Search PubMed⌕ Search

Biomedical subjects

Joris R Vermeesch

Publications and source records attributed to Joris R Vermeesch.

15 recordsLinked to original sources
PubMed2019

The 22q11 low copy repeats are characterized by unprecedented size and structural variability.

Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved. The difficulty in generating accurate maps of LCR22s has also hindered localization of the deletion end points in 22q11DS patients. Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines. Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb. Further, the incidence of various LCR22 alleles varied within different populations. Additionally, the analysis of LCR22s in 22q11DS patients and their parents enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion. The NAHR site was localized to a 160-kb paralog shared between the LCR22A and -D in seven 22q11DS patients. Thus, we present the most comprehensive map of LCR22 variation to date. This will greatly facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients.

22q11 Deletion Syndrome↗
PubMed2006

Single-cell chromosomal imbalances detection by array CGH.

Genomic imbalances are a major cause of constitutional and acquired disorders. Therefore, aneuploidy screening has become the cornerstone of preimplantation, prenatal and postnatal genetic diagnosis, as well as a routine aspect of the diagnostic workup of many acquired disorders. Recently, array comparative genomic hybridization (array CGH) has been introduced as a rapid and high-resolution method for the detection of both benign and disease-causing genomic copy-number variations. Until now, array CGH has been performed using a significant quantity of DNA derived from a pool of cells. Here, we present an array CGH method that accurately detects chromosomal imbalances from a single lymphoblast, fibroblast and blastomere within a single day. Trisomy 13, 18, 21 and monosomy X, as well as normal ploidy levels of all other chromosomes, were accurately determined from single fibroblasts. Moreover, we showed that a segmental deletion as small as 34 Mb could be detected. Finally, we demonstrated the possibility to detect aneuploidies in single blastomeres derived from preimplantation embryos. This technique offers new possibilities for genetic analysis of single cells in general and opens the route towards aneuploidy screening and detection of unbalanced translocations in preimplantation embryos in particular.

Aneuploidy↗
PubMed2006

Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic GISTs. In addition to sporadic occurrences, GISTs are increasingly being recognized in association with neurofibromatosis type 1 (NF1), yet the underlying pathogenic mechanism remains elusive. To gain an insight into the mechanisms underlying GIST formation in NF1 patients, we studied seven GISTs from three NF1 patients with a combination of different techniques: mutation analysis (KIT, PDGFRA and NF1), western blotting, array CGH and ex vivo imatinib response experiments. We demonstrate that (i) the NF1-related GISTs do not have KIT or PDGFRA mutations, (ii) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (iii) inactivation of neurofibromin is an alternate mechanism to (hyper) activate the MAP-kinase pathway, while the JAK-STAT3 and PI3K-AKT pathways are less activated in NF1-related GIST compared with sporadic GISTs. In conclusion, we report for the first time the molecular pathogenesis of GISTs in NF1 individuals and demonstrate that this type of tumor clearly belongs to the spectrum of clinical symptoms in NF1.

Adult↗
PubMed2005

Exon array CGH: detection of copy-number changes at the resolution of individual exons in the human genome.

The development of high-throughput screening methods such as array-based comparative genome hybridization (array CGH) allows screening of the human genome for copy-number changes. Current array CGH strategies have limits of resolution that make detection of small (less than a few tens of kilobases) gains or losses of genomic DNA difficult to identify. We report here a significant improvement in the resolution of array CGH, with the development of an array platform that utilizes single-stranded DNA array elements to accurately measure copy-number changes of individual exons in the human genome. Using this technology, we screened 31 patient samples across an array containing a total of 162 exons for five disease genes and detected copy-number changes, ranging from whole-gene deletions and duplications to single-exon deletions and duplications, in 100% of the cases. Our data demonstrate that it is possible to screen the human genome for copy-number changes with array CGH at a resolution that is 2 orders of magnitude higher than that previously reported.

Exons↗
PubMed2005

Molecular karyotyping: array CGH quality criteria for constitutional genetic diagnosis.

Array CGH (comparative genomic hybridization) enables the identification of chromosomal copy number changes. The availability of clone sets covering the human genome opens the possibility for the widespread use of array CGH for both research and diagnostic purposes. In this manuscript we report on the parameters that were critical for successful implementation of the technology, assess quality criteria, and discuss the potential benefits and pitfalls of the technology for improved pre- and postnatal constitutional genetic diagnosis. We propose to name the genome-wide array CGH "molecular karyotyping," in analogy with conventional karyotyping that uses staining methods to visualize chromosomes.

Cell Line↗
PubMed2004

Post-zygotic origin of isochromosome 12p.

OBJECTIVE: Advance knowledge about the mechanism of isochromosome formation. METHODS: Echographic examination of the foetus. G- and/or T-banded chromosome and FISH analysis using chromosome 12p subtelomeric probes on short- and long-term CVS cultures, amniocytes and foetal fibroblasts. Polymorphic CA repeat analysis on DNA from the foetus and both parents. RESULTS: Short-term CVS cultures showed a 46,XX karyotype, whilst long-term CVS cultures showed a 47,XX,+12 karyotype. FISH on amniocytes indicated 2, 3 and 4 signals. Foetal fibroblasts showed both 47,XX,+12 and 47,XX,+i(12)(p10) karyotypes. DNA analysis revealed the isochromosome to be paternal in origin, whilst the other two foetal chromosomes 12 were maternal, part iso- and part heterodisomy. CONCLUSION: The cytogenetic and DNA constitution of the foetus indicated the isochromosome 12p to be of paternal origin, and implied post-zygotic formation of the isochromosome 12p in the Pallister-Killian syndrome.

Adult↗
PubMed2004

A dysmorphic boy with 4qter deletion and 4q32.3-34.3 duplication: clinical, cytogenetic, and molecular findings.

An infant boy presented with trigonocephaly, mild craniofacial features, a small VSD, open ductus Botalli (ODB), bilateral hip dysplasia, psychomotor retardation, and hypotonia. The karyotype was 46,XY,del(4)(q34). Unexpectedly, fluorescence in situ hybridization (FISH) studies revealed not only a deletion but also a duplication. The deletion extends from 4qter to 4q34.3 and the duplication from 4q32.3 to q34.3. This is the first description of a deletion inverted duplication 4q. Possible mechanisms we can envision by which this deletion/duplication arose could be a U-type exchange causing end-to-end fusion or a two step event with a paracentric inversion and subsequent cross-over in the inverted segment. This observation suggests that the karyotype of patients with a 4q deletion should be confirmed by molecular cytogenetics.

Abnormalities, Multiple↗
PubMed2004

Chromosomal phenotypes and submicroscopic abnormalities.

The finding, during the last decade, that several common, clinically delineated syndromes are caused by submicroscopic deletions or, more rarely, by duplications, has provided a powerful tool in the annotation of the human genome. Since most microdeletion/microduplication syndromes are defined by a common deleted/duplicated region, abnormal dosage of genes located within these regions can explain the phenotypic similarities among individuals with a specific syndrome. As such, they provide a unique resource towards the genetic dissection of complex phenotypes such as congenital heart defects, mental and growth retardation and abnormal behaviour. In addition, the study of phenotypic differences in individuals with the same microdeletion syndrome may also become a treasury for the identification of modifying factors for complex phenotypes. The molecular analysis of these chromosomal anomalies has led to a growing understanding of their mechanisms of origin. Novel tools to uncover additional submicroscopic chromosomal anomalies at a higher resolution and higher speed, as well as the novel tools at hand for deciphering the modifying factors and epistatic interactors, are 'on the doorstep' and will, besides their obvious diagnostic role, play a pivotal role in the genetic dissection of complex phenotypes.

Animals↗
PubMed2003

Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane.

We have demonstrated previously that adult human synovial membrane-derived mesenchymal stem cells (hSM-MSCs) have myogenic potential in vitro (De Bari, C., F. Dell'Accio, P. Tylzanowski, and F.P. Luyten. 2001. Arthritis Rheum. 44:1928-1942). In the present study, we have characterized their myogenic differentiation in a nude mouse model of skeletal muscle regeneration and provide proof of principle of their potential use for muscle repair in the mdx mouse model of Duchenne muscular dystrophy. When implanted into regenerating nude mouse muscle, hSM-MSCs contributed to myofibers and to long term persisting functional satellite cells. No nuclear fusion hybrids were observed between donor human cells and host mouse muscle cells. Myogenic differentiation proceeded through a molecular cascade resembling embryonic muscle development. Differentiation was sensitive to environmental cues, since hSM-MSCs injected into the bloodstream engrafted in several tissues, but acquired the muscle phenotype only within skeletal muscle. When administered into dystrophic muscles of immunosuppressed mdx mice, hSM-MSCs restored sarcolemmal expression of dystrophin, reduced central nucleation, and rescued the expression of mouse mechano growth factor.

Adolescent↗
PubMedDate not supplied

Interstitial 6q deletion: clinical and array CGH characterisation of a new patient.

We report on a patient with an interstitial 6q deletion presenting with moderate mental retardation, persisting hypotonia, facial dysmorphism, but no internal malformations. Standard cytogenetic analysis identified a de novo interstitial 6q deletion. Molecular karyotyping using a 1 Mb array estimated the size of the deletion at approximately 14 Mb encompassing band q16 of chromosome 6. This case report illustrates how the molecular delineation enables improved genotype-phenotype correlations of chromosomal abnormalities to be made and may improve medical care and genetic counselling in individuals with chromosomal imbalances.

Child, Preschool↗
PubMedDate not supplied

Trisomy of chromosome 16p13.3 due to an unbalanced insertional translocation into chromosome 22p13.

A dysmorphic boy with severe mental retardation was found on array CGH to have an insertional translocation of chromosome 16p13.3 into the short arm of chromosome 22, karyotype 46,XY,.ish der(22),ins(22;16)(p13;p13.3p13.3) de novo. His clinical features overlap with the reported cases of 'duplication 16p' syndrome, namely a round face, hypertelorism, a long philtrum, micrognathia, a thin upper lip, a posterior cleft palate and low set, simple ears, clubbed feet, severe developmental delay, psychomotor retardation and seizures. This 4-year boy with trisomy 16p13.3 has the smallest duplication reported of this critical region, which could not be detected without array CGH. The maximal duplicated region is gene rich and contains about 80 genes and/or candidate genes. Assignment of the genes that contribute to the observed phenotype awaits the characterisation of other patients with small duplications in this region.

Abnormalities, Multiple↗