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ANNOTATIONS AMERICAN JOURNAL OF HUMAN GENETICS December 1989, Vol. 45, No. 6. The Natural History of Cytogenetically Abnormal Fetuses Detected at Midtrimester Amniocentesis which are not Terminated Electively: New Data and Estimates of the Excess and Relative Risk of Late Fetal Death Associated with 47, + 21 and Some Other Abnormal Karyotypes by E. B. Hook, B. B. Topol and P. K Cross. This paper gives the results of an ongoing survey of the rates of spontaneous fetal death associated with chromosome abnormalities detected by amniocentesis during the second trimester where the mother decided not to have an abortion. For 47, + 21 the estimated excess risk is 25.6 per cent, for 47, + 18 it is 63.8 per cent, and for 47, + 13 it is 36.5 per cent. There was little evidence for an excess risk of fetal death in 47, XXY, 47, XYY, or 47, XXX but for 45, X it was very high at 65.3 per cent. The Human Debrisoquine 4-Hydroxylase (CYP2D) Locus: Sequence and Identification of the Polymorphic CYP2D6 Gene, a Related Gene, and a Pseudogene by S. Kimura, M. Umeno, R C. Skoda, U. A. Meyer and F. J. Gonzalez. The debrisoquine-4-hydroxylase polymorphism is a genetic variation in oxidative drug metabolism which gives rise to two phenotypes, the extensive metabolizer (EM) and the poor metabolizer (PM). Between 5 and 10 per cent of the Caucasian populations of Europe and North America are of the PM type and are unable to metabolize debrisoquine and many other drugs, leading to exaggerated response to these drugs during clinical treatment. It is believed that the enzyme may have originally evolved to metabolize plant toxins, but as plants or habitats changed it was not needed for survival, was no longer of selective advantage, and so became effectively neutral in its effect on individuals until the development of modern drugs. The PM defect is caused by several mutant alleles of the CYP2D6 gene. The authors have investigated this and two other genes, CYP2D7 and CYP2D8P, which occur in the CYP2D region. CYP2D8P is a pseudogene containing several gene-disrupting insertions, deletions, and termination codons. CYP2D7 is apparently normal except that its first exon contains an insertion which disrupts the reading frame. They hypothesize that the pseudogene transfers detrimental mutations via gene conversions into the CYP2D6 gene, and this would account for the high frequency of mutations observed in this gene. Recessive Inheritance of a Relative Fat Pattern by S. J. Hasstedt, M. E. Ramirez, H. Kuida and R. R Williams. Obesity itself appears to be largely caused by environmental factors such as diet and training but evidence from twin and adoption studies suggests that the pattern of fat deposition is affected by genetic factors. In this study a relative-fat-pattern index (RFPI), defined as the ratio of subscapular skinfold thickness to the sum of subscapular and suprailiac skinfold thicknesses, was determined for 774 adults aged 25 or over in 59 pedigrees ascertained through cases of cardiovascular disease. There appears to be a major locus with alleles inherited in an autosomal recessive mode which largely accounts for the difference in fat distribution patterns. Homozygotes for a high RFPI were more frequent in younger than in older cases of obesity, coronary heart disease, essential hypertension, and diabetes. Though there is some doubt about what the RFPI defined in this manner is actually measuring, it seems to be biologically relevant. These findings suggest that while obesity is mainly environmental in causation, where fat accumulates is at least partly under genetic control and that the sites of fat deposition can be important factors in the progress of a number of common diseases. January 1990, Vol. 46, No. 1. Predictive Testing for Huntington Disease in Childhood: Challenges and Implications by M. Bloch and M. R. Hayden. Most genetic disorders for which predictive testing is now possible are early onset diseases, and prenatal testing for such disorders enables the parents to decide between ending the pregnancy or continuing it to term, the situation is very different with Huntington Disease (HD) which is an adult, late onset disorder. Now that predictive testing for HD is possible, young adults, even children, could be told that at some time, most probably in their third or fourth decade, they will experience the onset of this neurodegenerative disorder which will steadily get worse until they die between 15 and 25 years after diagnosis. They could also be told, or quite easily discover, that there is no known treatment for HD. The authors of this paper, who are involved in a research programme to develop guidelines for HD testing, discuss the ethical problems involved and defend their current position in which they would test only adults who, in theory at least, understand what the result could mean for them as individuals. How predictive testing for HD is handled could become the model for similar programmes for other late onset, incurable genetic disorders. The Phenotype of 45X/46XY Mosaicism: An Analysis of 92 Prenatally Diagnosed Cases by H. J. Chang, R. D. Clark and H. Bachman. A prenatal diagnosis of 45 X/46XY mosaicism poses a problem for the genetic counsellor since the phenotypic range of this condition is not really known. Cases in the literature have, inevitably, been ascertained mainly by some abnormality occurring. In an attempt to determine the phenotypic range of 45X/46XY mosaicism the authors analysed 92 prenatally diagnosed cases of the condition. They estimate that 95 per cent of 45X/46XY mosaics will have normal male genitalia but there is a significant, about 27 per cent, risk of abnormal gonadal histology. Long term follow-up of these cases will be necessary to determine the effects of the mosaicism on stature, fertility, and tumour risk. Heredity and Adoption: A Survey of Adoption Agencies by D. Plumridge, J. Burns and N. L. Fisher. This survey, conducted on behalf of the Social Issues Committee of the American Society of Human Genetics into the legal requirements for the public adoption agencies of the 50 states and Washington DC to collect genetic information about adopted children, revealed that only one state, Wisconsin, had a legal requirement to collect such information. Thirteen other states had laws requesting genetic information to be obtained "if possible." Twenty-one states required a medical/social history which might, or might not, include genetic data. Surprisingly 16 states required no medical information at all. Since genetic clinics are receiving an increasing number of requests from adoption agencies the authors believe that the interests of the adopted child and his or her adoptive family would be best served by collecting genetic information at the time of adoption in a standard form. For this purpose they believe that it will be necessary to provide adoption agency social workers with some formal training in genetics. Although this survey relates to the American experience the issues it raises may not be unimportant elsewhere. JOHN TIMSON JOURNAL OF MEDICAL GENETICS January 1990, Vol. 27, No. 1. A Consortium approach to molecular genetic services by D. J. H. Brock. In 1985 four University Medical Centres in Scotland formed a consortium to provide a molecular genetics service for the whole of Scotland, population 5 million. Such collaboration meant that each of the four laboratories could gain maximum experience with the probes required for the diseases assigned to them and could take on a consultative role. In addition, each centre could maintain a local educational role because of its personal expertise. The audit of the work carried out in the first three years of the consortium has illustrated the enormous work load, the efficiency with which genetic diseases have been attacked, and the resulting realisation by the Scottish Home and Health Department that further funding was required and would be well spent. For example, 8383 DNA samples relating to more than 25 genetic diseases have been stored, DNA from all the 254 Duchenne and Becker families has been analysed, and DNA has been obtained from 41% of the total number of living patients with Huntington’s Chorea. Fears about not being in control of specimens from one’s own families were unfounded and indeed the collaboration and semi-annual conferences between the four centres have been most beneficial. Search for consanguinity within and among families of patients with trichothiodystrophy associated with xeroderma pigmentosum by F. Nuzzo, G. Zie, M. Stefanini, R. Colognola, A. S. Santachiara, P. Lagomarsini, S. Marinoni and L. Salvaneschi. Four patients each with two rare autosomal recessive diseases were found among three families, apparently unrelated but living in the north-east Italian Alps. The authors used genealogy, the study of genetic markers and the analysis of surnames to determine whether the occurrence of two rare recessive diseases was independent (but related to isolation and probable consanguinity) or associated, due to linkage proximity of the two genes. It was concluded that the latter explanation was more likely, since in at least two out of the three families the two disease genes originated from the same ancestral couple. It is therefore of great interest that occasional patients from other countries have been affected by the same pair of recessive diseases. Ethical issues policy statement on Huntington’s disease molecular genetics predictive test. Recommendations drawn up by representatives of the International Huntington Association and the World Federation of Neurology. These are useful recommendations including, for example, the statement that any person at risk wanting the test should therefore be offered it, if he or she has reached the age of majority, and that the result should not be communicated to a third party. The recommendations include a sensible and practical protocol for administering the test and for follow-up. February 1990, Vol. 27, No. 2. Neuroblastoma in a patient with Sotos’ syndrome by M. A. Nance, J. P. Neglia, D. Taiwar and S. A. Berry. A fifteen month girl with Sotos’ syndrome developed neuroblastoma, and this observation led the authors to review the literature on tumours in Sotos’ syndrome, and to point out that the risk of neoplasia is increased not only in this syndrome but also in other syndromes which are associated with large birth weight and excessive growth. Compound heterozygosity for abetalipoproteinaemia and familial hypobetalipoproteinaemia by S. Keidar, A. Etziono, J. G. Brook, R Gershoni-Baruch and M. Aviram. An Ashkenazi Jewish boy with minor clinical problems was found to have the biochemical features of abetalipoproteinaemia, which is an autosomal recessive condition. However his mother and maternal grandfather had the dominant condition of familial hypobetalipoproteinaemia characterised by reduced levels of serum cholesterol and betalipoprotein. The patient’s father had normal levels of betalipoprotein consistent with his being a carrier for recessive abetalipoproteinaemia. The authors conclude that the patient is a compound heterozygote for the two conditions, thus suggesting that the two genes are allelic. Unilateral disomy as a possible explanation for the Russell-Silver syndrome by J. G. Hall. The asymmetrical and hitherto unexplained intrauterine growth retardation of the Russell-Silver syndrome may be due to uniparental disomy. An analogy is provided by transgenic mouse studies where maternal disomies are associated with intrauterine growth retardation, and by two reported patients who had cystic fibrosis, who were unusually small, and who had maternal disomy for chromosome 7. March 1990, Vol. 27, No. 3. A Chinese familial growth hormone deficiency with a deletion of 7.1 Kb of DNA by Y. A. He, S. S. Chen, Y. X. Wang, X. Y. Lin and D. F. Wang, Two sisters of normal size at birth suffered from severe post-natal growth deficiency so that by 8 and 11 years of age they were only the height of 1-2 year olds. They both had a 7.1 Kb deletion of DNA and the band derived from the normal human growth hormone gene was missing. Their mothers [parents? – ed.], who were third cousins, were heterozygous for the deletion. Most other patients with autosomal recessive growth hormone deficiency have also had consanguineous parents and similar (though not identical) deletions. They have come from a variety of countries, namely Iraq, Iran, the Yemen, Italy, Switzerland, Austria, Argentina and Japan. These observations suggest that this area of chromosome 17 is prone to deletions, perhaps as a secondary effect of a preceding mutation. Pontobulbar palsy and neurosensory deafness (Brown-Vialetto-Van Laere syndrome) with possible autosomal dominant inheritance by S. A. Hawkins, N. C. Nevin and A. E. Harding, The authors describe a rare and progressive condition in a girl who was fit and healthy to the age of 12. She then became deaf over a few weeks and subsequently developed bulbar palsy, muscle weakness and a mild neuropathy. By the age of 16 she needed assisted ventilation because of diaphragmatic weakness and she died at 17 years. Her father and some relatives became deaf during childhood and an aunt had some mild muscle weakness. Autosomal dominant inheritance is therefore postulated for this curious and unpleasant disorder. Focal dermal hypoplasia (Goltz syndrome) by I. K. Temple, P. MacDowall, M. Baraitser and D. J. Atherton. The characteristic features of this genetic syndrome comprise congenital red macules, fat herniation in the skin, sparse hair, nail dystrophy, limb anomalies and amputations, colobomata of the irides and deafness, although not all of these are always present. Most patients are females and this may be another example of an X-linked dominant condition with lethality in males. It is important to be aware of this condition since signs in an adult female may be very mild. Identical twins discordant for Kallmann’s syndrome by L. J. Hipkin, I. F. Casson and J. C. Davis. Kallmann’s syndrome consists of anosmia and hypogonadotrophic hypogonadism. It is often familial although different types of inheritance have been postulated. These male twins are interesting because the proband presented at the age of 20 with no secondary sexual development and was found to be unable to smell, while his monozygotic twin had anosmia only. Review of the literature revealed a similarly discordant monozygotic female twin pair and other familial cases in which either hypogonadism or anosmia occurred. The authors therefore wonder if there is a genetic predisposition which may lead either to hypogonadism or to an impaired sense of smell or to both. SARAH BUNDEY | ||||||