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Biomedical subjects

N C Nevin

Publications and source records attributed to N C Nevin.

At least 91 records · Page 5Linked to original sources
PubMed1994

Automated sequencing detects all mutations in Northern Irish patients with phenylketonuria and mild hyperphenylalaninaemia.

In the first phase of the Northern Ireland PKU Study, we used automated sequencing to identify the spectrum of mutations in a random group of 32 unrelated phenylketonuria (PKU) families. We also investigated 7 Northern Irish patients with mild hyperphenylalaninaemia not requiring dietary intervention (MHP, previously referred to as non-PKU HPA). Disease-causing mutations were identified on all 78 investigated chromosomes. We found 23 different mutations, including 20 missense, 1 nonsense and 2 splice site mutations. All mutations were located within exons or at intron-exon boundaries of the phenylalanine hydroxylase gene. Seven mutations occurred at CpG sites, confirming these sites as mutation hot-spots in PKU. Mutations R408W and I65T are the two commonest PKU mutations in the Northern Irish population. Two mutations (T380M and V245A) can be characterized as MHP mutations; they are quasi dominant markers for MHP since they cause mild hyperphenylalaninaemia even when occurring in conjunction with the most severe PKU mutations. The results have proven valuable for the development of a routine PKU mutation analysis system in Northern Ireland.

DNA Mutational Analysis↗
PubMed1994

The STR system in the human phenylalanine hydroxylase gene: true fragment length obtained with fluorescent labelled PCR primers.

We present a simple, fast, non-radioactive method for the analysis of the polymorphic short tandem repeat (STR) system in the human phenylalanine hydroxylase gene. Previously, sizing of the STR marker involved radiolabelling of PCR amplified fragments and resolution on denaturing polyacrylamide gels using M13 sequencing ladder as a standard. However, this method consistently gave sizes 2 bp longer than the known sequence. The fluorescent method presented here employs internal lane standards and enables accurate sizing of the fragments. To avoid confusion, we suggest that the true fragment lengths are used as reference values in the future. The analysis of STR alleles is valuable for population genetic studies and for targeted mutation screening in phenylketonuria (PKU). It can replace RFLP-based haplotype analysis for carrier detection, and we report its use for prenatal diagnosis in a Northern Irish family with PKU. The analysis of 250 Northern Irish chromosomes, including 128 PKU alleles, showed no significant difference between normal and PKU alleles, with fragment lengths of 238 and 242 bp most common in both groups.

Genetic Testing↗
PubMed1994

Genetic study of congenital heart defects in Northern Ireland (1974-1978).

Congenital heart defects are a major congenital abnormality and are assuming increasing importance. A study was undertaken to estimate the incidence of congenital heart defects in Northern Ireland over a five year period (1974-1978), to determine the age at diagnosis and to assess the risk of recurrence in sibs. An incidence rate of 7.3 per 1000 total births was found. This reduced to 3.1 per 1000 total births if only invasive methods of diagnosis (catheter studies, surgery, or necropsy) were considered. The overall risk of recurrence for sibs (excluding index patients with chromosomal abnormalities and syndromes) was 3.1%. In addition, excluding families with an affected parent and child gave a recurrence risk of 2.6%. By 6 weeks of age 63% of index patients had been diagnosed and this figure had risen to 88% by 1 year. This has important implications for studies which include only congenital heart defects diagnosed in the first year of life. Of 388 patients with a congenital heart defect confirmed by invasive criteria, 96 (24.7%) were found to have an extracardiac abnormality (ECA). Excluding those with epilepsy or mental handicap as the sole ECA left 91 (23.5%) with an ECA. This highlights the importance of looking for other abnormalities in a child with a congenital heart defect. The 388 index patients had 952 sibs of whom 72 (7.6%) had an ECA. Excluding those with minor abnormalities (inguinal hernias, undescended testes) as the sole ECA left 62 (6.5%) with a major ECA. In addition, excluding those with epilepsy or mental handicap as the sole ECA left 51 (5.4%) with a major ECA. Since parents are often reassured after the birth of a child with a congenital heart defect that their risk of having a child with a noncardiac abnormality is no greater than the general population this finding has important implications for genetic counselling.

Abnormalities, Multiple↗
PubMed1993

Axial mesodermal dysplasia spectrum.

We report on a 4-month-old boy with manifestations of both the oculo-auriculovertebral spectrum and the caudal regression sequence. He has preauricular appendages, thoracic and lumbar hemivertebrae, anomalies of the ribs, dextrocardia, sacral "dysplasia," dislocated hips, bilateral talipes equinovarus, imperforate anus, recto-vesical fistula, malformed scrotum, and undescended testes. As suggested by Russell et al. [1981], who reported a patient with similar anomalies, the spectrum of anomalies probably is due to a generalized alteration in mesodermal cell migration during the primitive streak period. The term "axial mesodermal dysplasia spectrum" best describes the widespread anomalies in the cranial and caudal regions.

Abnormalities, Multiple↗
PubMed1993

Autosomal dominant polycystic kidney disease with minimal clinical expression unlinked to the PKD1 locus.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations at the PKD1 locus in most families. This locus has been assigned to the short arm of chromosome 16 by linkage analysis. It has been estimated that approximately 5% of families have a disease that does not map to this locus and most of these families have clinical features indistinguishable from the disease caused by PKD1 mutations. We report a large three-generation Caucasian family from Northern Ireland with ADPKD in whom all affected individuals (age range 22-68) were normotensive and only the two eldest had mild renal impairment. Linkage was excluded between the disease and both the alpha-globin gene complex and the microsatellite marker D16S283. This family confirms that phenotypic heterogeneity exists between unlinked families and that certain non-PKD1 mutations cause mild disease expression. Many such individuals may therefore remain undetected and the incidence of families with ADPKD who have non-PKD1 mutations may be greater than previously estimated.

Adolescent↗
PubMed1993

Identification of an expanded CAG repeat in the Huntington's disease gene (IT15) in a family reported to have benign hereditary chorea.

Benign hereditary chorea (BHC) is a rare autosomal dominant disorder characterised by the onset of non-progressive chorea in childhood and the absence of cognitive impairment. Using primers flanking the (CAG)n repeat in IT15, expansion of which is associated with HD, we have detected an abnormal PCR product in four affected members from one family where affected subjects were originally reported to have BHC. The expanded allele contains 38 repeats in the affected parent and this undergoes further enlargement to 39 and 45 repeats in the two affected offspring. We conclude that the diagnostic criteria for BHC should include a normal result from analysis for the (CAG)n expansion identified in HD.

Adult↗
PubMed1993

Significant linkage disequilibrium between the Huntington's disease locus and markers at loci D4S10, D4S95, and D4S111 in Northern Ireland.

An analysis of the Northern Ireland Huntington's disease (HD) population of 75 families showed significant linkage disequilibrium between the HD gene and DNA markers at D4S95, D4S10, and D4S111. As the linkage disequilibrium at loci D4S10 and D4S111 is different from previous studies in the UK, but similar at locus D4S95, this suggests either that the HD mutation(s) in the Northern Ireland and British populations is not of common origin or that the haplotype of the common HD mutation has changed over time subsequent to divergence from a common origin.

Alleles↗
PubMed1993

Genetic linkage analysis, clinical features and prognosis of autosomal dominant polycystic kidney disease in Northern Ireland.

Fifteen families with autosomal dominant polycystic kidney disease were analysed for coinheritance of the disease and DNA markers flanking the PKD1 locus. Eleven families demonstrated linkage to PKD1 markers. Two families were unlinked to the PKD1 locus (non-PKD1) and in two families the markers were uninformative. The clinical features and prognosis of 49 subjects with a PKD1 genotype were compared with 17 non-PKD1 subjects. The age at diagnosis in non-PKD1 subjects (37 +/- 11 years) was significantly later than PKD1 subjects (25 +/- 13 years, p < 0.001). Only two (12%) non-PKD1 subjects presented initially with clinical features of autosomal polycystic kidney disease compared to 27 (55%) of PKD1 subjects (p < 0.002). Hypertension was more common in PKD1 compared to non-PKD1 subjects (29% vs. 12%), as was stage renal failure (25% vs. 6%). Seventy-five percent of non-PKD1 subjects had not developed end-stage renal failure by the age of 54 years compared to only 35% of PKD1 subjects. Most families with autosomal polycystic kidney disease in this population have disease due to mutations at the PKD1 locus. However, the proportion of non-PKD1 families appears to be higher than estimates for other populations. This study also confirms initial reports that subjects with a non-PKD1 genotype have a milder disease with a better prognosis than those with a PKD1 genotype.

Adult↗
PubMed1993

Huntington disease in County Donegal: epidemiological trends over four decades.

The prevalence rate of Huntington disease in County Donegal between 1961 and 1991 showed a decrease from 4.4 to 1.6 per 100,000 population. Emigration and reduction in family size probably account for the progressive decline in prevalence. Over the same time period in the rest of Europe, prevalence has declined only gradually, or has remained static.

Adult↗
PubMed1992

Cardiovascular abnormalities in the oculo-auriculo-vertebral spectrum (Goldenhar syndrome).

We describe the phenotypic characteristics of 25 individuals with oculo-auriculo-vertebral spectrum (OAVS) and its variants, seen in Northern Ireland between 1969-1989, with special reference to cardiovascular defects. We report the type and prevalence of cardiovascular findings and also estimate the minimum prevalence rate of OAVS to be 1 in 45,000.

Abnormalities, Multiple↗
PubMed1992

Interstitial deletion 8p21.3----p23.1 in a 6-year-old girl.

We present a 6-year-old mentally retarded girl. Chromosome analysis showed an interstitial deletion of chromosome 8; 46,XX,del(8) (pter----p23.1::p21.3----qter). The proposita had normal activities of glutathione synthetase reductase (GSR) and factor VII. Parental chromosomes were normal.

Child↗