Bilateral split hand and split foot malformation in a boy with a de novo interstitial deletion of 7q21.3.
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Abnormalities, Multiple↗
Biomedical subjects
A L Meredith
Publications and source records attributed to A L Meredith.
Exclusion testing in pregnancy for Huntington's disease.
The results of DNA analysis are presented for a series of 90 couples, with one partner at 50% risk for Huntington's disease (HD), who were referred for exclusion testing in pregnancy over a three year period. Thirty-seven couples were studied in detail. The aims of the study were to evaluate attitudes towards prenatal testing, before pregnancy and afterwards, and the effectiveness of our counseling and methods of organising the service. Problems which could arise in relation to presymptomatic testing are documented. It is concluded that exclusion testing is a valuable form of prediction for some couples, particularly where family structure does not permit prediction for the person at risk. The need for intensive counselling was highlighted by the difficulties experienced by many couples in understanding how the test worked. Particular ethical and organisational problems may arise which require careful consideration beforehand and some recommendations are made. The proportion of couples who will continue to request exclusion testing as pre-symptomatic testing becomes more widely applicable remains unknown.
Adult↗
Genetic analysis of treated and untreated phenylketonuria in one family.
We describe a family in which four subjects in two generations have a disorder of phenylalanine metabolism. Two first cousins had different biochemical presentations in the neonatal period. The older child was thought to have a more severe form of phenylketonuria (PKU), and the younger child a milder form. While carrying out family studies we discovered that their mutual grandfather and his older unmarried brother, both of normal intelligence, had a marked and previously undiagnosed hyperphenylalaninaemia. DNA analysis using RFLP haplotypes has shown that there are four independent mutant PKU alleles in this family which are found on three haplotype patterns. None of the affected family members carries a previously defined mutation at the phenylalanine hydroxylase (PAH) locus and so DNA analysis was not able to explain the apparently different biochemical phenotypes in the affected members of this family.
Adolescent↗
Presymptomatic detection and prenatal diagnosis for myotonic dystrophy by means of linked DNA markers.
The close genetic linkage between the loci for apolipoprotein CII (ApoCII) and myotonic dystrophy makes presymptomatic detection and prenatal diagnosis feasible. We report three years' service experience of providing presymptomatic detection and prenatal diagnosis for myotonic dystrophy in 99 families. Careful clinical study of older family members remains important. The introduction of new probes (CKMM and BCL4) has helped to solve the problem of uninformativeness owing to unhelpful genotype distribution in a family. Nevertheless, informativeness cannot be guaranteed and families should be studied before pregnancy is undertaken whenever possible. Presymptomatic testing and prenatal diagnosis for myotonic dystrophy are soundly based. All affected subjects should have DNA banked for future use when other family members may require genotype information.
Female↗
Identification of the haplotype pattern associated with the mutant PKU allele in the Gypsy population of Wales.
Using the full length cDNA probe, the RFLP haplotype patterns at the phenylalanine hydroxylase locus have been studied in the extensive and highly consanguineous Welsh Gypsy population. The pattern associated with the mutant PKU allele is identical to haplotype 4 in the northern European population. Two children with classical PKU are homozygous for this haplotype. We have tracked the mutant allele through four generations to a great grandfather who died 22 years ago. Both affected children almost certainly have inherited a double dose of the same mutant PKU allele from one common ancestor. It should be possible to identify the specific mutation that is associated with haplotype 4 which results in the more serious form of PKU.
Alleles↗
Molecular genetics in clinical practice: evolution of a DNA diagnostic service.
The development of a molecular genetics diagnostic service over a three year period was studied in a National Health Service region with a population of three million. Starting from a time when few diagnostic applications were possible, the number of disorders and the overall demand had grown rapidly. Conditions for which molecular genetic diagnosis had been provided included Duchenne and Becker muscular dystrophy, myotonic dystrophy, Huntington's disease, and cystic fibrosis. Of 405 requests for diagnosis, 151 (37%) related to determination of carrier state, 187 (46%) to determining the feasibility of future prenatal diagnosis, and 67 (17%) were prenatal diagnostic biopsy samples, almost exclusively of first trimester chorion. DNA samples for future diagnostic use with a wide range of genetic disorders had also been banked. The study showed a need for close integration with clinical genetics services to allow satisfactory genetic counselling and interpretation of risks.
Cystic Fibrosis↗
Exclusion testing for Huntington's disease in pregnancy with a closely linked DNA marker.
55 couples where one partner was at 50% risk of Huntington's disease (HD) were investigated with a DNA probe closely linked to HD, with a view to exclusion testing in a future pregnancy. In 3 of 9 pregnancies so far, HD was excluded in the absence of recombination. In 3 the risk was raised to around 50%, and in 2 exclusion tests were uninformative. The remaining couple changed their minds about termination of the pregnancy and the test was therefore judged inappropriate.
Chorionic Villi↗
Application of a closely linked polymorphism of restriction fragment length to counselling and prenatal testing in families with myotonic dystrophy.
The close genetic linkage between the loci for apolipoprotein CII (ApoC2) and myotonic dystrophy makes ApoC2 the closest fully validated marker for prediction of myotonic dystrophy. Application to genetic counselling and presymptomatic and prenatal prediction is reported in seven families with myotonic dystrophy, including one case in which the disorder was excluded prenatally. Only one of the families did not have members with ApoC2 genotypes that allowed prediction, but careful clinical study of older family members was found to be an important factor. ApoC2 typing of families with myotonic dystrophy should be of practical help both in prediction for asymptomatic relatives and for prenatal diagnosis in pregnancies of an affected parent.
Adult↗
First-trimester prediction in fetus at risk for myotonic dystrophy.
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Adult↗
Regional localisations and linkage relationships of seven RFLPs and myotonic dystrophy on chromosome 19.
We have studied the genetic linkage relationships of seven DNA polymorphisms on chromosome 19, with each other and with the myotonic dystrophy locus. The DNA sequences were localised to various regions of the chromosome using translocations in somatic cell hybrids. These results provide the basis for a linkage map of most of chromosome 19, and suggest that the myotonic dystrophy locus is close to the centromere.
Animals↗
Linkage relationships of the insulin receptor gene with the complement component 3, LDL receptor, apolipoprotein C2 and myotonic dystrophy loci on chromosome 19.
Myotonic dystrophy is associated with disturbances in the insulin response, possibly due to an abnormality of the insulin receptor. Both the myotonic dystrophy (DM) and insulin receptor (INSR) genes are on chromosome 19. Using a cloned gene probe for INSR, we have studied its linkage relationships with the DM locus and other chromosome 19 markers. The results show that INSR is not closely linked to DM, but is located very close to C3, in the region 19pter-19p13.2. This implies that the basic genetic defect which causes DM is not directly responsible for the disturbed insulin response in these patients.
Apolipoprotein C-II↗
Evidence against linkage of von Recklinghausen neurofibromatosis and chromosome 19 markers.
In this paper we report the study of the segregation of three chromosome 19 markers known to be linked to myotonic dystrophy in nine families with von Recklinghausen neurofibromatosis. Clear evidence against linkage was found for all three markers excluding the von Recklinghausen neurofibromatosis gene from the myotonic dystrophy region of chromosome 19.
Adult↗
Gene mapping and chromosome 19.
Chromosome 19 is currently the most fully mapped of the smaller chromosomes, with about 40 loci assigned to it (HGM8). Major inherited disorders on this chromosome include myotonic dystrophy and familial hypercholesterolaemia. Other loci include five blood groups, a cluster of apolipoprotein genes, and the receptors for insulin and polio virus. A number of cloned genes and random DNA sequences identify polymorphisms which, together with blood group and other protein polymorphisms, have been used to establish a framework for ordering the loci and estimating genetic distances. Hybrid cell lines allow loci to be assigned to one of eight different regions and a detailed genetic map of the chromosome will be possible in the near future.
ABO Blood-Group System↗
Linkage analysis of peripheral neurofibromatosis (Von Recklinghausen disease) and chromosome 19 markers linked to myotonic dystrophy.
Three chromosome 19 markers known to be linked to myotonic dystrophy have been studied in nine families with peripheral neurofibromatosis (Von Recklinghausen's disease). Clear evidence against linkage has been found for all three markers, excluding the peripheral neurofibromatosis gene from the myotonic dystrophy region of chromosome 19. Previous reports of co-inheritance of the two disorders in families cannot therefore be explained on the basis of close genetic linkage between the loci.
Adult↗
Mapping genetic markers on human chromosome 19 using subchromosomal fragments in somatic cell hybrids.
A series of mouse-human somatic cell hybrid lines (WILF) were derived from a hybrid that was originally thought to have chromosome 19 as its only human chromosome. In situ hybridization has been used to assess the amount of human material present in the different lines. All appear to contain different numbers of human chromosome fragments. A series of X-chromosome-specific DNA sequences hybridized against DNA from the lines revealed that material from the X long arm is present in several cases. Chromosome 19-specific DNA sequences used in a similar way show that fragmentation of this this chromosome has occurred with subsequent segregation of the fragments in different lines. The localization of these markers to various regions of chromosome 19, and their relation to the fragments observed in the WILF lines, is discussed.
Animals↗
The apolipoprotein CII gene: subchromosomal localisation and linkage to the myotonic dystrophy locus.
The human apolipoprotein CII gene probe detects a restriction fragment length polymorphism located on chromosome 19. We have investigated the linkage of this polymorphism to the myotonic dystrophy locus in families. The two loci are closely linked with a maximum Lod score of 7.877 at 4% recombination. The close linkage and informativeness of the APOC2 polymorphism suggest that this probe may be of use for presymptomatic diagnosis of the myotonic dystrophy gene. The APOC2 gene was localised to the region 19p13-19q13 using somatic cell hybrids, providing further evidence that the myotonic dystrophy locus is situated in the central region of chromosome 19.
Animals↗
Myotonic dystrophy and gene mapping on human chromosome 19.
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Base Sequence↗
In vitro studies on calcium activated phosphatidylinositol phosphodiesterase of erythrocyte ghosts from normal individuals and those with myotonic muscular dystrophy.
Myotonic muscular dystrophy is an inherited disorder affecting many organs, though the underlying biochemical defect is unknown. A recent publication [1] suggested that the metabolic lesion may be associated with defective phospholipid metabolism. These workers observed impaired calcium-stimulated phosphatidic acid accumulation in red cell ghosts from individuals with myotonic dystrophy compared with normal controls. The present study investigated some points of calcium-activated phosphatidylinositol metabolism in red cell ghosts from patients with myotonic dystrophy, those at risk of developing the disease and normal individuals. No differences between the three groups could be found in the incorporation of 32P into endogenous phosphatidylinositol nor in the distribution of label between the various phosphatidylinositols. Additionally, no differences were observed in either basal or calcium-activated phosphatidylinositol phosphate breakdown by phosphodiesterase. This would suggest that the observed decreased phosphatidate accumulation [1] may be due to impaired diacylglycerol kinase activity.
Calcium↗