Preliminary phenotypic map of chromosome 4p16 based on 4p deletions

Estabrooks, Laurel L.; Rao, Kathleen W.; Driscoll, Deborah A.; Crandall, Barbara F.; Dean, John; Ikonen, Elina; Korf, Bruce R.; Aylsworth, Arthur S.

doi:10.1002/ajmg.1320570413

Cited by 166 publications

(56 citation statements)

References 7 publications

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“…5 Thirteen of 32 patients in our study reported hearing loss. Four of these thirteen had 4p deletions smaller than 6 Mb and three of these four patients had unbalanced translocations, two of which were cryptic.…”

Section: Discussionmentioning

confidence: 67%

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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Section: Discussionmentioning

confidence: 67%

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

et al. 2007

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“…To our knowledge in this respect, there are no detailed literature data for comparison. The number of patients who are able to walk or to talk is too small to argue whether the degree of developmental delay correlates with the size of the deletion, as suggested by Johnson et al 40 Estabrooks et al 4,45 hypothesised that the size of the deletion and clinical severity do not correlate. This may be due to the fact that these authors included WHS patients only with small deletions.…”

Section: Discussionmentioning

confidence: 99%

“…Hearing loss was present in one patient with a small deletion in our group of patients and is in contrast to this map. These authors 4 suggest that seizures may be mapped to the distal region because they are present in nearly all patients. We do not agree with cleft lip/palate being localised distally as discussed above, because of the absence of this sign in our patients with small deletions.…”

Section: Discussionmentioning

confidence: 99%

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Effect of the size of the deletion and clinical manifestation in Wolf-Hirschhorn syndrome: analysis of 13 patients with a de novo deletion

et al. 2000

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We performed clinical, cytogenetic, and molecular analyses on 13 patients (8 females and 5 males, aged 6 months to 13 years) with Wolf-Hirschhorn syndrome due to de novo deletions of chromosome 4p. All patients presented with the typical facial gestalt, microcephaly, and profound mental retardation. Other clinical signs were low birth weight (10/13; 77%), postnatal short stature (8/12; 66%), muscular hypotonia (12/13; 92%), seizures (11/13; 85%), congenital heart defects (4/13; 31%), colobomata of iris (4/12; 33%), genital anomalies (4/13; 31%), deafness (3/13; 23%), and renal anomalies (3/13; 23%). The smallest deletion was a submicroscopic terminal deletion of nearly 2.5 Mb. The largest was a terminal deletion of nearly 30 Mb. Cleft lip/palate, preauricular pits/tags, and congenital heart defects were present only in patients with terminal deletions larger than 10 Mb. The deviations from mean birth weight, birth length, and postnatal head circumference correlated with the size of the deletion. Determining the parental origin of the deletion with microsatellite markers, the maternal allele was missing in three patients and the paternal allele in eight patients. Our observations support the existence of a partial genotype-phenotype correlation in Wolf-Hirschhorn syndrome.

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“…More than 120 cases of WHS have been reported (59). The clinical severity correlates with the extent of the deletion (60).…”

Section: Deletion Of the Short Arm Of Chromosome 4 Del(4)(pter->p15andmentioning

confidence: 99%

Chromosomal Abnormalities and Epilepsy: A Review for Clinicians and Gene Hunters

et al. 2002

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Summary:Purpose: We analyzed databases on chromosomal anomalies and epilepsy to identify chromosomal regions where abnormalities are associated with clinically recognizable epilepsy syndromes. The expectation was that these regions could then be offered as targets in the search for epilepsy genes.Methods: The cytogenetic program of the Oxford Medical Database, and the PubMed database were used to identify chromosomal aberrations associated with seizures and/or EEG abnormalities. The literature on selected small anomalies thus identified was reviewed from a clinical and electroencephalographic viewpoint, to classify the seizures and syndromes according to the current International League Against Epilepsy (ILAE) classification.Results: There were 400 different chromosomal imbalances described with seizures or EEG abnormalities. Eight chromosomal disorders had a high association with epilepsy. These comprised: the Wolf-Hirschhorn (4p-) syndrome, MillerDieker syndrome (del 17p13.3), Angelman syndrome (del 15q11-q13), the inversion duplication 15 syndrome, terminal deletions of chromosome 1q and 1p, and ring chromosomes 14 and 20. Many other segments had a weaker association with seizures. The poor quality of description of the epileptology in many reports thwarted an attempt to make precise karyotypephenotype correlations.Conclusions: We identified certain chromosomal regions where aberrations had an evident association with seizures, and these regions may be useful targets for gene hunters. New correlations with specific epilepsy syndromes were not revealed. Clinicians should continue to search for small chromosomal abnormalities associated with specific epilepsy syndromes that could provide important clues for finding epilepsy genes, and the epileptology should be rigorously characterized.

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Preliminary phenotypic map of chromosome 4p16 based on 4p deletions

Cited by 166 publications

References 7 publications

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

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

Effect of the size of the deletion and clinical manifestation in Wolf-Hirschhorn syndrome: analysis of 13 patients with a de novo deletion

Chromosomal Abnormalities and Epilepsy: A Review for Clinicians and Gene Hunters

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