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Biomedical subjects

D Ravine

Publications and source records attributed to D Ravine.

At least 19 recordsLinked to original sources
PubMed2000

Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location.

Mutations in the methyl-CpG-binding protein gene MECP2 at Xq28 cause Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder characterized by a period of stagnation followed by regression in the development of young girls. Mutations were sought in MECP2 in 48 females with classical sporadic RTT, seven families with possible familial RTT and five sporadic females with features suggestive, but not diagnostic of RTT. Long distance PCR coupled with long-read direct sequencing was employed to sequence the entire MECP2 gene coding region in all cases. Mutations were identified in 44/55 (80%) unrelated classical sporadic and familial RTT patients, but only 1/5 (20%) sporadic cases with suggestive but non-diagnostic features of RTT. Twenty-one different mutations were identified (12 missense, four nonsense and five frame-shift mutations); 14 of these were novel. All missense mutations were located either in the methyl-CpG-binding domain or in the transcription repression domain. Nine recurrent mutations were characterized in a total of 33 unrelated cases (73% of all cases with MECP2 mutations). Significantly milder disease was noted in patients carrying missense mutations as compared with those with truncating mutations ( P = 0. 0023), and milder disease was associated with late as compared with early truncating mutations ( P = 0.0190).

Amino Acid Sequence↗
PubMed2000

Co-occurrence of autosomal dominant polycystic kidney disease and Marfan syndrome in a kindred.

Several reports exist of the co-occurrence of autosomal dominant polycystic kidney disease (ADPKD) and Marfan syndrome, including a report of ADPKD and "overlap" connective tissue disorder in a family with linkage to the PKD1 locus. We report the results of clinical and linkage investigations of an ADPKD family in whom several affected subjects also had aortic vascular complications as well as features of Marfan syndrome. Detailed clinical assessment and linkage analysis were performed with polymorphic microsatellite markers closely linked to the PKD1 and FBN1 loci. Survival data were compared with 10 geographically matched PKD1 families. Although several subjects had features of both ADPKD and Marfan syndrome, detailed clinical examination of the extended family indicated that the two conditions had converged within the kindred. For those with ADPKD, linkage was established to the PKD1 locus (lod score, 6.04). Among those with features of Marfan syndrome, linkage was confirmed to the FBN1 locus (lod score, 1.87). Five of six subjects with both ADPKD and the high-risk FBN1 haplotype had associated vascular complications. In contrast, among the remaining nine individuals with PKD1 alone, seven had aortic assessments, and none were found to have aortic complications. Our experience suggests that when prominent features of connective tissue disease or vascular complications are found in ADPKD patients, alternative additional diagnoses should be considered, including the possibility of a coinherited FBN1 mutation responsible for Marfan syndrome or, alternatively, an associated milder FBN1 phenotype in the absence of sufficient other clinical features to allow Marfan syndrome to be diagnosed.

Adult↗
PubMed2000

Location of mutations within the PKD2 gene influences clinical outcome.

BACKGROUND: Since the cloning of the gene for autosomal dominant polycystic kidney disease type 2 (PKD2), approximately 40 different mutations of that gene have been reported to be associated with the disease. The relationship between the PKD2 genotype and phenotype, however, remains unclear. METHODS: Detailed clinical information was collected for PKD2 families in which the underlying mutation had been identified. Logistic regression analysis was employed to assess the influence of age and sex on hypertension, hematuria, renal calculi, and urinary tract infections, and a clinical phenotype score was computed. Patients were then grouped according to the relative location of their mutation within the cDNA sequence, and differences in the mean phenotypic score between groups were tested for statistical significance by means of a multiple pairwise t-test. RESULTS: While phenotypic scores for each mutational group revealed a considerable degree of intragroup variability, the variability in phenotypic scores was significantly higher between mutational groups than within groups. A group-wise comparison of the mean phenotypic scores confirmed the observation of significant nonlinear variation in disease severity, with high- and low-scoring mutational groups interspersed along the gene sequence. CONCLUSION: The identification of groups of mutations in the PKD2 gene, which differ significantly with respect to clinical outcome, is to our knowledge the first description of a genotype/phenotype correlation in autosomal dominant polycystic kidney disease. It also provides evidence against complete loss of function of the mutant PKD2 gene product.

Analysis of Variance↗
PubMed1999

Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group.

BACKGROUND: Although autosomal dominant polycystic kidney disease type 2 (PKD2) is known to have a milder clinical phenotype than PKD1, neither disorder has been compared with an unaffected control population in terms of survival. We report the findings of a multicentre survey that aimed to define more precisely the survival and clinical expression of PKD1 and PKD2. METHODS: Clinical data from 333 people with PKD1 (31 families) were compared with data from 291 people with PKD2 (31 families) and 398 geographically matched controls. Survival analysis was used to compare age-at-event data. Differences in the prevalence of complications were assessed by logistic regression. FINDINGS: Median age at death or onset of end-stage renal disease was 53.0 years (95% CI 51.2-54.8) in individuals with PKD1, 69.1 years (66.9-71.3) in those with PKD2, and 78.0 years (73.8-82.2) in controls. Women with PKD2 had a significantly longer median survival than men (71.0 [67.4-74.8] vs 67.3 [64.9-69.7] years), but no sex influence was apparent in PKD1. Age at presentation with kidney failure was later in PKD2 than in PKD1 (median age 74.0 [67.2-80.8] vs 54.3 [52.7-55.9] years). PKD2 patients were less likely to have hypertension (odds ratio 0.25 [95% CI 0.15-0.42]), a history of urinary-tract infection (0.50 [0.31-0.83]), or haematuria (0.59 [0.35-0.98]). INTERPRETATION: Although PKD2 is clinically milder than PKD1, it has a deleterious impact on overall life expectancy and cannot be regarded as a benign disorder.

Adult↗
PubMed1999

Automated mutation analysis.

Automated mutation analysis brings with it a vastly increased capacity in the number of test samples that can be processed at a time, as well as much improved test reproducibility. Until now, the introduction of automation into this field had been restricted to the use of semiautomated sequencing systems to make the most of the sequence information extractable from a single lane in an electrophoretic gel or in a polymer-filled glass capillary. Much effort is now being directed into harnessing the potential of DNA microarrays (DNA chips) and there is increasing interest in the potential of matrix-assisted mass spectrometry for determining the detail of large nucleic acid molecules. Meanwhile, there are other important recent developments already available, including robotic workstations, the further development of the allele-specific oligonucleotide assay into microtitre formats, and its use with fluorescence for real-time quantitative PCR analysis. Implementation of these developments in appropriate settings can further streamline the routine of molecular diagnostic laboratories, allowing them to take greater advantage of the recent surge of gene discoveries and their associated disease-causing mutations.

Automation↗
PubMed1999

Familial phenotype differences in PKD11.

UNLABELLED: Familial phenotype differences in PKD1. BACKGROUND: Mutations within the PKD1 gene are responsible for the most common and most severe form of autosomal dominant polycystic kidney disease (ADPKD). Although it is known that there is a wide range of disease severity within PKD1 families, it is uncertain whether differences in clinical severity also occur among PKD1 families. METHODS: Ten large South Wales ADPKD families with at least 12 affected members were included in the study. From affected members, clinical information was obtained, including survival data and the presence of ADPKD-associated complications. Family members who were at risk of having inherited ADPKD but were proven to be non-affected were included as controls. Linkage and haplotype analysis were performed with highly polymorphic microsatellite markers closely linked to the PKD1 gene. Survival data were analyzed by the Kaplan-Meier method and the log rank test. Logistic regression analysis was used to test for differences in complication rates between families. RESULTS: Haplotype analysis revealed that each family had PKD1-linked disease with a unique disease-associated haplotype. Interfamily differences were observed in overall survival (P = 0.0004), renal survival (P = 0.0001), hypertension prevalence (P = 0.013), and hernia (P = 0.048). Individuals with hypertension had significantly worse overall (P = 0.0085) and renal (P = 0.03) survival compared with those without hypertension. No statistically significant differences in the prevalence of hypertension and hernia were observed among controls. CONCLUSION: We conclude that phenotype differences exist between PKD1 families, which, on the basis of having unique disease-associated haplotypes, are likely to be associated with a heterogeneous range of underlying PKD1 mutations.

Genetic Linkage↗
PubMed1999

Growth in Sotos syndrome.

Although there are several reports on infant and childhood growth in patients with Sotos syndrome, there is little information on the final height achieved and puberty. Growth data on 40 patients (20 female and 20 male) aged 2-31 years were collected. These showed that patients with Sotos syndrome are excessively tall at birth, during infancy, and during childhood. Disproportionately long limbs constitute much of the increase in stature. However, the combination of advanced bone age and early onset of menarche led to a mean (SD) final height of 172.9 (5.7) cm in women. This is within the normal range for the population. Most of the men also attained a final height (mean, 184.3 cm; SD, 6.0) within the normal range, although exceptions were more likely in men than in women. Therefore, these results show that most patients with Sotos syndrome do not require intervention to limit their adult height.

Acromegaly↗
PubMed1999

Prenatal diagnosis for facioscapulohumeral muscular dystrophy (FSHD).

This study outlines the molecular DNA findings derived from 12 separate prenatal diagnoses offered to families with a history of facioscapulohumeral muscular dystrophy. A high risk of the fetus being affected was identified in five pregnancies. Several practical problems are discussed, particularly those arising from the quality and quantity of DNA made available for molecular diagnosis. Evidence of the 4q35 and 10q26 telomeric exchanges is present in 20 per cent of the general population and the specificity of the test is 95 per cent. The eventual isolation and functional characterization of the FSHD gene should allow us to unravel many of the complexities currently associated with the molecular diagnosis of this disorder.

Chromosomes, Human, Pair 10↗
PubMed1998

Novel and recurrent mutations in the PKD1 (polycystic kidney disease) gene.

A search has been conducted for disease-causing mutations in the PKD1 gene in 147 unrelated ADPKD index cases. Using the polymerase chain reaction with primer pairs located in the 3' single copy region of the gene and single-strand conformation polymorphism analysis, we detected novel aberrant bands in five individuals that were absent in 100 control samples. Sequencing revealed three nonsense mutations (Q4010X, E4024X, Q4041X), a frameshift mutation (12262 del 2 bp), and a missense mutation (G4031D). In addition, three polymorphisms were detected [12346 + 19delG, heterozygosity (0.13), I4044V (0.23), 12212-34C > A (0.07)]. The mutational mechanism for the recurrent mutation (Q4041X) is likely to be slipped mispairing of an adjacent direct imperfect repeat sequence.

Amino Acid Substitution↗
PubMed1997

Dominant coloboma-microphthalmos syndrome associated with sensorineural hearing loss, hematuria, and cleft lip/palate.

Ocular colobomas and microphthalmos, isolated or as part of a syndrome, are usually sporadic and only rarely found in large families. A 4-generation family with autosomal dominant uveal coloboma and microphthalmos associated with cleft lip and palate was re-evaluated. Wide variability in expression is evident and more recently recognized manifestations include a complete spectrum of eye involvement, impairment of extraocular movement, mid-frequency sensorineural hearing loss, and hematuria. Learning difficulties requiring remedial teaching were present in one third of those affected and a neural tube defect has occurred in one presumed affected member. This family appears to present a unique phenotype, which provides an opportunity to identify a genetic locus involved in eye, ear, renal, primary palate, and brain development.

Abnormalities, Multiple↗
PubMed1997

Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the widespread development of distinctive tumors termed hamartomas. TSC-determining loci have been mapped to chromosomes 9q34 (TSC1) and 16p13 (TSC2). The TSC1 gene was identified from a 900-kilobase region containing at least 30 genes. The 8.6-kilobase TSC1 transcript is widely expressed and encodes a protein of 130 kilodaltons (hamartin) that has homology to a putative yeast protein of unknown function. Thirty-two distinct mutations were identified in TSC1, 30 of which were truncating, and a single mutation (2105delAAAG) was seen in six apparently unrelated patients. In one of these six, a somatic mutation in the wild-type allele was found in a TSC-associated renal carcinoma, which suggests that hamartin acts as a tumor suppressor.

Amino Acid Sequence↗
PubMed1997

Association of the angiotensin I converting enzyme gene deletion polymorphism with early onset of ESRF in PKD1 adult polycystic kidney disease.

To determine the effect of the ACE gene insertion/deletion (I/D) polymorphism, angiotensinogen gene M235T polymorphism and the angiotensin 1 receptor gene A1166C polymorphism on the age of onset of end-stage renal failure (ESRF) in PKD1 adult autosomal-dominant polycystic kidney disease (ADPKD), 189 individuals from 46 families with PKD1 were genotyped for each polymorphism. Of the 189 patients 52 (28%) reached ESRF at an average age of 48 +/- 1 year. In patients genotyped for the ACE gene insertion/deletion polymorphism the frequencies of the DD, ID and II genotypes were similar to those expected from Hardy Weinberg equilibrium. In patients with ESRF there was an excess of patients homozygous for the deletion allele (DD: 48% chi2 = 9.97 (1df) P = 0.002). Cumulative renal survival was significantly reduced among those with DD genotype compared to ID and II genotypes. The estimated mean renal survival (95% confidence intervals) were: DD, 52 years [48, 57]; II, 59 years [54, 63]; ID, 64 years [56, 72]; chi2 = 6.13 (1df) P = 0.013, DD versus ID/II. The mean age of renal failure was significantly younger in the DD genotype compared to ID and II genotypes (DD, ID, and II: 44 +/- 2, 49 +/- 2 and 54 +/- 3 years, respectively; P < 0.05 DD vs. ID, P < 0.05 DD vs. II). Ten of the eleven patients who reached ESRF before the age of 40 were homozygous for the deletion allele. The relative risk for ESRF below the age 40 for DD genotype was 17. For all ages there was an overall increased risk of 1.4 for ESRF with the DD genotype. There was no interaction between age of onset of ESRF and either the angiotensinogen M235T allele or angiotensin 1 receptor A1166C polymorphism. This study strongly suggests that PKD 1 patients homozygous for the deletion allele of the ACE gene are at increased risk of developing ESRF at a early age.

Adult↗
PubMed1997

Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene.

Tuberous sclerosis is an autosomal dominant trait characterized by the development of hamartomatous growths in many organs. Renal cysts are also a frequent manifestation. Major genes for tuberous sclerosis and autosomal dominant polycystic kidney disease, TSC2 and PKD1, respectively, lie adjacent to each other at chromosome 16p13.3, suggesting a role for PKD1 in the etiology of renal cystic disease in tuberous sclerosis. We studied 27 unrelated patients with tuberous sclerosis and renal cystic disease. Clinical histories and radiographic features were reviewed, and renal function was assessed. We sought mutations at the TSC2 and PKD1 loci, using pulsed field- and conventional-gel electrophoresis and FISH. Twenty-two patients had contiguous deletions of TSC2 and PKD1. In 17 patients with constitutional deletions, cystic disease was severe, with early renal insufficiency. One patient with deletion of TSC2 and of only the 3' UTR of PKD1 had few cysts. Four patients were somatic mosaics; the severity of their cystic disease varied considerably. Mosaicism and mild cystic disease also were demonstrated in parents of 3 of the constitutionally deleted patients. Five patients without contiguous deletions had relatively mild cystic disease, 3 of whom had gross rearrangements of TSC2 and 2 in whom no mutation was identified. Significant renal cystic disease in tuberous sclerosis usually reflects mutational involvement of the PKD1 gene, and mosaicism for large deletions of TSC2 and PKD1 is a frequent phenomenon.

Adolescent↗
PubMed1997

A spectrum of mutations in the second gene for autosomal dominant polycystic kidney disease (PKD2).

Recently the second gene for autosomal dominant polycystic kidney disease (ADPKD), located on chromosome 4q21-q22, has been cloned and characterized. The gene encodes an integral membrane protein, polycystin-2, that shows amino acid similarity to the PKD1 gene product and to the family of voltage-activated calcium (and sodium) channels. We have systematically screened the gene for mutations by single-strand conformation-polymorphism analysis in 35 families with the second type of ADPKD and have identified 20 mutations. So far, most mutations found seem to be unique and occur throughout the gene, without any evidence of clustering. In addition to small deletions, insertions, and substitutions leading to premature translation stops, one amino acid substitution and five possible splice-site mutations have been found. These findings suggest that the first step toward cyst formation in PKD2 patients is the loss of one functional copy of polycystin-2.

Adult↗
PubMed1997

Adult-onset genetic disease: mechanisms, analysis and prediction.

Recombinant DNA technology has made possible the localization and isolation of disease-related genes, the tracking of disease-related alleles through family pedigrees, the direct detection of the pathological lesion itself and the in vitro expression of both normal and mutant genetic information at the mRNA and protein levels. Undoubtedly the most immediate practical spin-off from recombinant DNA technology in medical genetics has been in the sphere of improved disease diagnosis and prediction, where advances have been dramatic. We review the nature of inherited disease, current approaches to its analysis, diagnosis and prediction, mechanisms of gene mutation and the available techniques for mutation detection. Also examined are the various genetic factors that can alter the relationship between genotype and clinical phenotype. Finally, the genetics of selected adult-onset disorders are explored in the context of considering the accuracy and reliability of disease prediction.

Adult↗
PubMed1997

Improved molecular diagnosis of facioscapulohumeral muscular dystrophy (FSHD): validation of the differential double digestion for FSHD.

A major advance in the molecular diagnosis of facioscapulohumeral muscular dystrophy is the recently reported elimination of confounding DNA fragments arising from homologous sequences located at 10q26. In order to evaluate the specificity and sensitivity of this important diagnostic test, we have compared a group of 130 patients fulfilling the diagnostic criteria for FSHD with 200 control subjects not known to have an increased risk of having an FSHD mutation. Among the FSHD cases the smallest BlnI/EcoRI fragment sizes ranged from 10 to > 48 kb with 94.6% (95% CI 89.2-97.8%) of cases having fragment sizes of 34 kb or less. Among the 400 chromosomes from controls the smallest BlnI/EcoRI fragment observed with the EcoRI/BlnI double restriction enzyme digest was 38 kb +/- 2 kb, suggesting a test specificity at a fragment size < 34 kb of or very near to 100% (lower 95% CI 98.2%). Test sensitivity at < 34 kb is estimated at 94.6% (95% CI 89.2-97.8%), all outliers having fragments > 38 kb. The Southern blot analysis with DNA probe p13E-11 has created a valuable molecular diagnostic test for FSHD.

Alleles↗