Showing papers in "Journal of Medical Genetics in 1983"
TL;DR: The incidence of consanguineous matings in the general population was found to be 28.96% with an average inbreeding coefficient of 0.010, which could be considered high.
Abstract: A total of 26 554 Egyptians was ascertained to study the incidence of consanguineous marriages. They were of different ages, different socioeconomic standards, and from different areas. There were 7646 from urban areas, 11 280 from suburban areas, and 7628 from rural areas. The incidence of consanguineous matings in the general population was found to be 28.96% with an average inbreeding coefficient of 0.010, which could be considered high. The highest incidence was that in the rural areas. First cousin marriages occurred more often than the other types of consanguinity.
192Â citations
TL;DR: Seven excellent chapters include discussions on the analysis of MHC antigens at the protein and DNA levels, their organisation in the plasma membrane, restriction, properties of target cells, immune response genes and la antigen components, and finally speculations on evolution and function.
Abstract: seized to carry the factual descriptions into speculations about function and purpose. The seven excellent chapters include discussions on the analysis of MHC antigens at the protein and DNA levels, their organisation in the plasma membrane, restriction, properties of target cells, immune response genes and la antigens, MHC complement components, and finally speculations on evolution and function. This is not an easy book but it is certainly rewarding and brings together many of the threads of current research into the 'fine structure' of the MHC, surely itself the Rossetta stone of immunopathology.
134Â citations
132Â citations
TL;DR: Although there was an apparent excess of carcinoma of the lung, pancreas, and breast, the number of family members studied with specific organ cancer was too small; therefore, a larger sample size will be needed to verify this apparent excess.
Abstract: Genetic analysis was performed on four kindreds with clinical and pathological verification of the FAMMM syndrome. There were 80 affected or at risk members in these families. A segregation ratio of 0.47 was observed, which is consistent with an autosomal dominant mode of inheritance. Three obligate gene carriers who lacked any FAMMM phenotypic manifestations were observed and the rate of penetrance for the FAMMM gene was calculated to be 0.93. Cancer at all anatomical sites (exclusive of cutaneous malignant melanoma and intraocular malignant melanoma) showed a five-fold increase (p less than 0.004) in risk for gene carriers when age corrected and compared to the population expectation. Although there was an apparent excess of carcinoma of the lung, pancreas, and breast, the number of family members studied with specific organ cancer was too small; therefore, a larger sample size will be needed to verify this apparent excess. Our findings warrant further investigation in additional FAMMM kindreds.
102Â citations
TL;DR: The results indicate that persons who are 'poor metabolisers' of sparteine are also ' poor metaboliser' of debrisoquine and are autosomal Mendelian recessives.
Abstract: Debrisoquine and sparteine tests were carried out in 215 random white British subjects. There is a high degree of correlation between the urinary 'metabolic ratios' of the two drugs. New mathematical techniques have been developed (1) to define phenotypes and (2) to identify the genotypes within the dominant phenotype. The members of 15 families were tested with both debrisoquine and sparteine. The results indicate that persons who are 'poor metabolisers' of sparteine are also 'poor metabolisers' of debrisoquine and are autosomal Mendelian recessives.
95Â citations
TL;DR: The results show a significant association between the slow acetylator phenotype and bladder cancer and this association can be interpreted in one of two ways: (1) rapid acetylators may be protected against developing bladder cancer because they are better able to render amines non-carcinogenic by acetylation, or (2) slowacetylators have greater survival with bladder cancer than rapid acetYLators.
Abstract: There is an association between exposure to aromatic amines and the development of bladder cancer. Aromatic amines such as are known to occur in tobacco smoke are polymorphically acetylated. One hundred bladder cancer patients have been acetylator phenotyped. Only three of them were non-smokers at the time of diagnosis. This new series, together with four previous series (each with its own control), have been statistically analysed together. The results show a significant association between the slow acetylator phenotype and bladder cancer. The slow acetylator phenotype is associated about 39% more with bladder cancer than is the rapid acetylator phenotype. This association can be interpreted in one of two ways: (1) rapid acetylators may be protected against developing bladder cancer because they are better able to render amines non-carcinogenic by acetylation, or (2) slow acetylators have greater survival with bladder cancer than rapid acetylators. Further evidence will be required to differentiate between these alternatives.
95Â citations
TL;DR: SEM has allowed a more precise location of the fragile site to the Xq27 .
Abstract: Scanning electron microscopy (SEM) has been used to study the fragile X chromosome. The fragile site appears as an isochromatid gap in the majority of cases, confirming light microscope (LM) observations. SEM has allowed a more precise location of the fragile site to the Xq27 . 3 region.
92Â citations
TL;DR: A distinct and previously undescribed syndrome has been observed in six Saudi Arabian patients from two highly inbred families, indicating an autosomal recessive pattern of inheritance.
Abstract: A distinct and previously undescribed syndrome has been observed in six Saudi Arabian patients from two highly inbred families. The parents were normal, indicating an autosomal recessive pattern of inheritance. All the patients have a distinctive facial appearance, hypogonadism, sparse or absent hair, diabetes mellitus, mental retardation, mild deafness, and variable S-T and T wave abnormalities on the electrocardiograph.
91Â citations
TL;DR: It was concluded that the burden of telling children the risks is too great for most parents and that professional help is needed and the long term impact of genetic counselling on the incidence of the disease is impossible to assess without continued monitoring.
Abstract: Ninety-two patients suffering from Huntington's chorea (HC) and their spouses, and 91 subjects with an affected parent and their spouses, living in three counties of industrial South Wales, have been studied regarding their knowledge of their inheritance of the disorder. Particular attention was paid to its influence on their attitudes towards child-bearing, telling their children of the risks, and predictive tests. Only 12% of the patients were known to have received professional advice before completing their families, in contrast to 68% of the sample at risk. It is estimated that 82% of the patients and 60% of the subjects at risk had, or might have, restricted their family size had they known in time. The majority found genetic counselling helpful, but did not necessarily wish to alter their child-bearing plans in consequence. It was clear that information provided by the family alone was usually inadequate and that this applied to the present generation at risk as well as to previous generations. It was concluded that the burden of telling children the risks is too great for most parents and that professional help is needed. The long term impact of genetic counselling on the incidence of the disease is impossible to assess without continued monitoring, but preliminary results are encouraging. Attitudes towards a predictive test reflected much conflict: although 56% overall wished to take one, only 40% of those who were parents wished to know if they were at risk of passing the gene on to their children. Few subjects reported severe social stress on learning of their genetic risks, but about one in four reported experiencing significant anxiety.
86Â citations
TL;DR: The results suggest that the locus for Becker muscular dystrophy is on the short arm of the X chromosome, and further that these two loci may be closely linked or possibly allelic.
Abstract: A study of DNA restriction fragment polymorphisms and Becker muscular dystrophy has shown eight families informative for the cloned sequence L1.28, which is located on the short arm of the X chromosome between Xp110 and Xp113. Analysis of these families reveals linkage between the two loci, with the maximum likelihood estimate of the genetic distance being 16 centiMorgans (95% confidence limits between 7 and 32 centiMorgans). Since a study of DNA polymorphisms in Duchenne muscular dystrophy has shown a comparable linkage distance with L1.28, our results suggest that the locus for Becker muscular dystrophy, like that for Duchenne dystrophy, is on the short arm of the X chromosome, and further that these two loci may be closely linked or possibly allelic.
84Â citations
TL;DR: The authors consider this is still too high an estimate in view of the number of persons in the families only mildly affected by the inherited disease who cannot be identified, although their malignant disease will be known.
Abstract: The association of diaphyseal aclasis and neurofibromatosis with malignant neoplasms has been variously reported as between 5 and 28% of all cases, but malignant disease invariably presents at hospital and the true frequency from an unselected group is unknown. The current survey reviews not only hospital patients but also their affected relatives, with particular reference to malignant disease and the cause of death in all family members. A survey of 36 index patients and 80 known affected relatives with diaphyseal aclasis and 37 index patients and 33 known affected relatives with neurofibromatosis has been carried out. The observed proportions with associated malignant disease were 0.9% of all cases of diaphyseal aclasis and 4.3% of neurofibromatosis. The authors consider this is still too high an estimate in view of the number of persons in the families only mildly affected by the inherited disease who cannot be identified, although their malignant disease will be known. A more likely figure for malignant change in diaphyseal aclasis is calculated at 0.5% (or 1.3% of those over 21 years) and in neurofibromatosis 2.0% (or 4.2% of those over 21 years).
TL;DR: Finds that the patients with dentinogenesis imperfecta differ not only in their dental characteristics but also in other clinical features mean that they have a more severe disease with a greater fracture rate and a greater likelihood of growth impairment.
Abstract: We have studied 166 patients from 71 families with Sillence type I osteogenesis imperfecta (dominant inheritance and blue sclerae). We confirm earlier findings that there are two subgroups, those with and those without dentinogenesis imperfecta; each family can be allocated to one or other group. Our confidence that the two groups represent distinct disorders is increased by finding that the patients with dentinogenesis imperfecta differ not only in their dental characteristics but also in other clinical features. They have a more severe disease with a greater fracture rate and a greater likelihood of growth impairment.
TL;DR: In hereditary sensory radicular neuropathy, familial dysautonomia, and tabes dorsalis, changes in dorsal root ganglia cells cause similar clinical signs and thus it may be concluded that shooting pains in Fabry's disease may be caused by damage to dorsal rootganglia neurones.
Abstract: Bouts of shooting pain along the extremities are common in the early stages of Fabry's disease. No pathological explanation has been advanced to clarify the mechanism of such pain. In the present case neuronal storage of glycolipid was confined to dorsal root ganglia neurones only. It is suggested that this may explain the shooting pain in Fabry's disease. In hereditary sensory radicular neuropathy, familial dysautonomia, and tabes dorsalis, changes in dorsal root ganglia cells cause similar clinical signs and thus it may be concluded that shooting pains in Fabry's disease may be caused by damage to dorsal root ganglia neurones.
TL;DR: The segregation data for both the C2 protein polymorphism and the C3 RFLP support the linkage of myotonic dystrophy and C3, and can be readily used in linkage analyses of loci on chromosome 19.
Abstract: Variations in DNA sequence generate polymorphisms which can be followed through families. A cloned gene specific probe for human complement 3 (C3) was hybridised to DNA samples digested with restriction endonucleases. The C3 probe detects several restriction fragment length polymorphisms (RFLPs) that occur frequently in the general population. These DNA alleles can be readily used in linkage analyses of loci on chromosome 19, since most families studied are informative. The inheritance of one such polymorphism was followed through myotonic dystrophy families. The segregation data for both the C3 protein polymorphism and the C3 RFLP support the linkage of myotonic dystrophy (DM) and C3.
TL;DR: One patient has an interstitial deletion identical to that found in a previously reported patient, although they are phenotypically dissimilar, and the other patient has a terminal deletion, the first such deletion reported to date.
Abstract: We describe the clinical and cytogenetic findings of two patients with deletions of the long arm of chromosome 2. One has an interstitial deletion identical to that found in a previously reported patient, although they are phenotypically dissimilar. The other patient has a terminal deletion, the first such deletion reported to date.
TL;DR: A 2-year-old boy with psychomotor retardation, congenital unilateral ptosis, bilateral adducted thumbs, weakness of upper limbs, and Hirschsprung's disease, with complete agenesis of the corpus callosum and hypoplasia of the inferior vermis and cerebellum is reported.
Abstract: A 2-year-old boy with psychomotor retardation, congenital unilateral ptosis, bilateral adducted thumbs, weakness of upper limbs, and Hirschsprung's disease (aganglionosis), with complete agenesis of the corpus callosum and hypoplasia of the inferior vermis and cerebellum is reported. His 24-year-old maternal uncle, with severe psychomotor retardation but none of the other physical problems, also has agenesis of the corpus callosum demonstrated by CT scan. The implications for antenatal diagnosis are discussed.
TL;DR: The echocardiographic identification of cardiac tumours in antenatal life in a pregnancy where the father was known to have tuberous sclerosis allowed termination of an affected pregnancy in the second trimester.
Abstract: We report the echocardiographic identification of cardiac tumours in antenatal life in a pregnancy where the father was known to have tuberous sclerosis. This allowed termination of an affected pregnancy in the second trimester.
TL;DR: Two DNA restriction fragment length polymorphisms show genetic linkage to the Duchenne muscular dystrophy locus on the short arm of the X chromosome.
Abstract: Two DNA restriction fragment length polymorphisms show genetic linkage to the Duchenne muscular dystrophy locus on the short arm of the X chromosome. Examples are given of families in which these polymorphisms can be used in the prediction of genotype for this disorder.
TL;DR: The hitherto unrecognised but consistent pattern of multiple malformations found with agenesis of the gall bladder may imply a non-random tendency for these defects to occur together.
Abstract: Thirty-four cases (29 children and five adults) of congenital absence of the gall bladder were found in a retrospective necropsy study. When the distribution of associated malformations in these patients was analysed, the cases were found to fall into several groups. The largest group (13) had multiple anomalies involving the genitourinary (83% reproductive tract, 42% renal), gastrointestinal (46% imperforate anus, 23% tracheo-oesophageal fistula), cardiovascular (54% cardiac defects, 23% single umbilical artery), and skeletal (31%) systems. Eight other patients had predominantly cardiac anomalies in addition to the agenesis of the gall bladder. Five had abnormalities associated with defects of the anterior abdominal wall. There were no additional malformations in the remaining cases. Family history was negative in all, suggesting a sporadic occurrence. Comparison with previously reported cases confirmed a similar distribution of anomalies. The hitherto unrecognised but consistent pattern of multiple malformations found with agenesis of the gall bladder may imply a non-random tendency for these defects to occur together.
TL;DR: Two siblings were reported with severe congenital microcephaly, spasticity, and seizures and both had extensive intracranial calcification.
Abstract: Sibs are reported with severe congenital microcephaly, spasticity, and seizures. Both had extensive intracranial calcification.
TL;DR: It is concluded that there is probably a greatly increased risk of dissection of the aorta in Turner's syndrome even in the absence of any other abnormality of theAorta and aortic valve.
Abstract: Three deaths from dissection of the aorta in a series of 157 adult women with Turner's syndrome are reported. These are greatly in excess of the numbers expected. None of the three patients had a coarctation of the aorta. One had aortic regurgitation but there was no reason to believe that the aorta in the other two patients had been subjected to unusual haemodynamic stresses. Cystic medial necrosis of the aorta was described in two patients on whom necropsies were carried out. It is concluded that there is probably a greatly increased risk of dissection of the aorta in Turner's syndrome even in the absence of any other abnormality of the aorta and aortic valve. Previously reported cases of aortic dissection in Turner's syndrome are discussed.
TL;DR: The incidence of Down's syndrome in the Liverpool and Bootle areas from 1961 to 1979 was investigated and it is suggested that the fall in incidence can be explained by theFall in mean maternal age.
Abstract: The incidence of Down's syndrome in the Liverpool and Bootle areas from 1961 to 1979 was investigated. A total of 319 liveborn cases was ascertained over this period. Using 3-year moving averages, the incidence of the condition fell gradually from 1.62 per 1000 livebirths for 1961 to 1963 to 1.09 per 1000 livebirths for 1977 to 1979. This trend is significant at the 0.1% level. Over the same period the mean maternal age of Down's syndrome births fell gradually from 36.7 years in 1961 to 29.0 years in 1979. This trend is significant at the 1% level. There was a contemporaneous decrease in the proportion of total births to women over 35 years in the study area. Cytogenetic analysis was performed on 175 out of the 319 index cases (54.9%). Of these, there were 161 trisomies (92%), 11 translocations (6.3%), and three mosaics (1.7%). Between 1969 and 1979 four terminations of pregnancy for Down's syndrome were performed, all for trisomy. Quinquennial age specific incidences for Down's syndrome were calculated for the years 1960 to 1964, 1965 to 1969, 1970 to 1974, and 1975 to 1979. There have been no statistically significant changes over this time. It is suggested that the fall in incidence of Down's syndrome can be explained by the fall in mean maternal age.
TL;DR: The observations of a further female with DMD who carries a de novo translocation between Xp and 9p are reported, adding evidence for the assignment of this band as the site of the DMD gene.
Abstract: Females who fully manifest Duchenne muscular dystrophy (DMD), an X linked disorder, are extremely rare. Cytogenetic studies are indicated in such females to rule out an X chromosome abnormality, which could render a female hemizygous for X linked genes. At present there are six reports describing females with Duchenne muscular dystrophy and an X; autosome translocation. Although each of these six rearrangements involves a different autosome, (chromosomes 11, 21, 1, 3, 5, and 6) they have in common a breakpoint at Xp21. We report here our observations of a further female with DMD who carries a de novo translocation between Xp and 9p. The breakpoint in our patient is also located at Xp21, adding evidence for the assignment of this band as the site of the DMD gene.
TL;DR: It is argued that chromosome aneuploidy is more likely to be related to processes concerned with ageing rather than being specifically linked to the dementia of Alzheimer's disease.
Abstract: Lymphocyte chromosomes were examined in 36 patients with Alzheimer's presenile dementia, 36 healthy, age and sex matched controls, and 36 sex matched, non-demented, elderly controls, approximately 20 years older than the Alzheimer patients. Increased chromosome aneuploidy was found in females with Alzheimer's disease but not in male subjects. Chromosome abnormalities observed in female patients were similar to those observed in elderly controls, though in this latter group there was an increase in the frequency of cells that had lost an X chromosome. In the female Alzheimer patients and the elderly controls, there was an increase in the frequency of autosomal aneuploid cells but no single chromosome was preferentially affected. Because the chromosome abnormalities found in Alzheimer's disease are similar in nature but not as extensive as those observed in senescence in the absence of dementia, it is argued that chromosome aneuploidy is more likely to be related to processes concerned with ageing rather than being specifically linked to the dementia of Alzheimer's disease.
TL;DR: It appears that, in the X linked form, XY gonadal dysgenesis may be caused by a point deletion or mutation of a gene on the X chromosome, which controls the gonad specific receptor for the H-Y antigen.
Abstract: Five phenotypic females in one family had the genotype 46,XY and all had gonadal germ cell tumours. Studies of the family pedigree suggest that this form of XY gonadal dysgenesis is inherited in an X linked recessive manner. G banding of elongated metaphase chromosomes from two subjects with XY gonadal dysgenesis and a female carrier showed no aberrations of the X chromosome. The titres of H-Y antigen in three girls with XY gonadal dysgenesis were in the male control range. Thus it appears that, in the X linked form, XY gonadal dysgenesis may be caused by a point deletion or mutation of a gene on the X chromosome, which controls the gonad specific receptor for the H-Y antigen. Studies of Xg blood groups were uninformative about linkage of Xg with the X borne gene causing the XY gonadal dysgenesis. Dermatoglyphic studies in the girls with XY gonadal dysgenesis and female carriers revealed high a-b palmar ridge counts and a tendency for the A mainline to terminate in the thenar area. Both of these features have been described in patients with Turner's syndrome.
TL;DR: No unequivocal new mutation was identified among 101 kindreds containing 418 affected persons, which supports the extreme rarity of mutation in Huntington's chorea.
Abstract: A study of mutation, biological fitness, and patterns of family building in Huntington's chorea has been carried out, based on a previously reported population study of the disorder in South Wales. No unequivocal new mutation was identified among 101 kindreds containing 418 affected persons, which supports the extreme rarity of mutation in this disorder. Increased values of fertility and fitness were found, both in relation to unaffected relatives and to the general population of the area. The proportion of unmarried persons and pattern of family building was comparable in affected and unaffected subjects, and no correlation with age at onset or mode of clinical presentation could be found.
TL;DR: The chiasma distribution of bivalents 15 and 16 identified at diakinesis by a quadruple staining technique including DA-DAPI fluorescence has been investigated in two human males and it has shown that chiasmata are not distributed at random.
Abstract: The chiasma distribution of bivalents 15 and 16 identified at diakinesis by a quadruple staining technique including DA-DAPI fluorescence has been investigated in two human males. The study has shown that chiasmata are not distributed at random. Both chromosomes have distally localised chiasmata, but in the long arm of chromosome 15 chiasmata are also found to be localised proximally, adjacent to the centromere. Genetic lengths and recombination fractions have been calculated from chiasma distribution data for the major bands of chromosomes 15 and 16 under the assumptions that there is no chromatid interference, no chiasma movement, and no difference between mitotic and meiotic band positions. The localisation of chiasmata implies much discrepancy in recombination patterns between the acrocentric chromosome 15 and the submetacentric chromosome 16.
TL;DR: The mouse mutant curly-tail is an animal model for human neural tube defects (NTD) and it is suggested that the underlying mechanism causing NTD in the mice and also in man is a basic metabolic defect in DNA synthesis which affects cell replication and results in abnormal morphogenesis of the neuraxis.
Abstract: The mouse mutant curly-tail is an animal model for human neural tube defects (NTD). Around 60% spontaneously have NTD. It has been found that maternal administration of hydroxyurea, mitomycin C, or 5-fluorouracil on day 9 of pregnancy, that is, when the fetal neural tube is in the final stages of closure, leads to a significant reduction in the proportion of NTD (to 15 to 20%) in the offspring, while total litter size is unaffected. All these substances are inhibitors of DNA synthesis, yet are apparently beneficial to subjects predisposed to NTD. As a consequence, it is suggested that the underlying mechanism causing NTD in the mice, and also in man, is a basic metabolic defect in DNA synthesis which affects cell replication and results in abnormal morphogenesis of the neuraxis.
TL;DR: In this article, identical twins with Huntington's disease were described who were raised in separate households from birth, and age at onset, landmarks of the disease, and behavioural abnormalities were strikingly similar.
Abstract: Monozygotic twins, identical by serological studies, with Huntington's disease are described who were raised in separate households from birth. Age at onset, landmarks of the disease, and behavioural abnormalities were strikingly similar. Previously reported twin studies in Huntington's disease are reviewed. Twin data support the hypothesis that age at onset and several other clinical features of the illness are substantially determined by genetic mechanisms.
TL;DR: Linkage analysis of 28 genetic markers was undertaken in 108 subjects from 11 families with well-documented, classic, peripheral neurofibromatosis, and suggested close linkage with 12 markers, including the secretor locus, closely linked to myotonic dystrophy.
Abstract: Linkage analysis of 28 genetic markers was undertaken in 108 subjects from 11 families with well-documented, classic, peripheral neurofibromatosis. Fifty-four persons were affected in one four-generation family, seven three-generation families, and three two-generation families. Lod scores were calculated using the standard LIPED programme for 49 combinations of theta male and theta female from 0.01 to 0.50. Lod scores excluded close linkage with 16 markers, including most tested on chromosome 1 and HLA on chromosome 6, and were inconclusive for 12 markers, including the secretor locus, closely linked to myotonic dystrophy. Analysis of five informative families resulted in a lod score of +2.2 for close linkage with GC on chromosome 4. However, the lod score for GC in the one additional informative family was negative, so that the final interpolated maximum was Z = 0.89 for theta male = 0.03, theta female = 0.28. Further studies are needed to evaluate this suggestion of linkage and possible genetic heterogeneity.