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Biomedical subjects

J M Connor

Publications and source records attributed to J M Connor.

At least 37 records · Page 2Linked to original sources
PubMed1998

Mosaic supernumerary ring chromosome 19 identified by comparative genomic hybridisation.

We report the use of comparative genomic hybridisation (CGH) to define the origin of a supernumerary ring chromosome which conventional cytogenetic banding and fluorescence in situ hybridisation (FISH) methods had failed to identify. Targeted FISH using whole chromosome 19 library arm and site specific probes then confirmed the CGH results. This study shows the feasibility of using CGH for the identification of supernumerary marker chromosomes, even in fewer than 50% of cells, where no clinical or cytogenetic clues are present.

Aged↗
PubMed1998

1.4 Mb candidate gene region for X linked dyskeratosis congenita defined by combined haplotype and X chromosome inactivation analysis.

Dyskeratosis congenita (DC) is a rare inherited disorder characterised by the early onset of reticulate skin pigmentation, nail dystrophy, and mucosal leucoplakia. In over 80% of cases bone marrow failure develops and this is the main cause of early mortality. The DC1 gene responsible for the X linked form (MIM 305000) of dyskeratosis congenita has been mapped to Xq28. In order to narrow the candidate gene region, genetic linkage analysis was performed in eight X linked pedigrees using a set of markers spanning Xq28. A maximum lod score of 5.31 with no recombinations was achieved with marker DXS1073. Two recombination events were identified; one of these uses X chromosome inactivation pattern analysis to determine carrier status and haplotype analysis to fine map the recombination breakpoint. The fine mapping of these recombination events has enabled the candidate gene region for X linked dyskeratosis congenita to be defined as the 1.4 Mb interval between Xq3274 and DXS1108.

Child↗
PubMed1998

A new strategy for cryptic telomeric translocation screening in patients with idiopathic mental retardation.

Cryptic unbalanced chromosome rearrangements in the telomeric bands of human chromosomes constitute a significant cause of "idiopathic" mental retardation. Here, we have described a new strategy based upon comparative genomic hybridisation (CGH) to screen for these abnormalities. A modified CGH analysis showed three unbalanced cryptic rearrangements in five patients from three families. These chromosome abnormalities and their balanced forms in the relatives were then confirmed by fluorescence in situ hybridisation (FISH). This study describes a new approach to the diagnosis of cryptic translocations between the G band negative ends of chromosomes and confirms the significant contribution of cryptic telomeric rearrangements to idiopathic mental retardation.

Child, Preschool↗
PubMed1998

Prediction of liability to orofacial clefting using genetic and craniofacial data from parents.

BACKGROUND: Cleft lip with or without cleft palate (CL(P)) and isolated cleft palate (CP) are separate clinical entities and for both polygenic multifactorial aetiology has been proposed. Parents of children with orofacial clefting have been shown to have distinctive differences in their facial shape when compared to matched controls. OBJECTIVE: To test the hypothesis that genetic and morphometric factors predispose to orofacial clefting and that these markers differ for CL(P) and CP. Methods-Polymorphisms at the transforming growth factor alpha (TGFalpha) locus in 83 parents of children with nonsyndromic orofacial clefts were analysed, and their craniofacial morphology was assessed using lateral cephalometry. RESULTS: Parents of children with CL(P) and CP showed an increased frequency of the TGFalpha/TaqI C2 allele (RR=4.10, p=0.009) relative to the comparison group. Also the TGFalpha/BamHI A1 allele was more prevalent in the CP parents. MULTIVARIATE STATISTICAL ANALYSIS: Using stepwise logistic regression analysis the TGFalpha/TaqI C2 polymorphism provides the best model for liability to orofacial clefting. To determine the type of clefting a model involving interaction between the parental TGFalpha/BamHI and TGFalpha/RsaI genotypes showed the best fit. Using genotype only to predict the clefting defect in the children according to parental genotype, 68.3% could be correctly classified. By adding information on craniofacial measurements in the parents, 76% of CP and 94% of CL(P) parents could be correctly classified. CONCLUSIONS: This study provides a model for prediction of liability to orofacial clefting. These findings suggest that different molecular aberrations at the TGFalpha locus may modify the risk for CP and CL(P).

Alleles↗
PubMed1998

Human alpha-adducin gene, blood pressure, and sodium metabolism.

The adducin genes contribute significantly to population variation in rat blood pressure and cell membrane sodium transport. The 460Trp mutation of the human alpha-adducin gene has been associated with hypertension, in particular hypertension sensitive to sodium restriction. We studied the relationship between the 460Trp mutation and population variation in blood pressure and sodium metabolism. From 603 Scottish families, we selected 151 offspring and 224 parents with blood pressures in either the upper (high) or bottom (low) 30% of the population distribution and measured the 460Trp mutation using allele-specific hybridization. In offspring, we also measured exchangeable sodium, plasma volume, and total body water. Plasma levels of components of the renin-angiotensin system, atrial natriuretic peptide, and cellular sodium and transmembrane sodium efflux were also estimated. The overall frequency of the 460Trp mutation was 27.1%. In offspring and parent groups, we found no difference in the genotype or allele frequencies of the 460Trp mutation between subjects with high or low blood pressure. There was no overall association between the alpha-adducin genotypes and blood pressure variation. In offspring, the 460Trp mutation was not associated with any significant differences in body fluid volumes or exchangeable sodium; levels of plasma renin, angiotensin II, aldosterone, or atrial natriuretic peptide; intracellular sodium; or ouabain-sensitive transmembrane sodium efflux. These findings suggest that in our Scottish population, the alpha-adducin 460Trp polymorphism is not related to blood pressure and does not affect whole body or cellular sodium metabolism.

Adolescent↗
PubMed1997

Acute intermittent porphyria: the in vitro expression of mutant hydroxymethylbilane synthase.

Acute intermittent porphyria (AIP) is an inborn error of haem biosynthesis caused by a variety of mutations in the gene coding for hydroxymethylbilane synthase (HMB-S). The entire coding sequence of this gene, from each of three South African AIP patients, was therefore screened for mutations using chemical cleavage mismatch (CCM) analysis and any changes detected characterized by DNA sequencing. Three single base changes were identified; a G77 to A in exon 3, a C346 to T in exon 8 and a G518 to A in exon 10. These missense mutations, previously reported to be present in other populations, are known to be responsible for the structurally deleterious amino acid replacements R26H, R116W and R173Q, respectively. The in vitro expression of the enzymes containing these mutations and the subsequent measurement of their specific activities revealed a reduction to approximately 4% of normal activity.

Escherichia coli↗
PubMed1997

Evidence for a familial pregnancy-induced hypertension locus in the eNOS-gene region.

Pregnancy-induced hypertension may be regarded as a manifestation of endothelial-cell dysfunction. The role of the eNOS gene in the development of a familial pregnancy-induced hypertension was evaluated by analysis of linkage among affected sisters and in multiplex families (n = 50). Markers from a 4-cM region encoding the eNOS gene showed distortion from the expected allele sharing among affected sisters (P = .001-.05), and the statistic obtained from the multilocus application of the affected-pedigree-member method also showed distortion (T[f(P)=sqrt(P)] = 3.53; P < .001). A LOD score of 3.36 was obtained for D7S505 when a best-fitting model derived from genetic epidemiological data was used, and LOD scores of 2.54-4.03 were obtained when various other genetic models were used. Estimates of recombination rate, rather than maximum LOD-score values, were affected by changes in the genetic parameters. The transmission-disequilibrium test, a model-free estimate of linkage, showed strongest association and linkage with a microsatellite within intron 13 of the eNOS gene (P = .005). These results support the localization of a familial pregnancy-induced hypertension-susceptibility locus in the region of chromosome 7q36 encoding the eNOS gene.

Adult↗
PubMed1997

Screening for Down's syndrome: changes in marker levels and detection rates between first and second trimesters.

OBJECTIVE: To monitor changes with gestation in levels of alpha-fetoprotein (AFP), free beta human chorionic gonadotrophin (F beta hCG) and pregnancy associated plasma protein-A (PAPP-A) in Down's syndrome pregnancies and to compare risks estimated in the first trimester with those obtained by routine screening in the second trimester for the same pregnancies. DESIGN: In each of 47 Down's syndrome pregnancies two maternal serum samples were obtained, one in the first trimester and one in the second trimester. Comparison of marker levels with 10,600 first trimester controls and a smaller sample of second trimester controls allowed case identification criteria based on optimum marker combinations to be developed and compared directly between trimesters. SETTING: Biochemical genetics laboratory. RESULTS: F beta hCG was an effective marker of Down's syndrome in both the first and second trimesters. PAPP-A levels were significantly reduced in trisomy 21 pregnancies in the first trimester only. Using a population model, these two markers in combination with maternal age gave an overall detection rate of 55% for a 5% false positive rate in the first trimester. For the paired first and second trimester samples, three of six cases classified as low risk by routine second trimester screening were classified as high risk by the first trimester screening protocol of F beta hCG/PAPP-A/maternal age. However, fifteen cases identified as high risk by routine second trimester screening were classified as low risk in the first trimester, a net loss in detection of 12 cases by first trimester screening. CONCLUSION: The data suggest that first trimester detection rates for Down's syndrome using a combination of F beta hCG and PAPP-A may vary with gestation and will be lower than those currently obtained by routine second trimester screening with AFP/hCG.

Biomarkers↗
PubMed1997

Biochemical markers of trisomy 21 and the pathophysiology of Down's syndrome pregnancies.

Using biochemical and immunocytochemical methods, we have investigated endogenous levels of various markers in tissues obtained from 67 Down's syndrome pregnancies after therapeutic abortion in the second trimester and in corresponding tissues from unaffected abortuses. Alpha-fetoprotein (AFP), intact and free beta human chorionic gonadotrophin (hCG), pregnancy-specific beta-1 glycoprotein (SP-1), placental alkaline phosphatase (PALP), pregnancy-associated plasma protein A (PAPP-A), and gamma glutamyl transferase (GGT) were investigated in placental tissue; AFP and GGT in fetal liver; and GGT in fetal intestine. The results indicate that maternal serum levels of placental products reflect those found in the placenta: intact hCG, free beta hCG, and SP-1 levels were elevated in Down's syndrome pregnancies, while PAPP-A and PALP levels were little changed. This suggests that membrane passage of these markers is not affected but there is altered synthesis of hCG and SP-1. AFP levels were strikingly elevated in placental homogenates and unchanged in liver homogenates from Down's syndrome pregnancies, while the levels in maternal serum were reduced, pointing to a possible transport defect specific to AFP. GGT levels were high in placenta and liver from Down's syndrome pregnancies but low in fetal intestine.

Biomarkers↗
PubMed1996

Genetic localisation of MRX27 to Xq24-26 defines another discrete gene for non-specific X-linked mental retardation.

A large family with non-specific X-linked mental retardation (MRX) was first described in 1991 [Glass et al., 1991], with a suggestion of linkage to Xq26-27. The maximum lod score was 1.60 (theta = 0.10) with the F9 locus. The localisation of this MRX gene has now been established by linkage to microsatellite markers. Peak pairwise lod scores of 4.02 and 4.01 (theta = 0.00) were attained at the DXS1114 and DXS994 loci respectively. This MRX gene is now designated MRX27 and is localised to Xq24-26 by recombination events detected by DXS424 and DXS102. This regional localisation spans 26.2 cM on the genetic background map and defines another distinct MRX interval by linkage to a specific region of the X chromosome.

Chromosome Mapping↗
PubMed1996

Dimeric inhibin A as a marker for Down's syndrome in early pregnancy.

BACKGROUND: In screening for Down's syndrome in the second trimester of pregnancy, the concentrations of alpha-fetoprotein, the beta subunit of human chorionic gonadotropin, and intact human chorionic gonadotropin in material serum are widely used markers. We investigated a new marker, dimeric inhibin A, and compared its predictive value with that of the established markers. METHODS: Serum samples were obtained at 7 to 18 weeks of gestation from 58 women whose fetuses were known to be affected by Down's syndrome, 32 whose fetuses were affected by trisomy 18, and 438 whose fetuses were normal, and the samples were analyzed for each marker. Individual serum concentrations of each marker were converted to multiples of the median value at the appropriate length of gestation in the women with normal pregnancies, and rates of detection of Down's syndrome by screening for inhibin A in various combinations with the other markers were estimated by multivariate analysis. RESULTS: In the women with fetuses affected by Down's syndrome, the serum inhibin A concentrations were 2.06 times the median value in the women with normal pregnancies (P < 0.001). This compared with 2.00 times the median for the beta subunit of human chorionic gonadotropin, 1.82 times the median for intact human chorionic gonadotropin, and 0.72 for alpha-fetoprotein. The serum concentrations of inhibin A in the women with fetuses affected by Down's syndrome did not appear to be significantly elevated above normal until the end of the first trimester and were not significantly different from normal in the women with fetuses affected by trisomy 18 (P = 0.17). The rate of detection of Down's syndrome was 53 percent and the false positive rate was 5 percent when alpha-fetoprotein, the beta subunit of human chorionic gonadotropin, the maternal age were used together as predictors. The detection rate increased to 75 percent when inhibin A was added (P = 0.002). CONCLUSIONS: In the second trimester of pregnancy, measuring inhibin A in maternal serum, in combination with measurements of alpha-fetoprotein and beta subunit of human chorionic gonadotropin, significantly improved the rate of detection of Down's syndrome.

Biomarkers↗
PubMed1996

Prenatal diagnosis by enzyme analysis in 15 pregnancies at risk for the Lesch-Nyhan syndrome.

Fifteen pregnancies at risk for Lesch-Nyhan syndrome were investigated between 8 and 17 weeks' gestation by measurement of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and adenine phosphoribosyl transferase (APRT) enzyme activities in chorionic villus samples (cultured and uncultured) or in cultured amniotic fluid cells. Ten pregnancies had normal enzyme levels and a normal outcome while a further two predicted to be normal miscarried later in the pregnancy. Three pregnancies had low levels of residual HGPRT activity in chorionic villi. Comparable levels of residual activity in the index case in two pregnancies and in cells from the abortus in the third case confirmed that the pregnancies were affected.

Adenine Phosphoribosyltransferase↗
PubMed1996

Insulin-dependent diabetes mellitus and prenatal screening results: current experience from a regional screening programme.

From around 91,000 women having routine prenatal screening for Down's syndrome and neural tube defects between July 1992 and October 1995, 261 women were identified as having insulin-dependent diabetes mellitus (IDDM). Alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) levels were reduced in these women, with median levels of 0.89 and 0.91 multiples of the median (MOM), respectively. The IDDM patients had a median weight which was 6 kg heavier than that of non-IDDM women. After correction for maternal weight, the AFP and hCG levels in the IDDM patients were 0.98 and 0.92 MOM, respectively. In routine practice, using results which were not weight-corrected, the IDDM women were neither over- nor under-represented in the high-risk group for Down's syndrome, but showed a tendency to be under-represented in the high-risk group for neural tube defects.

Adolescent↗
PubMed1996

Heat-stable and immunoreactive placental alkaline phosphatase in maternal serum from Down's syndrome and trisomy 18 pregnancies.

Placental alkaline phosphatase (ALP) activity was investigated in second-trimester maternal sera from 37 pregnancies with Down's syndrome, 28 pregnancies with trisomy 18, and in a series of 497 controls using a fluorimetric heat inactivation assay and specific immunoassay. After conversion of individual analyte values to multiples of the normal gestational median (MOM), no significant differences in total or placental ALP activities were found in the trisomy 21 or trisomy 18 cases (P > 0.01). In the Down's syndrome pregnancies, total ALP activity was 0.93 MOM, heat-stable ALP activity was 1.09 MOM, and placental ALP (by immunoassay) 0.96 MOM. In the trisomy 18 cases, total ALP activity was 0.90 MOM, heat-stable ALP activity was 0.79 MOM, and placental ALP (by immunoassay) 0.94 MOM. We conclude that neither total nor placental ALP activity is a useful marker for Down's syndrome or trisomy 18 screening.

Alkaline Phosphatase↗
PubMed1996

Detection of four mutations in six unrelated South African patients with acute intermittent porphyria.

We have screened the hydroxymethylbilane synthase cDNA from six South African patients with acute intermittent porphyria, using a combination of chemical cleavage mismatch analysis and direct sequencing of asymmetrically amplified PCR products. Four mutations were detected, a novel T insertion (771insT) and three missense mutations (R26H, R116W and R173Q). The 771insT mutation produces a stop codon, thirty-three codons downstream and a loss of approximately 20% of the protein is predicted. The R116W mutation, which was found to have a high prevalence in the Dutch population, was detected in three unrelated South African patients.

DNA Mutational Analysis↗
PubMed1996

A practical strategy for detection of major chromosome aneuploidies using ratio-mixing fluorescence in situ hybridization.

We describe the use of ratio-mixing FISH to visualize simultaneously probe sets specific for chromosomes 13, 18 and 21 as well as both sex chromosomes in uncultured lymphocytes and amniocytes. This method has the advantage of a smaller sample requirement than uni-colour FISH and potential for analysis of a larger number of chromosome aneuploidies using a minimum number of different probe haptenization and detection systems. An unselected series of uncultured lymphocytes and amniocytes was used to investigate the reliability of ratio-mixing FISH for diagnostic applications. The results indicate that the five-colour ratio-mixing FISH is a reliable technique and can be used for simultaneous detection of major aneuploidies. However, as a diagnostic approach, the strategy of using a three-colour ratio-mixing FISH and a dual colour to detect the five clinically important aneuploidies on two slides from the same sample, appears to be simpler and more practical.

Aneuploidy↗