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D J Bunyan

Publications and source records attributed to D J Bunyan.

10 recordsLinked to original sources
PubMed2006

Epimutation of the TNDM locus and the Beckwith-Wiedemann syndrome centromeric locus in individuals with transient neonatal diabetes mellitus.

Transient neonatal diabetes mellitus (TNDM) is characterised by intra-uterine growth retardation, while Beckwith-Wiedemann syndrome (BWS) is a clinically heterogeneous overgrowth syndrome. Both TNDM and BWS may be caused by aberrant loss of methylation (LOM) at imprinted loci on chromosomes 6q24 and 11p15.5 respectively. Here we describe two patients with a clinical diagnosis of TNDM caused by LOM at the maternally methylated imprinted domain on 6q24; in addition, these patients had LOM at the centromeric differentially methylated region of 11p15.5. This shows that imprinting anomalies can affect more than one imprinted locus and may alter the clinical presentation of imprinted disease.

Beckwith-Wiedemann Syndrome↗
PubMed2004

Dosage analysis of cancer predisposition genes by multiplex ligation-dependent probe amplification.

Multiplex ligation-dependent probe amplification (MLPA) is a recently described method for detecting gross deletions or duplications of DNA sequences, aberrations which are commonly overlooked by standard diagnostic analysis. To determine the incidence of copy number variants in cancer predisposition genes from families in the Wessex region, we have analysed the hMLH1 and hMSH2 genes in patients with hereditary nonpolyposis colorectal cancer (HNPCC), BRCA1 and BRCA2 in families with hereditary breast/ovarian cancer (BRCA) and APC in patients with familial adenomatous polyposis coli (FAP). Hereditary nonpolyposis colorectal cancer (n=162) and FAP (n=74) probands were fully screened for small mutations, and cases for which no causative abnormality were found (HNPCC, n=122; FAP, n=24) were screened by MLPA. Complete or partial gene deletions were identified in seven cases for hMSH2 (5.7% of mutation-negative HNPCC; 4.3% of all HNPCC), no cases for hMLH1 and six cases for APC (25% of mutation negative FAP; 8% of all FAP). For BRCA1 and BRCA2, a partial mutation screen was performed and 136 mutation-negative cases were selected for MLPA. Five deletions and one duplication were found for BRCA1 (4.4% of mutation-negative BRCA cases) and one deletion for BRCA2 (0.7% of mutation-negative BRCA cases). Cost analysis indicates it is marginally more cost effective to perform MLPA prior to point mutation screening, but the main advantage gained by prescreening is a greatly reduced reporting time for the patients who are positive. These data demonstrate that dosage analysis is an essential component of genetic screening for cancer predisposition genes.

Adenomatous Polyposis Coli↗
PubMed2001

Minisatellite instability is found in colorectal tumours with mismatch repair deficiency.

Microsatellite instability (MSI) in colorectal tumours is demonstrated by PCR amplification of several different microsatellite loci. Minisatellites, which are repeats of longer sequences also found throughout the genome, may also be affected by tumorigenesis. Certain minisatellite alleles contain 2 types of similar repeat unit that are randomly interspersed. The interspersion pattern can be analysed by mapping variant repeat units along an amplified allele, minisatellite variant repeat unit mapping PCR (MVR-PCR). We have applied microsatellite analysis with 10 markers and MVR-PCR for locus D7S21 to 33 cases of colorectal neoplasia, 27 sporadic and 6 from patients suspected of having hereditary non-polyposis colorectal cancer (HNPCC). Of the 27 sporadic cases, 3 were MSI-high on microsatellite analysis and one MSI-low. Instability with MVR-PCR was observed, but only in the MSI-high cases. Four of the HNPCC patients had mismatch repair (MMR) gene mutations in either hMLH1 or hMSH2. All 4 had DNA instability by MVR-PCR, but only two of these had MSI (one high, one low). The other 2 of the 6 patients with suspected HNPCC were negative to mutation analysis. One had features strongly suggestive of HNPCC and was unstable by both microsatellite analysis (MSI-high) and by MVR-PCR. The other tumour, from an Amsterdam criteria positive kindred, did not demonstrate instability by any technique. Thus MVR-PCR detects DNA instability in MSI-high sporadic tumours and in those associated with HNPCC where MSI is observed. Further, in some MMR mutation positive cases MSI was not seen but instability was observed by MVR-PCR. MVR-PCR may be a valuable adjunct to the detection of MMR deficiency in colorectal tumours and it may allow new insights into the nature of DNA instability in this condition.

Aged↗
PubMed2000

Cytogenetically cryptic AML1-ETO and CBF beta-MYH11 gene rearrangements: incidence in 412 cases of acute myeloid leukaemia.

The rearrangements t(8;21)(q22;22) and inv(16)(p13q22) are two of the most frequently seen in acute myeloid leukaemia (AML), accounting for 8% and 4% of cases respectively. Detection of these abnormalities is important for disease management as both are associated with good responses to conventional chemotherapy and prolonged disease-free survival. Recent reports using reverse transcriptase polymerase chain reaction (RT-PCR) suggest that significant proportions of AML cases without a visible t(8;21) or inv(16) show expression of an abnormal fusion gene transcript and, consequently, they could not be detected using conventional cytogenetic analysis alone. We present here a four centre study involving 412 cases of AML screened using both standard cytogenetics and RT-PCR for AML1-ETO and CBF beta-MYH11. We detected a cytogenetic t(8;21) in 31 out of 412 (7.5%) cases and an inv(16) or t(16;16) variant in 27 out of 412 (6.6%) cases. RT-PCR detected only two cases (0.5%) of cryptic t(8;21) and no instances of cryptic inv(16). Both cryptic t(8;21) cases had the classic M2 FAB morphology for this type of disease. Our data concur with the established FAB type distribution of the rearrangements and indicate that cryptic t(8;21) and inv(16) may be much less frequent than reported elsewhere.

Acute Disease↗
PubMed1997

A small intraexonic deletion within the dystrophin gene suggests a possible mechanism of mutagenesis.

A case of Duchenne muscular dystrophy is described with an unusual mutation consisting of a 17-bp deletion within exon 47 of the dystrophin gene. The sequences on either side of the deletion have a high degree of intrastrand base complementarity. It is hypothesised that the mechanism generating the deletion may have been the formation of hairpin loop structure in a single strand of DNA followed by enzymatic degradation at unpaired regions within the loop.

Algorithms↗
PubMed1995

Fluorescence in situ hybridisation studies provide evidence for somatic mosaicism in de novo dystrophin gene deletions.

The fluorescence in situ hybridisation (FISH) technique was tested for its ability to detect somatic mosaicism in mothers of isolated deletion cases of Duchenne/Becker muscular dystrophy. A control female with known germline and somatic mosaicism was examined, and both the normal cell line and the carrier cell line were detected. Subsequent FISH analysis of three other mothers of boys with apparent de novo dystrophin gene deletions revealed a second patient with a high level of somatic mosaicism, suggesting that a proportion of de novo dystrophin gene deletions occur as mitotic errors early in development rather than as meiotic errors during gametogenesis.

Cells, Cultured↗
PubMed1995

Genotype-phenotype correlations of new causative APC gene mutations in patients with familial adenomatous polyposis.

Nine new causative mutations and seven previously characterised mutations of the APC gene of patients with familial adenomatous polyposis (FAP) were analysed for any genotype-phenotype correlations. The only clear genotype-phenotype correlation found was between the position of the mutation site and the presence or absence of congenital hypertrophy of the retinal pigment epithelium (CHRPE). A more distal mutation site was associated with an earlier age of onset of symptoms and a larger number of colonic polyps, but a notable amount of intrafamilial variation was observed.

Adenomatous Polyposis Coli↗
PubMed1994

Germline and somatic mosaicism in a female carrier of Duchenne muscular dystrophy.

The family of a male with Duchenne muscular dystrophy (DMD) and a deletion within the dystrophin gene has been studied. Polymerase chain reaction analysis of ectopic mRNA from peripheral blood T+B lymphocytes and the use of (CA)n repeat polymorphisms in and around the deleted region showed the proband's mother to be both a germline mosaic and a somatic mosaic for the deletion seen in her son. The mutation therefore occurred as a mitotic event early in embryogenesis.

Child, Preschool↗