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Biomedical subjects

N C Nevin

Publications and source records attributed to N C Nevin.

At least 73 records · Page 4Linked to original sources
PubMed1996

A molecular variant of angiotensinogen is associated with diabetic nephropathy in IDDM.

Recent studies have suggested that an inherited predisposition to essential hypertension may increase susceptibility to nephropathy for patients with IDDM. Essential hypertension has been linked to the angiotensinogen (AGT) gene in genetic linkage studies in American and European populations. A molecular variant (M235T), which has a functional effect, has been described with highest plasma AGT levels being associated with the TT genotype. In a case-control study, we have evaluated the role of this functional genetic marker in patients with IDDM and nephropathy and in IDDM patients without nephropathy. We studied 195 IDDM patients, of whom 95 had established diabetic nephropathy; the remaining 100 patients, who had no evidence of microalbuminuria, served as control subjects. All patients were whites born in Northern Ireland. The point mutation in the AGT gene was analyzed using restriction typing. The background frequency of the M235T variant was assessed in 80 healthy blood donors, and the TT genotype was present in 9%. This genotype occurred in 8% of control IDDM patients without nephropathy and 19% of IDDM patients with nephropathy (P = 0.025). The odds ratio for diabetic nephropathy associated with the TT genotype was 2.7 (95% CI 1.04-7.52). There was no relationship between blood pressure and AGT genotypes in the control group. We cannot exclude the possibility that the observed association in the nephropathy group is due to an association between AGT genotype and hypertension. This evidence may help to explain the predisposition to diabetic nephropathy afforded by hypertension and merits further investigation.

Adult↗
PubMed1996

Hereditary breast cancer in Northern Ireland.

The aim of this investigation was to document hereditary breast cancer in Northern Ireland. Family history details from over nine hundred women were obtained by postal survey and one hundred and twenty nine home visits were carried out to collect pedigree information. The families documented varied in the number of affected women from three, which was the minimum criteria for inclusion, to a maximum of nine and many families described other features of hereditary disease such as bilateral breast cancer, ovarian and gastrointestinal malignancies.

Breast Neoplasms↗
PubMed1995

Hereditary breast cancer and linkage analysis to BRCA1.

In this study, over 1000 women with breast cancer were contacted by questionnaire and 164 families with a strong history of breast cancer were identified. Home visits to obtain full pedigree details took place for 123 women, and members of 24 families gave venous blood samples. The extracted DNA was typed by polymerase chain reaction amplification and the derived haplotypes submitted to linkage analysis which confirmed that in 12 families breast cancer susceptibility could be traced to BRCA1. The study demonstrates the number of women at risk of breast cancer in the population, illustrates the complexity of genetic analysis for hereditary breast cancer and demonstrates the problems of predictive analysis in clinical management.

Breast Neoplasms↗
PubMed1995

Detection of maternal cell contamination in amniotic fluid cell cultures using fluorescent labelled microsatellites.

A rapid PCR based assay was used to ascertain the presence of maternal cell contamination (MCC) in amniotic fluid cell cultures and to exclude MCC in cases where cytogenetic analysis was possible only from one primary cell culture. Six 6-carboxyfluorescein (FAM) and three 6-carboxyfluorescein hexachloride (HEX) labelled primer sets were used to amplify two tetra- and seven dinucleotide repeat polymorphisms. The PCR amplifications were multiplexed in (three) three primer set reactions and visualised on an Applied Biosystems 373A sequencer running Genescan 672 software. The microsatellite products obtained from 200 amniotic fluid cell cultures where the karyotype was female were compared against corresponding maternal blood PCR products. A single case of MCC was detected indicating the usefulness of such assays. We suggest that screening for MCC should be considered in instances where the amniotic fluid sample is bloodstained or was obtained with difficulty, or where the karyotype is female and chromosome analysis is not possible from more than one primary cell culture.

Amniocentesis↗
PubMed1995

The epidemiology of Huntington's disease in Northern Ireland.

A survey of Huntington's disease (HD) in Northern Ireland, with a population of 1.5 million, has shown a 1991 prevalence rate of 6.4/100,000. Virtually complete ascertainment was achieved, enabling prevalence rate estimates and age statistics to be calculated over the last 20 years. The prevalence rate is similar to the high prevalence rates of HD found in most European populations, suggesting the presence of either one extremely ancient or a number of separate mutational origins, resulting in a uniform European HD prevalence. The ages at diagnosis and duration of the disease are similar to previous studies, suggesting a consistent effect of the HD gene in all families. Estimates of heterozygote frequency (HF), direct and indirect mutation rate, fertility, and genetic fitness (W) were made. Reliable HF estimates gave values between 10 and 11 x 10(-5). The direct and indirect mutation rates were 0.32 x 10(-6) and 1.05 x 10(-6) respectively. W was increased in the affected HD population but decreased in the at risk population. Fertility in HD is not reduced, but it appears that at risk patients have actively limited their family size. Factors responsible include, among others, the fear of developing HD and genetic counselling of families. This is the first published epidemiological survey to include ascertainment data in a population both before and after isolation of the HD gene, and with the diagnosis in virtually all patients confirmed by DNA mutation testing.

Adolescent↗
PubMed1995

Anonychia and absence/hypoplasia of distal phalanges (Cooks syndrome): report of a second family.

We describe a second family with four affected members in three successive generations with a rare nail dysplasia syndrome. The syndrome, which was first reported by Cooks et al in 1985, is characterised by bilateral nail hypoplasia of digits 1-3, with absence of nails of digits 4-5 of the hands, and total absence of all toe nails. In addition, there is absence/hypoplasia of the distal phalanges of the hands and feet. Our family confirms this syndrome as a distinct entity with autosomal dominant inheritance.

Adult↗
PubMed1995

Phenylketonuria mutation analysis in Northern Ireland: a rapid stepwise approach.

We present a multistep approach for the rapid analysis of phenylketonuria (PKU) mutations. In the first step, three common mutations and a polymorphic short tandem repeat (STR) system are rapidly analyzed with a fluorescent multiplex assay. In the second step, minihaplotypes combining STR and VNTR data are used to determine rare mutations likely to be present in an investigated patient, which are then confirmed by restriction enzyme analysis. The remaining mutations are analyzed with denaturant gradient-gel electrophoresis and sequencing. The first two steps together identify both mutations in 90%-95% of PKU patients, and results can be obtained within 2 d. We have investigated 121 Northern Irish families with hyperphenylalaninemia, including virtually all patients born since 1972, and have found 34 different mutations on 241 of the 242 mutant alleles. Three mutations (R408W, I65T, and F39L) account for 57.5% of mutations, while 14 mutations occur with a frequency of 1%-6%. The present analysis system is efficient and inexpensive and is particularly well suited to routine mutation analysis in a diagnostic setting.

Base Sequence↗
PubMed1994

Polydactyly in a carrier of the gene for the Meckel syndrome.

Much of the Meckel syndrome literature has been concerned with the criteria for diagnosis but little has been said concerning heterozygote expression. We describe 3 affected brothers whose father and his paternal first cousin had postaxial polydactyly of both feet. A review of the literature was undertaken with regard to possible manifesting heterozygotes. We conclude that it is important to examine the relatives of patients with the Meckel syndrome for mild abnormalities, as these may be evidence of a manifesting heterozygote. Such information may be useful for genetic counselling.

Abnormalities, Multiple↗
PubMed1994

Oral-facial-digital syndrome with retinal abnormalities: OFDS type IX. A further case report.

The oral-facial-digital syndromes (OFDS) are a heterogeneous group. Recently, Gurrieri et al. [1992: Am J Med Genet 42:789-792] described a new OFDS characterised by typical oral, facial and digital abnormalities but distinguishable from previously reported OFDS by the presence of retinochoroidal lacunae of an apparently colobomatous origin. Toriello [1993: Clin Dysmorph 2:95-105] designated this possible new OFDS as Type IX. We describe a young woman presenting with oral, facial and digital anomalies and with the specific retinal abnormality reported by Gurrieri et al. [1992], thus confirming the existence of OFDS Type IX. As the patients of Gurrieri et al. [1992] were two affected brothers, they were unable to distinguish between autosomal and X-linked recessive inheritance. As our patient is an affected female, an autosomal recessive mode of inheritance is more likely.

Adult↗
PubMed1994

ACE gene typing.

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Cardiovascular Diseases↗
PubMed1994

Absence of PAX6 gene mutations in Gillespie syndrome (partial aniridia, cerebellar ataxia, and mental retardation).

The PAX6 gene is expressed at high levels in the developing eye and cerebellum and is mutated in patients with autosomal dominant aniridia. We have tested the role of PAX6 mutations in three families with Gillespie syndrome, a rare autosomal recessive condition consisting of partial aniridia, cerebellar ataxia, and mental retardation. Single-strand conformational polymorphism analysis of affected individuals revealed no alteration of PAX6 sequences. In two families, the disease trait segregates independently from chromosome 11p markers flanking PAX6. We conclude that Gillespie syndrome is genetically distinct from autosomal dominant aniridia.

Alleles↗
PubMed1994

Non-phenylketonuria hyperphenylalaninaemia in Northern Ireland: frequent mutation allows screening and early diagnosis.

Up to 10% of newborn children with a positive Guthrie test have non-phenylketonuria hyperphenylalaninaemia, i.e., mild elevation of serum phenylalanine that does not require dietary treatment. Depending on the relative frequencies of different phenylalanine hydroxylase mutations in a particular population, non-PKU HPA is usually caused by the combined effect of a mild HPA mutation and a severe PKU mutation. Presented here is a comprehensive analysis of non-PKU HPA in Northern Ireland. Of particular interest is one prevalent HPA mutation (T380M), which is present in over 70% of non-PKU HPA patients in Northern Ireland. Screening for this mutation is easy and inexpensive and can help confirm the diagnosis of non-PKU hyperphenylalaninaemia in the majority of cases at a very early stage. This may be clinically useful and reassuring for the parents. Other mutations described are V245A, L194P, and E390G.

Adolescent↗
PubMed1994

Serum iron, total iron binding capacity and ferritin in early Huntington disease patients.

Serum iron, total iron binding capacity and ferritin was estimated in 42 patients with early Huntington disease (HD) and in 148 matched controls. Ferritin levels were significantly low in affected male subjects as compared to controls. Iron levels and total iron binding capacity were normal in HD patients. The importance of this finding, that occurs early in the pathogenesis of HD, is unknown.

Adolescent↗
PubMed1994

Genetic linkage of familial expansile osteolysis to chromosome 18q.

Familial expansile osteolysis is a rare bone dysplasia which is transmitted as an autosomal dominant trait in a large kindred in Northern Ireland. The gene which causes the disease shows tight linkage with several polymorphic markers on chromosome 18q with a maximum lod score of 11.53 at a recombination fraction of 0.00 with D18S64. The gene is flanked by D18S35 and D18S61 and is located at chromosome 18q21.1-q22. Mapping a new locus for a gene involved in regulation of bone metabolism may also have implications in the study of Paget's disease of bone which is a common related bone dysplasia.

Animals↗
PubMed1994

Microcephaly with large anterior fontanelle, generalized convulsions, micropenis, and distinct anomalies of the hands and feet. Another example of Wiedemann syndrome?

Wiedemann et al. (1985) described a rare syndrome characterised by microcephaly, psychomotor delay, short stature, short fingers and toes with stubby broad thumbs and halluces. Unilateral undescended testis, inguinal hernias, scrotal hypoplasia, and micropenis were also features. They described two males, first cousins, whose mothers and maternal grandfather had short broad thumbs and halluces. We report a male with identical features whose parents were normal. This is only the second report of this syndrome. Autosomal or X-linked dominant inheritance is most likely.

Abnormalities, Multiple↗