Biomedical subjects

Reinhard Ullmann

Publications and source records attributed to Reinhard Ullmann.

15 recordsLinked to original sources

PubMed2007

Characterization of a 16 Mb interstitial chromosome 7q21 deletion by tiling path array CGH.

We report on a 42-year-old female patient with an interstitial 16 Mb deletion in 7q21.1-21.3 and a balanced reciprocal translocation between chromosomes 6 and 7 [karyotype 46,XX,t(6;7)(q23.3;q32.3)del(7)(q21.1q21.3)de novo]. We characterized the size and position of the deletion by tiling path array comparative genomic hybridization (CGH), and we mapped the translocation breakpoints on chromosomes 6 and 7 by FISH. The clinical features of this patient-severe mental retardation, short stature, microcephaly and deafness-are in accordance with previously reported patients with 7q21 deletions. Chromosome band 7q21.3 harbors a locus for split hand/split foot malformation (SHFM1), and part of this locus, including the SHFM1 candidate genes SHFM1, DLX5, and DLX6, is deleted. The absence of limb abnormalities in this patient suggests either a location of the SHFM1 causing factor distal to this deletion, or reduced penetrance of haploinsufficiency of a SHFM1 factor within the deleted interval.

Adult↗

PubMed2007

Characterization of a 5.3 Mb deletion in 15q14 by comparative genomic hybridization using a whole genome "tiling path" BAC array in a girl with heart defect, cleft palate, and developmental delay.

High-resolution array CGH utilizing sets of overlapping BAC and PAC clones ("tiling path") covering the whole genome is a powerful novel tool for fast detection of submicroscopic chromosome deletions or duplications. We describe the successful application of a submegabase resolution whole genome "tiling path" BAC array to confirm and characterize a de novo interstitial deletion of chromosome 15. The deletion has a size of 5.3 Mb and is located within chromosome band 15q14, distal to the Prader-Willi/Angelman region. The affected girl had a heart defect, cleft palate, recurrent infections, and developmental delay. In contrast to GTG banding, array CGH determined the exact number of deleted genes and thus allowed the identification of candidate genes for cleft palate (GREM1, CX36, MEIS2), congenital heart defect (ACTC, GREM1, CX36, MEIS2), and mental retardation (ARHGAP11A, CHRNA7, CHRM5).

Adult↗

PubMed2007

Mutations in autism susceptibility candidate 2 (AUTS2) in patients with mental retardation.

We report on three unrelated mentally disabled patients, each carrying a de novo balanced translocation that truncates the autism susceptibility candidate 2 (AUTS2) gene at 7q11.2. One of our patients shows relatively mild mental retardation; the other two display more profound disorders. One patient is also physically disabled, exhibiting urogenital and limb malformations in addition to severe mental retardation. The function of AUTS2 is presently unknown, but it has been shown to be disrupted in monozygotic twins with autism and mental retardation, both carrying a translocation t(7;20)(q11.2;p11.2) (de la Barra et al. in Rev Chil Pediatr 57:549-554, 1986; Sultana et al. in Genomics 80:129-134, 2002). Given the overlap of this autism/mental retardation (MR) phenotype and the MR-associated disorders in our patients, together with the fact that mapping of the additional autosomal breakpoints involved did not disclose obvious candidate disease genes, we ascertain with this study that AUTS2 mutations are clearly linked to autosomal dominant mental retardation.

Abnormalities, Multiple↗

PubMed2007

Allelic loss in a minimal region on chromosome 16q24 is associated with vitreous seeding of retinoblastoma.

In addition to RB1 gene mutations, retinoblastomas frequently show gains of 1q and 6p and losses of 16q. To identify suppressor genes on 16q, we analyzed 22 short tandem repeat loci in 58 patients with known RB1 mutations. A subset of tumors was also investigated by conventional and matrix comparative genomic hybridization. In 40 of 58 (69%) tumors, we found no loss of heterozygosity (LOH) at any 16q marker. LOH was detected in 18 of 58 (31%) tumors, including five with allelic imbalance at some markers. In one tumor LOH was only observed at 16q24. As the parental origin of allele loss was unbiased, an imprinted locus is unlikely to be involved. Analysis of gene expression by microarray hybridization and quantitative RT real-time PCR did not identify a candidate suppressor in 16q24. Cadherin 13 (CDH13), CBFA2T3, and WFDC1, which are candidate suppressors in other tumor entities with 16q24 loss, did not show loss of expression. In addition, mutation and methylation analysis showed no somatic alteration of CDH13. Results in all tumors with chromosome 16 alterations define a single minimal deleted region of 5.7 Mb in the telomeric part of 16q24 with the centromeric boundary defined by retention of heterozygosity for a single nucleotide variant in exon 10 of CDH13 (Mb 82.7). Interestingly, clinical presentation of tumors with and without 16q alterations was distinct. Specifically, almost all retinoblastomas with 16q24 loss showed diffuse intraocular seeding. This suggests that genetic alterations in the minimal deleted region are associated with impaired cell-to-cell adhesion.

Cadherins↗

PubMed2006

Ulnar-mammary syndrome with dysmorphic facies and mental retardation caused by a novel 1.28 Mb deletion encompassing the TBX3 gene.

Ulnar-mammary syndrome (UMS) is a rare autosomal-dominant disorder caused by mutations in TBX3. The condition is characterized by hypoplasia or aplasia of upper limbs on the ulnar side, mammary glands and nipples, and of apocrine glands in both sexes (MIM #181450). We report on a girl presenting with an UMS like phenotype, a dysmorphic facies, and mental retardation. Mutation analysis of TBX3 and G-banded chromosome analysis from lymphocytes were performed. We used microarray-based comparative genomic hybridization (array CGH) to investigate the patient's genomic DNA for submicroscopic aberrations. No mutation of the TBX3 gene was detected in our patient and chromosome analysis revealed a normal female karyotype (46,XX). Hybridization of a whole-genome tiling path array consisting of more than 36 000 BAC clones revealed an interstitial 1.28 Mb deletion within chromosomal band 12q24.21. The deleted region encompasses one known gene, TBX3. The deletion and haploinsufficiency of TBX3 was confirmed by fluorescence in situ hybridization using BAC clones representing the deletion on the BAC array. To our knowledge, this is the first description of TBX3 haploinsufficiency caused by a genomic deletion in a patient with UMS. We suggest that the UMS phenotype in conjunction with the characteristic facial changes and mental retardation observed in our patient is owing to the deletion of TBX3 and the involvement of neighbouring genes.

Abnormalities, Multiple↗

PubMed2006

A novel 8 Mb interstitial deletion of chromosome 8p12-p21.2.

We report on a girl with delayed mental and motor development, ophthalmological abnormalities, and peripheral neuropathy. Chromosome analysis suggested a deletion within chromosome 8p. Further investigation by array-based comparative genomic hybridization (array-CGH) delineated an 8 Mb interstitial deletion on the short arm of chromosome 8. The breakpoints are located at chromosome bands 8p12 and 8p21.2. Forty-two known genes including gonadotropin-releasing hormone 1 (GNRH1), transcription factor EBF2, exostosin-like 3 (EXTL3), glutathione reductase (GSR), and neuregulin 1 (NRG1), are located within the deleted region on chromosome 8p. A comparison of our patient with the cases described in the literature is presented, and we discuss the genotype-phenotype correlation in our patient. This is the first report of array-CGH analysis of an interstitial deletion at chromosome 8p.

Base Sequence↗

PubMed2005

SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly.

Very little is known about the molecular basis of autosomal recessive MR (ARMR) because in developed countries, small family sizes preclude mapping and identification of the relevant gene defects. We therefore chose to investigate genetic causes of ARMR in large consanguineous Iranian families. This study reports on a family with six mentally retarded members. Array-based homozygosity mapping and high-resolution microarray-based comparative genomic hybridization (array CGH) revealed a deletion of approximately 150-200 kb, encompassing the promoter and the first six exons of the MCPH1 gene, one out of four genes that have been previously implicated in ARMR with microcephaly. Reexamination of affected individuals revealed a high proportion of prematurely condensed chromosomes, which is a hallmark of this condition, but in spite of the severity of the mutation, all patients showed only borderline to mild microcephaly. Therefore the phenotypic spectrum of MCPH1 mutations may be wider than previously assumed, with ARMR being the only consistent clinical finding.

Adolescent↗

PubMed2005

CGHPRO -- a comprehensive data analysis tool for array CGH.

BACKGROUND: Array CGH (Comparative Genomic Hybridisation) is a molecular cytogenetic technique for the genome wide detection of chromosomal imbalances. It is based on the co-hybridisation of differentially labelled test and reference DNA onto arrays of genomic BAC clones, cDNAs or oligonucleotides, and after correction for various intervening variables, loss or gain in the test DNA can be indicated from spots showing aberrant signal intensity ratios. Now that this technique is no longer confined to highly specialized laboratories and is entering the realm of clinical application, there is a need for a user-friendly software package that facilitates estimates of DNA dosage from raw signal intensities obtained by array CGH experiments, and which does not depend on a sophisticated computational environment. RESULTS: We have developed a user-friendly and versatile tool for the normalization, visualization, breakpoint detection and comparative analysis of array-CGH data. CGHPRO is a stand-alone JAVA application that guides the user through the whole process of data analysis. The import option for image analysis data covers several data formats, but users can also customize their own data formats. Several graphical representation tools assist in the selection of the appropriate normalization method. Intensity ratios of each clone can be plotted in a size-dependent manner along the chromosome ideograms. The interactive graphical interface offers the chance to explore the characteristics of each clone, such as the involvement of the clones sequence in segmental duplications. Circular Binary Segmentation and unsupervised Hidden Markov Model algorithms facilitate objective detection of chromosomal breakpoints. The storage of all essential data in a back-end database allows the simultaneously comparative analysis of different cases. The various display options facilitate also the definition of shortest regions of overlap and simplify the identification of odd clones. CONCLUSION: CGHPRO is a comprehensive and easy-to-use data analysis tool for array CGH. Since all of its features are available offline, CGHPRO may be especially suitable in situations where protection of sensitive patient data is an issue. It is distributed under GNU GPL licence and runs on Linux and Windows.

Algorithms↗

PubMed2005

Chromosomal alterations in low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma as detected by comparative genomic hybridization.

OBJECTIVE: Endometrial stromal sarcomas (ESS) are very rare neoplasms constituting less than 0.5% of all malignant uterine tumors. The aim of the present study was to characterize the karyotypic abnormalities in these malignant mesenchymal tumors and to find specific chromosomal aberrations with eventual correlation with histologic grades. METHODS: Twelve cases of endometrial stromal sarcomas consisting of nine low-grade ESS and three undifferentiated endometrial sarcomas (UES) were investigated by comparative genomic hybridization (CGH). RESULTS: Ten of the twelve cases (83.3%) displayed chromosomal gains or losses. Deletions occurred more frequently than gains (63.4% versus 36.6%). In low-grade ESS, gains on 1, 6q, 9q, 16p, 19, 20q, 22q and losses on 2, 4q, 6, 7, 11q, 13q, 15q, 16q, 20p, X were detected. CGH with UES exhibited gains on 2q, 4q, 6q, 7p, 9q, 20q and losses on 3q, 10p, 14q. One low-grade ESS and one UES did not reveal any chromosomal aberration. CONCLUSIONS: Chromosomal aberrations in endometrial sarcomas are heterogeneous and do not clearly correlate with the histologic grades. There is no increased accumulation of aberrations from low-grade ESS to UES. Despite the karyotypic variations, chromosomal deletion on 7p was the most common finding (55.6%) in low-grade ESS and may play a role in tumor development and progression.

Chromosome Aberrations↗

PubMed2004

Analysis of chromosome-11 aberrations in pulmonary and gastrointestinal carcinoids: an array comparative genomic hybridization-based study.

Carcinoid tumors are a heterogeneous group of neoplasms arising from the diffuse neuroendocrine system. Pulmonary as well as gastrointestinal carcinoids can be separated into those with low malignant and intermediate malignant potential. DNA losses of chromosome arm 11q are commonly seen in pulmonary neuroendocrine tumors. Conflicting results have been published comparing atypical with typical lung carcinoids with respect to imbalances of chromosome 11. In the present study, a DNA microarray with genomic clones mapped to chromosome 11 was created, and array comparative genomic hybridization (CGH) with DNA derived from formalin-fixed, paraffin-embedded tissue was performed. We investigated 4 typical and 12 atypical carcinoids of the lung and, for comparison, 9 gastrointestinal carcinoids and 6 endocrine pancreatic tumors. We have shown that formalin-fixed, paraffin-derived DNA can be successfully used for array CGH. Alterations of 11q were rarely detected not only in typical carcinoids of the lung but also in gastrointestinal carcinoids. Atypical lung carcinoids that comprised extensive DNA losses also presented retained fragments in between these deleted regions. The array CGH data were consistent with the data of a previously published classical CGH study and were additionally confirmed using fluorescence in situ hybridization in the present investigation.

Adolescent↗

PubMed2004

Distinct sequences on 11q13.5 and 11q23-24 are frequently coamplified with MLL in complexly organized 11q amplicons in AML/MDS patients.

Amplification within chromosome arm 11q involving the mixed-lineage leukemia gene (MLL) locus is a rare but recurrent aberration in acute myeloid leukemia and myelodysplastic syndrome (AML/MDS). We and others have observed that 11q amplifications in most AML/MDS cases have not been restricted to the chromosomal region surrounding the MLL gene. Therefore, we implemented a strategy to characterize comprehensively 11q amplicons in a series of 13 AML/MDS patients with MLL amplification. Analysis of 4 of the 13 cases by restriction landmark genomic scanning in combination with virtual genome scan and by matrix-based comparative genomic hybridization demonstrated that the 11q amplicon in these four cases consisted of at least three discontinuous sequences derived from different regions of the long arm of chromosome 11. We defined a maximally 700-kb sequence around the MLL gene that was amplified in all cases. Apart from the core MLL amplicon, we detected two additional 11q regions that were coamplified. Using fluorescence in situ hybridization (FISH) analysis, we demonstrated that sequences in 11q13.5 and 11q23-24 were amplified in 8 of 13 and 10 of 12 AML/MDS cases, respectively. Both regions harbor a number of potentially oncogenic genes. In all 13 cases, either one or both of these regions were coamplified with the MLL amplicon. Thus, we demonstrated that 11q amplicons in AML/MDS patients display a complex organization and have provided evidence for coamplification of two additional regions on the long arm of chromosome 11 that may harbor candidate target genes.

Acute Disease↗

PubMed2004

Protein expression profiles in adenocarcinomas and squamous cell carcinomas of the lung generated using tissue microarrays.

With the appearance of defect-targeted therapies, the definition of tumour protein expression profiles has gained increasing importance. Two lung carcinoma tissue microarrays, one including 75 primary adenocarcinomas (ACs) and the other comprising 67 primary squamous cell carcinomas (SQCCs), were generated in the present study. On both arrays, each tumour was represented by an average of five cores. In addition, one punch of normal lung parenchyma adjacent to each tumour was included in the array. Immunohistochemical expression of 86 proteins was evaluated and the results were analysed by non-parametric tests, hierarchical clustering, and principal component analysis. In both tumour entities, parenchyma and tumours were clearly separated by hierarchical clustering. By the same statistical approach, it was possible to distinguish ACs from SQCCs with 98% accuracy and to distinguish parenchyma adjacent to ACs from that adjacent to SQCCs with 96% accuracy. It was also possible to separate ACs into three groups that significantly differed in survival. Cathepsin E and hsp105 were identified as previously unknown predictors of survival in lung AC. In summary, this study has shown that protein profiles are feasible tools for anticipating biological behaviour.

Adenocarcinoma↗

PubMed2004

Atypical goblet cell hyperplasia in congenital cystic adenomatoid malformation as a possible preneoplasia for pulmonary adenocarcinoma in childhood: A genetic analysis.

Congenital cystic adenomatoid malformation (CCAM) of the lung is a congenital lesion that is sometimes complicated by bronchioloalveolar adenocarcinoma (BAC). In some cases foci of atypical goblet cell hyperplasia (AGCH) can be found within the cysts. It has been proposed that CCAM and AGCH predispose to the development of BAC. The present study used comparative genomic hybridization (CGH) to screen 22 cases of CCAM (epithelium, surrounding normal lung tissue, and both preneoplastic and neoplastic lesions) for chromosomal imbalances. Of these 22 cases, 10 were CCAM type 1, 10 were type 2, and 2 were type 3. Of the 10 cases of CCAM type 1, 2 were associated with AGCH, 1 was associated with atypical adenomatous hyperplasia (AAH) and associated tubular adenocarcinoma (AC), and 2 were associated with BAC (1 mucinous and 1 predominantly nonmucinous). The present study also involved immunohistochemistry for interleukin (IL)-13, IL-4 receptor-alpha (IL-4r alpha), cytokines involved in the differentiation of goblet cells, and mucin 2 protein (Muc2). Chromosomal aberrations were not detected in the epithelium or the surrounding normal lung tissue, whereas varying aberrations were found in the neoplastic lesions. The most frequent genomic imbalances observed in both AGCH and the carcinomas were gains in chromosomes 2 and 4. Interestingly, a predominance of gains was also reported in AC of nonsmokers. Chromosomal aberrations in AGCHs arising in CCAMs support their preneoplastic status. Nuclear expression of IL-13, IL-4r alpha, and Muc2 was detected in AGCH, whereas a cytoplasmic and nuclear reaction was seen in normal epithelium. This likely reflects an association with goblet cell differentiation, but it also drives proliferation in AGCH.

Adenocarcinoma↗

PubMed2003

Bronchiolar columnar cell dysplasia--genetic analysis of a novel preneoplastic lesion of peripheral lung.

Atypical adenomatous hyperplasia is the only known precursor lesion of lung adenocarcinomas (ACs) so far. Here, we describe a new dysplastic lesion in the bronchioles of peripheral lung for which we propose the name bronchiolar columnar cell dysplasia (BCCD). Eight of fourteen BCCDs were successfully analyzed by means of comparative genomic hybridization (CGH). The average number of chromosomal aberrations was 2.6 in BCCD and 14.7 in concomitant AC. Among the aberrations were losses of 3p, 9, 13, 14 and gains of 1q, 17, 19q and 20q. Summarizing our data from morphological and genetic analysis, we conclude that BCCD is a preneoplasia of the bronchiolar epithelium and most probably represents an additional precursor lesion of lung adenocarcinomas.

Adenocarcinoma↗

PubMed2002

The position of pulmonary carcinoids within the spectrum of neuroendocrine tumors of the lung and other tissues.

Bronchopulmonary carcinoids comprise 25% of all human carcinoids. The World Health Organization divides them into typical (TC) and atypical forms (ATC), distinguished by differences in mitotic counts lower or higher than 2/2 mm(2) and the presence or absence of necrosis. The reproducibility of this classification with respect to the borderline cases with 1-2 mitotic counts/2 mm(2) has been questioned. We have analyzed 15 TCs and 20 ATCs by comparative genomic hybridization. Loss of 11q was the most frequent aberration in ATC (55%), but was observed only twice in TC (13%). Deletions of 3p were seen only in ATC (25%). Meta-analysis of our data and data from 218 neuroendocrine tumors and 50 non-small-cell lung carcinomas obtained from the literature revealed differences between carcinoids and carcinomas. For example, loss of 5q is frequent in lung carcinomas (75%) but is rarely seen in carcinoids (1.4%). Deletions of 11q are less frequent in neuroendocrine lung carcinomas than in ATC. To obtain a more objective survey of the relationship of pulmonary carcinoids to other neuroendocrine tumors and lung carcinomas, we created a hierarchical clustering dendrogram. This statistical approach resulted in a clear separation of carcinoids and carcinomas, which both built up different clusters. In summary, this study demonstrates the benefit of chromosomal analysis supplementary to the diagnosis of bronchopulmonary carcinoids. We also identified the feasibility of hierarchical clustering to get some clues on relationship between different tumor types. This study further argues against a transition of ATC to high-grade neuroendocrine lung carcinoma.

Allelic Imbalance↗