Ring chromosomes are uncommon cytogenetic findings and are often associated with clinical features overlapping the phenotype of patients with terminal deletions of the corresponding chromosome.... Show moreRing chromosomes are uncommon cytogenetic findings and are often associated with clinical features overlapping the phenotype of patients with terminal deletions of the corresponding chromosome. Most of the ring chromosomes arise sporadically and parental transmission is rarely observed. We report five patients carrying a ring chromosome 11, with three of the patients belonging to the same family. SNP array analysis was performed to characterize the different ring chromosomes and the clinical phenotypes were compared with previously reported patients with ring chromosome 11. Show less
BACKGROUND Deletions including chromosome 14 band q13 have been linked to variable phenotypes. With current molecular methods the authors aim to elucidate a genotype-phenotype correlation by... Show moreBACKGROUND Deletions including chromosome 14 band q13 have been linked to variable phenotypes. With current molecular methods the authors aim to elucidate a genotype-phenotype correlation by accurately determining the size and location of the deletions and the associated phenotype. METHODS Here the authors report the molecular karyotyping and phenotypic description of seven patients with overlapping deletions including chromosome 14q13. RESULTS The authors show that deletions including 14q13 result in a recognisable phenotype mainly due to haploinsufficiency of two genes (NKX2-1, PAX9). FOXG1 (on chromosome band 14q12) involvement seems to be the main determinant of phenotype severity. The patients in this study without FOXG1 involvement and deletions of up to 10 Mb have a relatively mild phenotype. The authors cannot explain why some patients in literature with overlapping but smaller deletions appear to have a more severe phenotype. A previously presumed association with holoprosencephaly could not be confirmed as none of the patients in this series had holoprosencephaly. CONCLUSIONS FOXG1 appears the main determinant of the severity of phenotypes resulting from deletions including 14q13. The collected data show no evidence for a locus for holoprosencephaly in the 14q13 region, but a locus for agenesis of the corpus callosum cannot be excluded. Show less
The advent and application of high-resolution array-based comparative genome hybridization (array CGH) has led to the detection of large numbers of copy number variants (CNVs) in patients with... Show moreThe advent and application of high-resolution array-based comparative genome hybridization (array CGH) has led to the detection of large numbers of copy number variants (CNVs) in patients with developmental delay and/or multiple congenital anomalies as well as in healthy individuals. The notion that CNVs are also abundantly present in the normal population challenges the interpretation of the clinical significance of detected CNVs in patients. In this review we will illustrate a general clinical workflow based on our own experience that can be used in routine diagnostics for the interpretation of CNVs. Show less
Chromosomal rearrangements are an important cause of distinctive and recognizable clinical phenotypes. For many years conventional karyotyping has been a successful tool to detect such chromosomal... Show moreChromosomal rearrangements are an important cause of distinctive and recognizable clinical phenotypes. For many years conventional karyotyping has been a successful tool to detect such chromosomal rearrangements. However, this technique has a limited resolution of 5-10 Mb. In the past decades, the development of new high-resolution techniques has led to the field of molecular cytogenetics. One of the most significant changes has been the use of molecular karyotyping by high-resolution whole-genome array techniques in the diagnostic setting. This technology is able to detect chromosomal aberrations at a resolution beyond the detection level of conventional karyotyping. Many new microdeletion and microduplication syndromes have been identified by this new method. In this review, we will focus on the most commonly used (molecular) cytogenetic techniques. Show less
Gijsbers, A.C.J.; Dauwerse, J.G.; Bosch, C.A.J.; Boon, E.M.J.; Ende, W. van den; Kant, S.G.; ... ; Ruivenkamp, C.A.L. 2011
Mosaicism involving a normal cell line and an unbalanced autosomal translocation are rare. In this study we present three new cases with such a mosaicism, which were detected by Single Nucleotide... Show moreMosaicism involving a normal cell line and an unbalanced autosomal translocation are rare. In this study we present three new cases with such a mosaicism, which were detected by Single Nucleotide Polymorphism (SNP) array analysis in our routine diagnostic setting. These cases were further characterized using Fluorescence in situ Hybridisation (FISH) analysis and conventional karyotyping. The first case is a mentally retarded male who carries an unbalanced translocation in 87% of his cells. The phenotypically normal mother carries the balanced form of the translocation in all her cells. The second case is a phenotypically normal female who has an unbalanced translocation in 52% of her cells. The inheritance could not be determined. The third case is a female referred for Rubinsteine-Taybi syndrome who carries an unbalanced translocation in 60% of her cells. Both parents of this case showed a normal karyotype. The mechanisms that might be responsible for these mosaic karyotypes are discussed. Furthermore, we demonstrate that high-resolution whole-genome SNP array is a powerful tool to reveal cryptic unbalanced translocations and mosaicisms, including the more rare cases. (C) 2011 Elsevier Masson SAS. All rights reserved. Show less
Studies to identify copy number variants (CNVs) on the X-chromosome have revealed novel genes important in the causation of X-linked mental retardation (XLMR). Still, for many CNVs it is unclear... Show moreStudies to identify copy number variants (CNVs) on the X-chromosome have revealed novel genes important in the causation of X-linked mental retardation (XLMR). Still, for many CNVs it is unclear whether they are associated with disease or are benign variants. We describe six different CNVs on the X-chromosome in five male patients with mental retardation that were identified by conventional karyotyping and single nucleotide polymorphism array analysis. One deletion and five duplications ranging in size from 325 kb to 12.5 Mb were observed. Five CNVs were maternally inherited and one occurred de novo. We discuss the involvement of potential candidate genes and focus on the complexity of X-chromosomal duplications in males inherited from healthy mothers with different X-inactivation patterns. Based on size and/or the presence of XLMR genes we were able to classify CNVs as pathogenic in two patients. However, it remains difficult to decide if the CNVs in the other three patients are pathogenic or benign. Show less
Conventional karyotyping has been used as the standard cytogenetic technique since the 1970s. With conventional karyotyping one can detect aberrations larger than 5 __ 10 Mb and it can detect... Show moreConventional karyotyping has been used as the standard cytogenetic technique since the 1970s. With conventional karyotyping one can detect aberrations larger than 5 __ 10 Mb and it can detect chromosomal aberrations in approximately 5% of patients with mental retardation (MR). To identify smaller copy number variants (CNVs) new molecular cytogenetic techniques have been developed. One of these techniques is the Single Nucleotide Polymorphism (SNP) array. This method allows the detection of SNP-genotype as well as the presence of small deletions and amplifications. In this thesis we have studied patients with MR and/or congenital malformations. The question we have tried to answer by studying the genome of the patient is whether we can find a cause for the signs and symptoms observed in the patient. The SNP array was successfully used for the detection of novel CNVs and has replaced the conventional karyotyping in the routine diagnostic flow in MR patients in our diagnostic setting. We are therefore able to make a diagnosis in a higher number of MR patients, thus improving medical care and genetic counselling. However, a major complexity is the finding of potentially pathogenic CNVs for which the clinical significance is not immediately clear. Show less
Apparently balanced chromosome abnormalities are occasionally associated with mental retardation (MR). These balanced rearrangements may disrupt genes. However, the phenotype may also be caused by... Show moreApparently balanced chromosome abnormalities are occasionally associated with mental retardation (MR). These balanced rearrangements may disrupt genes. However, the phenotype may also be caused by small abnormalities present at the breakpoints or elsewhere in the genome. Conventional karyotyping is not instrumental for detecting small abnormalities because it only identifies genomic imbalances larger than 5-10 Mb. In contrast, high-resolution whole-genome arrays enable the detection of submicroscopic abnormalities in patients with apparently balanced rearrangements. Here, we report on the whole-genome analysis of 13 MR patients with previously detected balanced chromosomal abnormalities, five de novo, four inherited, and four of unknown inheritance, using Single Nucleotide Polymorphism (SNP) arrays. In all the cases, the patient had an abnormal phenotype. In one familial case and one unknown inheritance case, one of the parents had a phenotype which appeared identical to the patient's phenotype. Additional copy number variants (CNVs) were identified in eight patients. Three patients contained CNVs adjacent to one or either breakpoints. One of these patients showed four and two deletions near the breakpoints of a de novo pericentric inversion. In five patients we identified CNVs on chromosomes unrelated to the previously observed genomic imbalance. These data demonstrate that high-resolution array screening and conventional karyotyping is necessary to tie complex karyotypes to phenotypes of MR patients. (C) 2010 Elsevier Masson SAS. All rights reserved. Show less
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