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R D Wegner

Publications and source records attributed to R D Wegner.

At least 19 recordsLinked to original sources
PubMed2003

Epignathus: always a simple teratoma? Report of an exceptional case with two additional fetiforme bodies.

We report on a case of a fetal epignathus combined with two fetus-like structures resembling acardius acranius. The anomaly was detected at 23 weeks of gestation and led to termination of pregnancy at 24 weeks. This is the first description of epignathus with parasitic fetuses detected prenatally. It shows that the boundary between fetal teratoma and multiple pregnancy in special cases may be difficult to define.

Abnormalities, Multiple↗
PubMed2001

Functional hemizygosity of PAFAH1B3 due to a PAFAH1B3-CLK2 fusion gene in a female with mental retardation, ataxia and atrophy of the brain.

We report on the molecular characterization of a translocation t(1;19)(q21.3;q13.2) in a female with mental retardation, ataxia and atrophy of the brain. Sequence analysis of the breakpoints revealed an ALU:-repeat-mediated mechanism of recombination that led to truncation of two genes: the kinase CLK2 and PAFAH1B3, the gene product of which interacts with LIS1 as part of a heterotrimeric G protein complex PAF-AH1B. In addition, two reciprocal fusion genes are present. One expressed fusion gene encodes the first 136 amino acids of PAFAH1B3 followed by the complete CLK2 protein. Truncated PAFAH1B3 protein lost its potential to interact with LIS1 whereas CLK2 activity was conserved within the fusion protein. These data emphasize the importance of PAF-AH1B in brain development and functioning and demonstrate the first fusion gene apparently not associated with cancer.

Abnormalities, Multiple↗
PubMed2001

Prenatal diagnosis of familial absent pulmonary valve syndrome: case report and review of the literature.

We report on a case of absent pulmonary valve syndrome in a woman with a history of one healthy child and one child with tetralogy of Fallot with absent pulmonary valve. The diagnosis was missed at the first ultrasound examination performed at 13 + 5 weeks of gestation and correctly diagnosed at 21 + 5 weeks. Re-evaluation of the ultrasound examination recorded at 13 + 5 weeks exhibited severe insufficiency of the pulmonary valve at this time. However, neither dilatation of the right and left pulmonary arteries nor asymmetry of the ventricles were present at that time. The pregnancy was terminated at 22 + 1 weeks of gestation when autopsy confirmed the diagnosis of absent pulmonary valve syndrome. Karyotyping of the fetus after termination of pregnancy revealed normal chromosomes. Echocardiography of the parents and the healthy sibling revealed normal results.

Adult↗
PubMed2001

High frequency of spontaneous translocations revealed by FISH in cells from patients with the cancer-prone syndromes ataxia telangiectasia and Nijmegen breakage syndrome.

The application of fluorescence in situ hybridization (FISH) using whole-chromosome paints (WCPs) is proving to be a very powerful technique for revealing chromosomal instability that, for the most part, has gone undetected by conventional cytogenetic analysis. We have analyzed the frequency of translocations in lymphocytes and lymphoblastoid cell lines from ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) homozygotes and heterozygotes using a three-color chromosome-painting technique (WCP 1, 2, 4). With this assay we were able to detect an increased frequency of spontaneous translocations in AT homozygotes (median, 18.47 +/- 10.82 translocations per 1,000 metaphase cells; 10 patients) and AT heterozygotes (median, 7.87 +/- 3.15 translocations per 1,000 cells; 7 patients), in comparison to controls (median, 2.26 +/- 1.75 translocations per 1,000 cells; 10 controls). Analysis of NBS homozygotes (median, 19.05 +/- 11.27 translocations per 1,000 cells; 5 patients) and NBS heterozygotes (median, 6.93 +/- 3.04 translocations per 1,000 cells; 6 patients) also showed an increased frequency of translocations in these patients compared to controls. The presence of such hitherto undetected chromosomal aberrations corroborate previous findings of spontaneous chromosomal instability in AT and NBS patients, as manifested by an increased rate of open breaks and rearrangements involving chromosomes 7 and 14. Moreover, we show that the degree of genomic instability in AT and NBS patients is even higher than previously established and that some AT and NBS heterozygotes evidence spontaneous chromosomal instability as well. These increased levels of nonspecific translocations could be an important risk factor for the development of malignancies in homozygotes and heterozygotes for ATM or NBS1 gene mutations.

Ataxia Telangiectasia↗
PubMed2001

Comparative genomic hybridization based strategy for the analysis of different chromosome imbalances detected in conventional cytogenetic diagnostics.

Today, conventional cytogenetics (CC) is the main technique in routine genetic diagnostics for the analysis of genotype/phenotype correlations. Additionally, fluorescence in situ hybridization (FISH) has proven to be useful for the characterization of structural chromosome aberrations found in conventional cytogenetics. Comparative genomic hybridization (CGH) is a molecular cytogenetic FISH approach developed for the detection of genomic imbalances with cytogenetic resolution. CGH allows the genome-wide assessment of relative DNA copy number changes using extracted specimen DNA as a probe. We investigated the capacity of CGH in cases referred for conventional cytogenetic diagnostics for the detection of chromosome imbalances. Three different groups of conspicuous karyotypes after CC (intrachromosomal rearrangements, interchromosomal rearrangements, and additional marker chromosomes) in pre- and postnatal diagnostic cases were surveyed by CGH to characterize the underlying imbalances of chromosome segments. All together, we investigated more than 100 cases by CGH and validated the results with other molecular cytogenetic methods. Here we present eight of these cases in order to demonstrate our CGH based strategy to analyze chromosomal de novo rearrangements. CGH provided additional cytogenetic information to complement conventional cytogenetic investigations. Additionally, CGH refined the description of the aberrant chromosome segments allowing us to further characterize the underlying mechanisms involved.

Chromosome Aberrations↗
PubMed2000

Clinical variability of Larsen syndrome: diagnosis in a father after sonographic detection of a severely affected fetus.

Larsen syndrome shows a broad spectrum of clinical manifestation ranging from a lethal form of the disorder to a mild clinical expression with absence of major diagnostic features. Here we show that even intrafamilial manifestation may vary extremely to the point that Larsen syndrome in a father has been diagnosed only by typical sonographic features in an affected fetus.

Adult↗
PubMed1999

The Fanconi anemia group E gene, FANCE, maps to chromosome 6p.

Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive disease with bone marrow failure and predisposition to cancer as major features, often accompanied by developmental anomalies. The cells of patients with FA are hypersensitive to DNA cross-linking agents in terms of cell survival and chromosomal breakage. Of the eight complementation groups (FA-A to FA-H) distinguished thus far by cell fusion studies, the genes for three-FANCA, FANCC, and FANCG-have been identified, and the FANCD gene has been localized to chromosome 3p22-26. We report here the use of homozygosity mapping and genetic linkage analysis to map a fifth distinct genetic locus for FA. DNA from three families was assigned to group FA-E by cell fusion and complementation analysis and was then used to localize the FANCE gene to chromosome 6p21-22 in an 18.2-cM region flanked by markers D6S422 and D6S1610. This study shows that data from even a small number of families can be successfully used to map a gene for a genetically heterogeneous disorder.

Cell Fusion↗
PubMed1999

Characterization of ATM gene mutations in 66 ataxia telangiectasia families.

Ataxia telangiectasia (AT) is an autosomal recessive disease characterized by neurological and immunological symptoms, radiosensitivity and cancer predisposition. The gene mutated in AT, designated the ATM gene, encodes a large protein kinase with a PI-3 kinase-related domain. In this study, we investigated the mutational spectrum of the ATM gene in a cohort of AT patients living in Germany. We amplified and sequenced all 66 exons and the flanking untranslated regions from genomic DNA of 66 unrelated AT patients. We identified 46 different ATM mutations and 26 sequence polymorphisms and variants scattered throughout the gene. A total of 34 mutations have not been described in other populations. Seven mutations occurred in more than one family, but none of these accounted for more than five alleles in our patient group. The majority of the mutations were truncating, confirming that the absence of full-length ATM protein is the most common molecular basis of AT. Transcript analyses demonstrated single exon skipping as the consequence of most splice site substitutions, but a more complex pattern was observed for two mutations. Immunoblot studies of cell lines carrying ATM missense substitutions or in-frame deletions detected residual ATM protein in four cases. One of these mutations, a valine deletion proximal to the kinase domain, resulted in ATM protein levels >20% of normal in an AT lymphoblastoid cell line. In summary, our results survey and characterize a plethora of variations in the ATM gene identified by exon scanning sequencing and indicate a high diversity of mutations giving rise to AT in a non-isolated population.

Ataxia Telangiectasia↗
PubMed1998

Characterization of cell cycle checkpoint responses after ionizing radiation in Nijmegen breakage syndrome cells.

Nijmegen breakage syndrome (NBS), which in the past also has been classified as a variant of ataxia telangiectasia (AT), is characterized by cancer proneness and extreme sensitivity to ionizing radiation. We investigated the DNA damage responses of four independent primary NBS fibroblast cell lines. Following a low dose of ionizing radiation, p53 is mostly induced with slower kinetics and shows more transient induction in NBS fibroblasts. Nonetheless, this damage-induced protein appears biologically functional: unsynchronized and synchronized NBS cells show a G1 arrest after ionizing radiation as determined by bivariate flow cytometry. Neither an AT cell line nor a NBS cell line transformed with human papillomavirus genes E6 and E7 shows a G1 arrest. Furthermore, NBS cells show a normal G2 block, unlike that shown for AT cells. These data provide a cellular distinction between NBS and AT, thereby clearly separating the NBS from the AT syndrome.

Abnormalities, Multiple↗
PubMed1997

Linkage studies exclude the AT-V gene(s) from the translocation breakpoints in an AT-V patient.

An 8-year-old girl with severe microcephaly of prenatal onset, borderline intelligence, defects of skin pigmentation, deficiency of both humoral and cellular immunity, a normal serum alpha-fetoprotein level and hypersensitivity to ionizing irradiation is described. Spontaneous chromosomal breakage in lymphocytes together with the clinical presentation led to the diagnosis of ataxia telangiectasia variant (AT-V). In addition, the patient carried a constitutional translocation of paternal origin: 46,XX,t(3;7)(q12;q31.3) pat. In subsequent linkage and haplotype studies in 12 AT-V families with microsatellite markers from each of the translocation breakpoint regions, we could clearly exclude the localization of an AT-V gene to these regions.

Ataxia Telangiectasia↗
PubMed1997

The gene for the ataxia-telangiectasia variant, Nijmegen breakage syndrome, maps to a 1-cM interval on chromosome 8q21.

Nijmegen breakage syndrome (NBS; Seemanová II syndrome) and Berlin breakage syndrome (BBS), also known as ataxia-telangiectasia variants, are two clinically indistinguishable autosomal recessive familial cancer syndromes that share with ataxia-telangiectasia similar cellular, immunological, and chromosomal but not clinical findings. Classification in NBS and BBS was based on complementation of their hypersensitivity to ionizing radiation in cell-fusion experiments. Recent investigations have questioned the former classification into two different disease entities, suggesting that NBS/BBS is caused by mutations in a single radiosensitivity gene. We now have performed a whole-genome screen in 14 NBS/BBS families and have localized the gene for NBS/BBS to a 1-cM interval on chromosome 8q21, between markers D8S271 and D8S270, with a peak LOD score of 6.86 at D8S1811. This marker also shows strong allelic association to both Slavic NBS and German BBS patients, suggesting the existence of one major mutation of Slavic origin. Since the same allele is seen in both former complementation groups, genetic homogeneity of NBS/BBS can be considered as proved.

Alleles↗
PubMed1997

Prenatal diagnosis in Germany.

Prenatal diagnosis (PND) in Germany is well established. A wide spectrum of sonographic, cytogenetic, molecular and biochemical investigations can be chosen by pregnant women. While sonographic examinations are offered to all pregnant women, the methods requiring invasive procedures are performed predominantly when there is a higher risk than in the general population. However, PND is also performed on request by the mother in the absence of an increased risk. Pretest genetic counselling is recommended before invasive techniques. PND is performed in public as well as in private settings. Guidelines are in effect for specialisation of gynaecologists and human geneticists. Quality assessment for cytogenetic and molecular laboratories is performed on a voluntary basis. Since October 1995, termination of pregnancies is regulated by a new law.

Female↗
PubMed1996

Partial trisomy/monosomy 6q in fetal cells and CVS long-term culture not present in CVS short-term culture.

A cytogenetic discrepancy in chorionic villi with implications for prenatal diagnosis is described. Chromosome analysis revealed a normal karyotype in banded metaphases from short-term culture and a chromosome count of 46 in cells of the long-term culture. After the birth of a malformed infant, a structurally aberrant chromosome 6 was found in lymphocytes and skin fibroblasts. Re-analysis of chorionic villi confirmed the result from short-term culture but disclosed the presence of the structural aberration in cells of the long-term culture. This type of inconsistency is reported for the first time and stresses the importance of a numerical and structural analysis of both short-term and long-term culture. The application of three techniques, chromosome banding, comparative genomic hybridization (CGH), and fluorescence in situ hybridization (FISH) analysis, was essential to prove that the derivative chromosome carried a combined partial trisomy/monosomy for 6q. The findings are discussed with respect to the origin of the structural aberration and to the consequences for prenatal diagnosis on chorionic villi and genetic counselling.

Adult↗
PubMed1996

Predominance of null mutations in ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a Pl 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the Pl 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.

Amino Acid Sequence↗
PubMed1996

Fanconi anemia complementation group E: clinical and cytogenetic data of the first patient.

The clinical and cytogenetic data of the first patient proven to belong to the fifth Fanconi anemia complementation group are described. The Turkish boy presented with psychomotoric retardation, growth retardation, retarded bone age, brachycephaly, hypotelorism, epicanthus, syndactyly, brachydactyly, renal dystopia, and cryptorchism. In addition, an asymmetrical skeletal anomaly was seen with a double distal phalanx of the left thumb and hypoplasia of the right thumb. Typical hematological features of the disorder developed, at the age of 2.5 years, about 1 year after diagnosis. Cytogenetic studies confirmed the clinical diagnosis and revealed a spontaneous chromosomal instability and hypersensitivity to the cross-linking agents diepoxybutane and Trenimon. The findings in the patient, who is considered to be the standard for the fifth Fanconi anemia complementation group, are compared with data reported for other patients affected with Fanconi anemia.

Cell Line, Transformed↗
PubMed1995

Classification of Fanconi anemia patients by complementation analysis: evidence for a fifth genetic subtype.

Fanconi anemia (FA) is an autosomal recessive disease with diverse clinical symptoms, life-threatening progressive panmyelopathy, and cellular hypersensitivity to cross-linking agents. Currently, 4 genetic subtypes or complementation groups (FA-A through FA-D) have been distinguished among 7 unrelated FA patients. We report the use of genetically marked FA lymphoblastoid cell lines representing each of the 4 presently known complementation groups to classify 13 unrelated FA patients through cell fusion and complementation analysis. Twelve cell lines failed to complement cross-linker sensitivity in fusion hybrids with only 1 of the 4 reference cell lines and could thus be unambiguously classified as FA-A (7 patients), FA-C (4 patients), or FA-D (1 patient). One cell line complemented all 4 reference cell lines and therefore represents a new complementation group, designated FA-E. These results imply that at least 5 genes appear to be involved in a pathway that, when defective, causes bone marrow failure in FA patients.

Cell Fusion↗
PubMed1995

DNA, FISH and complementation studies in ICF syndrome: DNA hypomethylation of repetitive and single copy loci and evidence for a trans acting factor.

ICF syndrome (ICFS) is a rare immunodeficiency disorder characterized by instability of the pericentromeric heterochromatin predominantly of chromosomes 1 and 16. DNA methylation studies in two unrelated ICFS patients provide further evidence for a marked hypomethylation of satellite 2 DNA. The ICFS-specific disturbances of chromatin structure take place within the satellite 2 DNA regions, as demonstrated by fluorescence in situ hybridization analysis. Moreover, methylation studies of genomic imprinted loci D15S63, D15S9, and H19 have revealed hypomethylation to different degrees in both patients; this provides evidence for hypomethylation at autosomal single copy loci in ICFS. Cell fusion experiments have revealed a distinct reduction of chromosomal abnormalities in ICFS cells after fusion with normal cells, suggesting that the abnormalities are caused by the loss of function of an as yet unknown trans acting factor. Although it is now clear that wide-spread DNA hypomethylation is a characteristic feature of ICFS, neither the cause and mechanism of hypomethylation nor their relationship to the clinical symptoms is known. We speculate that a phenotypic effect might result from tissue-dependent abnormal gene expression and/or from a possible structural disturbance of DNA domains, which, with respect to the immunodeficiency, partially prevents the normal somatic recombinations in immunologically active cells.

Cell Line, Transformed↗