and postnatal growth delay, microcephaly, seizures, hypotonia, developmental delay, congenital anomalies and a recognizable facial appearance, which includes: hypertelorism, protruding eyes, epicanthus, arched eyebrows, prominent nasal bridge, downturned corners of the mouth, micrognathia and short philtrum, and, with increasing age, a more prominent nose. Dental anomalies, some occurring in more than half of WHS patients, have been described: delayed eruption and hypodontia, retained primary teeth, peg-shaped teeth and taurodontism.…”

Section: Wolf-hirschhorn Syndrome (Whs; Omim 194190) Is a Contiguous mentioning

confidence: 99%

Fine-grained facial phenotype–genotype analysis in Wolf–Hirschhorn syndrome

Hammond¹,

Hannes

Suttie³

et al. 2011

Eur J Hum Genet

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Wolf-Hirschhorn syndrome is caused by anomalies of the short arm of chromosome 4. About 55% of cases are due to de novo terminal deletions, 40% from unbalanced translocations and 5% from other abnormalities. The facial phenotype is characterized by hypertelorism, protruding eyes, prominent glabella, broad nasal bridge and short philtrum. We used dense surface modelling and pattern recognition techniques to delineate the milder facial phenotype of individuals with a small terminal deletion (breakpoint within 4p16.3) compared to those with a large deletion (breakpoint more proximal than 4p16.3). Further, fine-grained facial analysis of several individuals with an atypical genotype and/or phenotype suggests that multiple genes contiguously contribute to the characteristic Wolf-Hirschhorn syndrome facial phenotype.

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Unexpected high frequency of de novo unbalanced translocations in patients with Wolf-Hirschhorn syndrome (WHS)

Cited by 47 publications

References 55 publications

A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf–Hirschhorn syndrome

A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf–Hirschhorn syndrome

Comprehensive analysis of Wolf–Hirschhorn syndrome using array CGH indicates a high prevalence of translocations

Fine-grained facial phenotype–genotype analysis in Wolf–Hirschhorn syndrome

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