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MeetingsThe First South American Workshop on Genomics and Community Genetics 2005 Genetics and Population Health 2004 Community Genetics in Asia 2004 Bangalore 2002
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Community Genetics in developing countries
1, 2, 6 UAE University,3Al Ain Hospital,4Oasis Hospital, Al Ain, and5Tawam Hospital, United Arab Emirates A congenital anomalies register can be defined as a system for the collection, storage and application of data on cases affected with congenital anomalies. Although such registries have been established in most of the developed world, they are still lagging behind in developing countries even though evidence from such countries indicate a relatively high birth prevalence of infants with congenital abnormalities. The Congenital Abnormalities Study Group of the Emirates was established in 1992 and became a member of International Clearing House of Birth Defects in 1995. It collects and maintains a computerized permanent records of medical and personal information about malformed newborns and infants in Al Ain Medical District which has a population of 300,000 with annual birth of 8000. Our experience over the past few years indicates that the frequency of congenital anomalies in the UAE population is not higher than other populations but the pattern is different with a high frequency of congenital anomalies of genetic origin particularly autosomal recessive types. Furthermore, these anomalies tend to cluster in specific families and tribes. Once these families are identified they could be offered special preventive programs and genetic counseling. algazali@hotmail.com ' Molecular aspects of inherited hearing defects Anand, A. Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India No abstract submitted The role of the media in promoting knowledge of genetics Balasubramanian, D. L.V. Prasad Eye Institute, Hyderabad, India No abstract submitted ' Neutral and pathological mitochondrial DNA variation: implications in genetic affinities of Indian and mitochondrial disorders Barnabas, S. National Chemical Laboratory, Pune, India The journey of the 'Homo' lineage 'Out Of Africa' resulted in the colonization of new continents including the Indian sub-continent. These migrations have been traditionally studied by palaeontologists, anthropologists, and archaeologists. More recently, the use of genes to trace human pre-history has generated great interest in these ancient travels. Genetic information has provided significant information about the origins, prehistoric migrations, genetic relationships and genetic variation of the various world ethnic groups. The study of global genetic variation is also making it possible to study pathological mutations and will lead to better understanding of genetic diseases. Mitochondrial DNA (mtDNA) has proved to be a very important tool for the study of human evolutionary history, due to its non-recombinant and maternal mode of inheritance, large copy number and rapid rate of evolution. The understanding of human mtDNA variation and genetics has provided new and interesting insights into human evolution, degenerative diseases and aging. MtDNA mutates ten to twenty times faster than the nuclear DNA. Mitochondrial ATP production via the oxidative phosphorylation (OXPHOS) is essential for normal function and maintenance of human organ systems. Pathological mutations in mtDNA result in impaired electron transport and ATP synthesis, causing tissue dysfunction which ultimately expresses as human diseases, ranging from systemic lethal pediatric diseases to late onset tissue-specific neurodegenerative disorders. john@ems.ncl.res.in ' Endogamy, consanguinity and Community Genetics in developing countries Bittles, A.H. Centre for Human Genetics, Edith Cowan University, Perth, Australia From a historical perspective, India has played a major role in the development of Community Genetics. State decennial census returns from 1871 onwards contained questions on the prevalence of insanity, deaf-mutism, blindness and leprosy. By 1921 these data were collected at caste and biraderi level, and in the Punjab specific comparisons were made between disease prevalence at community level, to determine whether consanguineous marriage was disadvantageous. Intra-community marriage continues to be strongly favoured in most Developing Countries, and in many populations the practice of clan/tribal/caste endogamy is combined with preferential consanguineous marriage. To assess the effects of consanguinity on gene pool composition and structure, national, regional and community-based collaborative studies have been conducted in India and Pakistan. STR analysis of autosomal markers indicates that, despite consanguineous marriages over multiple generations, there is significant residual heterozygosity within individual communities. The studies also show major differences in the gene pools of co-resident, endogamous communities, with individual patterns of Y-chromosome haplotypes and mtDNA markers. These intra-population divisions are of particular significance in Community Genetics, and strongly suggest that the investigative approaches adopted in populations where endogamous marriage is the rule should differ from those applied in panmictic populations. Besides population genetics and genetic epidemiology, knowledge of the history, demography and social structure of individual communities also contribute significantly to a better understanding and appreciation of their health needs. a.bittles@ecu.edu.au Intellectual disability and cerebral palsy Corry, P.C.1, Sinha, G.1, Karbani, G.2, Woods, C.G.2, Markham, A.F.3 and Mueller, R.F.2 1St Luke's Hospital, Bradford, 2Yorkshire Regional Genetics Service, St James's University Hospital, Leeds, and 3Molecular Medicine Unit, University of Leeds, U.K. Bradford is a northern English city with a population of 370,000 and about 5,500 births each year. In recent years a large community of Pakistani families has grown up and, in 2000, 39.5% of Bradford births were Pakistani. There is a very high prevalence of consanguinity in this group. More than 300 children are now referred to the Child Development Centre each year, and there are striking differences in the prevalence of many disabling conditions. Data will be presented on cerebral palsy, microcephaly and neurodegenerative conditions. Socio-economic status and maternal health may be linked to cerebral palsy, but we also found evidence of genetic factors with a large number of similarly affected siblings. Primary microcephaly was much more common in the Pakistani population. About 7% of children reported in an ongoing U.K. study of Progressive Intellectual and Neurological Deterioration are from Bradford, with 39 out of 45 Bradford cases being Pakistani. The large number of children with disabilities presents a challenge for us to provide appropriate health care and support for the families. We have also been able to identify some causes for these conditions, with progress on genes for primary microcephaly and ataxic cerebral palsy. postmaster@pccorry.demon.ac.uk Consanguineous marriage and genetic service delivery - a multidisciplinary approach Darr, A. The Open University, Milton Keynes, U.K. Kinship is a central concept in anthropology, and is an important determinant both of the configuration of societies and the distribution of gene variants within populations. Genetic information, including the impact of consanguineous marriage on genetic disorders, once imparted to families, is not only clinical in nature, but also has social consequences. This paper examines a number of kinship patterns to illustrate the social relations that can be affected by genetic information on consanguineous marriage. The success of public health programmes on consanguineous marriage lies in incorporating this social perspective when devising appropriate policies. The paper also details the experience from the U.K. in devising an appropriate national policy on consanguineous marriage and genetic service delivery. The issues have relevance for minority ethnic groups in the Europe as well as other parts of the world where consanguineous marriage is a preferred marriage option. AAMRADARR@aol.com Cerebrovascular diseases among young adults in Sri Lanka De Silva, K.R.D.1, Jayasekara, R.W.2, Johnson, E.W.3, Wang, X.L.4 and Silva, T.R.N.5 1,5University of Sri Jayewardenepura, Nugegoda, Sri Lanka, 2University of Colombo, Sri Lanka, 3Barrow Neurological Institute, Phoenix, U.S.A. and 4Southwest Foundation for Biomedical Research, San Antonio, U.S.A. Intracerebral hemorrhage (ICH) is responsible for 5-10%, 27-35% and 19% of first-ever, life-time stroke in the West, East and Sri Lanka respectively, and lacunar infarction for 10-24%, 29%, 41% of cases in these three population groups. Hypertension is a leading cause of ICH and lacunar infarction in the West, but the incidence of hypertension in these disorders in Sri Lanka is lower. Stroke in younger persons (below 45 years of age) in Sri Lanka increased from 10.4% in 1974 to 33.6% in 1990, whereas in the West it accounts 3-5%. The majority of cases in Sri Lanka do not have recognized causative factors and the pathogenesis remains obscure. A non-atherogenic and transient emboligenic aortoarteritis has been described in some persons. In 225 adult Sri Lankan cadaver brains the incidence of the 'typical circle of Willis' was low (14.2%), but hypoplasia of the component arteries was high (85.8%), with smaller average diameters when compared with South Indian and Japanese populations. Conventional risk factors account for one third of the ischemic episodes. We hypothesize that genetic variants may contribute significantly to the disparity in their susceptibility to premature stroke. Many marriages take place within religion, caste, or tribal boundaries. Identification of the contributing gene variants would have significant impact on premature stroke. ranilds@sltnet.lk Apoptosis: a novel death promoter gene Y-81 Dharmarajan, A. The University of Western Australia, Perth, Australia Apoptotic cell death occurs in response to a variety of signals, but to date the requirement of molecular biology have limited the systems studied in detail to those which are somewhat artificial. Attempts to go the other way, to analyze in vivo systems undergoing physiological cell death, have proved difficult to interpret. We have studied three ostensibly hormone-regulated developmental processes which lead to apoptotic cell death: mammary gland involution after forced weaning, prostate involution after castration, and corpus luteum involution following parturition. In this study, we decided to look for genes that were dramatically changed in their expression. Using differential display method we identified a novel gene, Y81, which sharply up-regulated in all three apoptosis models following induction. Y81 (frizzled related protein) plays a role in tumor suppression and apoptosis. Tumour suppressor genes, like proto-oncogenes, are involved in the regulation of cell growth and division. The two-hit mutation model for cancer states that two mutational events are needed for cancer to develop, one in each allele if a critical cancer-mutation is inherited thus predisposing the person to cancer, the other mutation occurs later in somatic cells. Inactivation of tumour suppressor genes is involved in the development of a wide variety of human cancers, including breast, ovarian, prostate, colon and lung cancer. dharma@cyllene.uwa.edu.au Predictive testing for familial cancers Edkins, E. Princess Margaret Hospital for Children and Edith Cowan University, Perth, Australia Familial cancer forms a small, but important, component of cancers in general and recent advances have indicated that single gene cause around 10 different forms of familial cancer. These range from the more common cancers, including Hereditary Non-Polyposis Colorectal Cancer (HNPCC), in which mutations in a number of genes can cause the cancer, to the rare forms, such as Li-Fraumeni and Cowden's syndromes in which single genes are involved. Denaturing High Pressure Liquid Chromatography is now the preferred screening method to isolate the exons for subsequent sequencing, and our laboratory uses this method for all of the familial cancer genes for which we test. Attention needs to be focussed on the age at which predictive testing is performed on family members once the mutation has been found. The testing of young children for propensity to an adult disease, and prenatal diagnosis, are issues which require thorough pre-test counselling and will be affected by family, ethnic, community, and religious background. Familial cancers that occur in childhood are more easily dealt with than malignancies which manifest in the 3rd and 4th decades of life, with breast cancer a particular example. Predictive testing will be discussed from a Western Australian viewpoint and parallels drawn with Developing Countries. Edward.Edkins@health.wa.gov.au The implications of gene patenting for health care delivery in Developing Countries Edkins, E. Princess Margaret Hospital for Children and Edith Cowan University, Perth, Australia There has been a concerted push to identify genes involved in single gene disorders, and in recent years most of these genes have been patented by the group involved in their discovery. In many cases the patent-holders do not exercise their rights to stop non-profit organisations, such as hospitals, using the information to test patients for the presence of a mutation. This is exemplified by the patent on the CFTR gene, with no demands for royalty payments from hospitals studying patients with cystic fibrosis. However, the company holding the patent on the brca1gene has stopped many laboratories in North America offering mutation detection, and are attempting to do likewise in Europe and elsewhere. If successful in its demands, henceforth brca1 mutation analysis could only be conducted in the U.S.A. by the company itself. A number of problems with this approach can be identified: 1. The company may not use the best method(s) for mutation detection. 2. The best approach to mutation testing may not be used simply because the company had invested heavily in the acquisition of now-obsolete technology. 3. The cost to the consumer may be so high that only the rich or those supported by health schemes can utilise the service. 4. No counselling may be involved, which is to the detriment of the patients and their families with work undertaken that is unnecessary or may be incorrectly interpreted. Edward.Edkins@health.wa.gov.au Neural tube defects in developing and developed countries Farhud, D.D., Hadavi, V. and Sadighi, H. 1Department of Human Genetics and Anthropology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran A thirty year review (1966-1995) of neural tube defects has shown that India (Asia) with frequency of 181.8 in 10,000 individuals has the highest prevalence in the world and Denmark (in Europe) with 5.8 has the lowest. In the American continent, Venezuela has the highest prevalence of 38.9 and some Latin American countries show the low of 7.7. In Europe, Norway has the highest prevalence of 68, and Denmark the lowest, 5.8. In Asia India has the highest of 181.8 and Pakistan the lowest of 11.76. In Africia, Nigeria has the highest of 70 and negroes of South Africa have the lowest of 9.9. In Australia, the figure is 20.05. Review of a developmental anomaly, with large absence of neural tissue in the cranium of newborn, known as anencephaly, from 1967 till 1996, shows that China has the highest prevalence of 87 and Congo has the lowest of 1.2. In the American continent, state of Michigan in the USA has the highest of 10.5 and Jamaica, in Central America, has the lowest of 2.6. In Europe, Turkey with 46.4 and Italy with 2.73 in Asia, China with 87 and Iran with 0.8, in Africa, Nigeria with 3.5 and Congo with 1.2 and finally New Zealand with 7.8 in 10,000 individuals have the highest and lowest prevalences, respectively. Review of spina bifida, a defect in the closure of the posterior vertebral arches and laminae, from the years 1968 till 1991 show the highest prevalence in China, 36 and the lowest in the Alps mountains, 0.55 in 10,000 individuals. In the American continent, state of Arkansas with 7.8 and California with 3. 87: in Europe, England with 23.1 and Rhein-Alp with 0.55 in 10,000 have the highest and lowest prevalences. Finally, in China the prevalence is 36, in Australia 10, in New Zealand 9.4 and in Nigeria 7 in 10,000 individuals. An investigation carried out by the authors in a maternity hospital in Tehran, Iran, from 1969 till 1978, out of 13037 birth, 23 (17.6 in 10,000) newborns had neural tube defects, with anencephaly 0.8, spina bifida and hydrocophaly each 3.8 in 10,000 individuals. Community oriented criteria of genetic disorders and congenital malformations Farhud, D.D. Department of Human Genetics and Anthropology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran National regional and international plannings have always been based on priorites in every area; this fact has been also valid for genetic disorders. Determination of priorities and plannings by the WHO experts in genetic disorders (single gene, multifactorlals, chromosomal and congenital) have been based on various indices, the most important of which are: pevalence, intensity, age of onset, age of disability, death age, curability, cost of treatment, tariffs, efficiency of insurance organizations, possibilities of employment of patients or disabled persons, preventive measures, prenatal diagnosis and type of inheritance of the disorders. To determine the above indices, methods in genetic epidemiology, bio-statistics, community oriented studies, cost and benefit, genetic screening, demography, economic, and cultural features of the community, and finally, social infrastructures and religious beliefs must be used. Priority settings of genetic disorders can not be possible unless regional prevalence of each genetic disorder, age and sex pyramids of the population, growth and death rates, size of the family, ratio of urban and rural populations, and as such, are determined. Priority criteria are the basis of plannings are necessities for prevention, budgetting and man power education. Genetics components of Human infertility and consanguinity Fellous, M. Institut Pasteur, Paris, France The existence of a genetic components to human infertility has been suggested, although neither specific abnormalities involved nor their genetic mechanism of transmission are currently defined. For theses purposes we have analysed 25 families with consanguineous marriage where infertility was detected. These families with first or second cousin marriage are originated from the Middle East. In 13 families, 2 families and 7 families, we observed respectively male, female or both sex infertilities. In 4 other cases infertilities was associated with a complex syndrome such as deafness or sex reversal. We will described the genetic and candidate gene approach analysis. Moreover, with the help of an EEC INCO MED program we plan to evaluate the impact of consanguinity on human infertility, in different country of Mediterranean basin including inner and islands populations. I will present our multidisciplinary project: "Socio-Demographic Determinants and health impact of consanguinity in the Mediterranean Area" mfellous@pasteur.fr Feasibility and strategies for integrating Community Genetic Services into existing health care systems in Jordan Hamamy, H. Amman, Jordan The estimated population in Jordan in the year 2000 was 5,039,000 with a reported rate of 19 physicians/10,000 population and 27.3 nursing and midwifery personnel/10,000 population, and with a total fertility rate of 3.6. Attached to the Ministry of Health are 990 health centres distributed throughout the country. Hospital deliveries accounted for 99.5% of the total deliveries of 132462 in the year 2000 (30% in the private sector). About 25% of expecting mothers visited the maternal and child health centers of the MOH in the prenatal period. Available data, though scarce, suggest the importance of genetic and congenital disorders in contributing to the health burden in Jordan. These data include the high consanguinity rate of over 50%, the high prevalence of haemoglobinopathies and G6PD deficiency, the trend of continuing reproduction to menopause which increases the number of over 35 years mothers. The paper discusses strategies for integrating the prevention and control of genetic and congenital disorders into reproductive health programmes and primary health care in Jordan. The feasibility and approaches for delivering community genetic services to control common disorders will be discussed. hhamamy@hotmail.com Consanguineous marriages in Arab countries: prevalence, counselling and public education Hamamy, H. Amman, Jordan Consanguinity rates in most Arab countries are amongst the highest worldwide, ranging from 30 to over 50%. First cousin marriages are the most common, accounting for almost 30% of all marriages in for example Jordan, Iraq, Kuwait and, Saudi Arabia. These marriages seem to be strongly preferred because of socioeconomic factors, rather than because of religious or economic causes. The effects of consanguinity on health have been investigated; however, data are scarce regarding the social and cultural impact of consanguineous marriages in countries where half the marriages are consanguineous. Genetic counselling regarding consanguinity for families with known autosomal recessive disorders is based on estimating recurrence risks and carrier diagnosis, and is usually offered in genetic centres. Premarital counselling related to consanguinity could be offered as part of community genetic services in countries with high consanguinity rates. Health care professionals performing this service need special training and specific guidelines to diagnose high-risk couples and refer them to specialized genetic centres. Public educational campaigns need to be carefully prepared and strictly based on scientific evidence. Media messages that condemn consanguineous marriages as the main underlying cause for most genetic and congenital disease can do more harm than good. This approach nullifies the social benefits of consanguinity, and neglects the confusion that can take place in a society where, for centuries, one in every two marriages has been consanguineous. hhamamy@hotmail.com Perceptions about adverse health effects of close cousin marriages in Pakistan Hussain, R. University of New England, Armidale, Australia In line with many other countries of the region, marriage between close cousins (consanguinity) is a very common occurrence in Pakistan. The focus of the present paper is to provide information, through qualitative data, on community perceptions of health risks associated with consanguinity. The study population included Muslim, Christian and Hindu respondents and was representative of all the major ethnic groups of Pakistan. An analysis of the study data revealed that across all study groups, there was very limited awareness about the possible adverse health effects of consanguineous marriages. Many respondents discredited the medical practitioners' explanations of the genetic mode of disease inheritance even in cases where there was an affected child in the family. The absence of genetic disorder(s) among all the children of an affected couple was quoted repeatedly as evidence that the problem was not hereditary. The belief in fate and evil eye was common across all three religious groups. Health implications of consanguineous marriages were, by and large, not considered to be an important factor in the marriage decision process. The paper discusses the implications of the above-mentioned study findings for policy makers, health practitioners as well as the lay communities. rhussain@metz.une.edu.au Molecular genetic studies on retinoblastoma in Indian patients Kannabiran, C.1, V. Kiran, S.1, Ata-ur-Rasheed, M.1, Vemuganti Geeta, K.1, Ahmed, N.2, Hasnain, S. E.2 and Honavar, S.1 1L.V.Prasad Eye Institute, Hyderabad and2Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India Retinoblastoma is a malignancy of retinal precursor cells usually occurring in the first few years of life. It is one of the major solid malignancies in children in India. It occurs as hereditary as well as non-hereditary disease which differ in their manifestation. The hereditary form is transmitted as autosomal dominant with high penetrance and entails the inheritance of one mutant allele of the retinoblastoma (RB1) gene. Development of malignancy requires the inactivation of the second RB1 allele which occurs somatically. In non-hereditary retinoblastoma, both mutational events are somatic. We undertook a molecular genetic study of retinoblastoma in order to determine the range of mutations that cause disease, to determine the potential for disease inheritance and to explore the possible utility of patient screening and counselling based on this data. About 40 unrelated probands were screened for mutations in the RB1 gene using DNA isolated from blood leukocytes and tumours. Of these, 3 cases were familial with the rest being either unilateral or bilateral sporadic disease. Mutations were identified based on amplification of exons and direct sequencing as well as by single-strand conformation polymorphism. Most mutations identified to date appear to reside within the 'large pocket' of the retinoblastoma protein. Knowledge of the types of mutations and their prevalence may be useful in designing screening tests for patients and relatives at risk. chitra@lupeye.stph.net Transcultural genetic counselling in the U.K. Karbani, G.A., Mason, G.C., Corry, P.C., Campbell, J., Chu, C., Woods, G.C. and Mueller, R.F. St. James's University Hospital, Leeds, U.K. Transcultural genetic counselling is not about being an expert on any given culture, rather it is a way of thinking about patients, where culture is acknowledged and valued. D'Ardenne and Mahtami, 1989 defined culture as the "shared history, practices, beliefs and values of a racial, regional and religious group of people". Transcultural genetic counselling aims to provide a service to focus attention on aspects of the genetic counselling process which can easily be overlooked as we strive to improve the ways in which we deliver complex genetic information to all cultural groups that we serve. We are interested in the way in which patients fantasise about genetic disease, about the information given and about the course of action taken which may play a part in this process. We are also interested in how clinicians fantasise about how different cultures may influence the way they interact with patients. Examples to illustrate particular problems will be given: 1) A family with a lethal skin disorder and Down Syndrome diagnosed prenatally; 2) Two children with juvenile Sandoff's disease; 3) Dealing with Bosnian and Kosovan families; 4) A Caucasian family presented with a twin pregnancy and a history of infertility. Genetic Counsellors, who view these differences as positive attributes, will be most likely to meet and resolve the challenges that arise in transcultural genetic counselling. These individuals will be "culturally skilled counsellors". medgk@hydel.leeds.ac.uk Consanguinity and ocular genetic diseases in South India: a five-year analysis Kumaramanickavel, G., Joseph, B., Vidhya, A., Arokiasamy, T., Shetty, N.S. Medical and Vision Research Foundations, Sankara Nethralaya, Chennai, India Consanguinity is a social custom that is widely practised in Asia and northern Africa. Dravidian Hindus in southern India have practised consanguinity for over 2000 years. No data were retrievable on the relationship between consanguinity and ophthalmic genetic disorders. Between January 1996 to December 2000, we studied the incidence of consanguinity in patients attending a genetic eye clinic in south India and calculated the coefficient of inbreeding. In five years, 673 (28.8%) of the 2335 patients with ophthalmic genetic disorders screened showed parental consanguinity. The majority (85.3%) of families who practised consanguinity were from south India. The most preferred consanguineous union was between first cousins (54.5%) followed by (uncle-niece (26.3%). The mean disorders coefficient of inbreeding (a) was 0.0632. In the consanguineous group, there were 319 (13.66%) persons with autosomal recessive type of the 239 isolated cases (10.2%). In this study most of the inherited ophthalmic diseases were blinding diseases, with retinitis pigmentosa constituting a majority of cases. gkumarmvel@rediffmail.com Fertility and genetics McElreavey, K. Institut Pasteur, Paris, France Infertility, particularly the decline in sperm counts is a serious concern in Western European countries, with declines of around 2% per year. This reduction is associated with male subfertility, reflected in an increased time to achieve pregnancy by the female partner. Considerable interest has focused on the role of the human Y-chromosome in male infertility. Approximately 12% of men diagnosed as idiopathic severe oligozoospermic or azoospermic carry microdeletions of the long arm of the Y-chromosome. These microdeletions remove putative fertility genes and in the majority of cases the deletions are de novo. We have observed a similar deletion frequency in European, Brazilian, Iranian and Indian populations. In men carrying Y-microdeletions, we classifed their Y-chromosomes into different groups using binary markers. The distribution of these Y haplogroups (hg) was then compared between Y-microdeleted men and the general population. The distribution of the hgs was not significantly different between Y-microdeleted men and the general population, suggesting that there is not a Y-genetic background associated with deletion formation. However, when we applied the same strategy to men with reduced sperm counts and an intact Y chromosome, we found that one class of Y-chromosome (hg26), was significantly over-represented in men with reduced sperm counts (28%) compared to the unselected general male population (4%). This indicates that there may be classes of Y-chromosome that are currently being lost from the population because they are associated with reduced sperm counts and by inference reduced fertility. We are determining if there are classes of Y chromosome that are associated with high sperm counts. Looking beyond the Y-chromosome in human infertility, genetic heterogeneity appears likely. Studies in European populations suggest there is familial aggregration of infertility with non-Mendelian multifactorial inheritance playing a significant role. However, in a study of the Iranian population, we noted a family history of infertility in 17% of all cases. The analysis of the modes of inheritance amongst the Iranian male infertile population suggests genetic heterogeneity underlying male infertility. Inter- and intra-familial variability of the phenotype was observed, including one pedigree with affected females. In contrast to European studies, the models of transmission are consistent with monofactorial X-linked, autosomal dominant and autosomal recessive sex-limited modes of inheritance. A considerable degree of consanguinity was observed in these familial cases, however since consanguinity is high in Iran, it is not yet clear to what extent this influences the incidence of familial infertility. kenmce@pasteur.fr Population diversity in South-West Asia McElreavey, K. Institut Pasteur, Paris, France The study of genetic diversity of South-West Asian populations (Iran, Pakistan and India) can be used for a number of purposes - to trace population movements, infer population histories, understand the relationship between genetics and language, define the genetic background in different populations and determine to which extent there is genetic isolation or gene flow between different populations. These data can also be used to define the general genetic background and form the basis for future studies of genetic susceptibility to disease. The genetic constitution of South-West Asian populations remains largely unknown. Recently we have used both mtDNA and Y-chromosome data from different populations in Iran, Pakistan and India to understand the relationship between populations in the region and trace major migratory pathways. We have demonstrated that the mtDNA haplogroup M, first regarded as an ancient marker of East-Asian origin, is found at high frequency in India and Ethiopia. Its variation and geographical distribution suggest that Asian haplogroup M separated from eastern-African haplogroup M more than 50,000 years ago, and is the first genetic indicator for the hypothesized exit route from Africa through eastern Africa/western India following the coastline. This was possibly the only successful early dispersal event of modern humans out of Africa. The analysis of Y-chromosome haplogroups and their distribution is also highly informative in South-West Asia. The origins and dispersal of farming and pastoral nomadism in southwestern Asia are complex, and there is controversy about whether they were associated with cultural transmission or demic diffusion. In addition, the spread of these technological innovations has been associated with the dispersal of Dravidian and Indo-Iranian languages in southwestern Asia. Y-chromosome analysis indicates two major population movements, supporting a model of demic diffusion of early farmers from southwestern Iran, and of pastoral nomads from western and central Asia-into India, associated with Dravidian and Indo-European-language dispersals, respectively. These results highlight how genetic data must be interpreted in a wide social and geographic context. The interpretation of both mtDNA and Y-chromosome data assumes that is no selection acting on mtDNA or Y-chromosome haplogroups, an assumption that may be false. kenmce@pasteur.fr The role of A in Alzheimer's Disease Martins, R.N. Sir James McCusker Alzheimer's Disease Research Unit and The University of Western Australia, Perth, Australia The neuropathological changes occurring in the AD brain were first described by Alois Alzheimer in 1907. Extracellular deposits of amyloid in the form of amyloid plaques and congophilic amyloid angiopathy as well as intracellular neurofibrillary tangles are major features of AD pathology. The major protein constituent of these extracellular deposits is a 4 kDa peptide termed amyloid protein or A. Levels of A are shown to be increased with the severity of disease and mutations in three genes (APP, PS1, and PS2) cause early on-set familial AD (FAD) by directly increasing synthesis of the toxic, plaque-promoting A 42 peptide. Given the strong association between A and AD, therapeutic strategies to alter the activity of this peptide in the brain should prove beneficial for the treatment of AD. We and others have demonstrated that the metal ions, copper and zinc, are required to bind A in order for this peptide to exert its neurotoxic activity. One promising approach undertaken in our laboratory is to screen for molecules, using phage display technology, that will selectively inhibit the binding of these metal ions to A. martins@cyllene.uwa.edu.au Studies on mucopolysaccharidoses in Central and Northern Tamil Nadu Maya Sundari, R., Janani, S., Mahalingam, K., Priya, S. and Elango, E.M. Dr. A.L. Mudaliar Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai, India Mucopolysaccharidoses (MPS) belong to a larger family of genetic disorders, the lysosomal storage disorders. Six main types of MPS, caused by the deficiency or absence of 10 different lysosomal enzymes are known, all of which except MPS II are autosomal recessive disorders. The deficiency affects glycosaminoglycan (GAG) catabolism leading to their accumulation in the lysosomes, and mucopolysacchariduria. Overlapping phenotypic characters presented by various lysosomal storage disorders make the clinical diagnosis of MPS highly problematic, and biochemical analysis obligatory. With the exception of our laboratory, no earlier reports on a systematic analysis of MPS are available from India. The present study reports such an attempt towards the biochemical analysis of clinically suspected MPS patients from Central and Northern Tamil Nadu. The methodology for identification and preliminary grouping of the patients to different MPS types involves isolation, quantitation and qualitative analysis of urinary GAGs by CAME and sequential TLC. Further confirmation of MPS types is undertaken by leukocyte enzyme assays. Biochemical and enzymatic analysis of 205 clinically suspected MPS patients indicated 79 to be MPS negative. Of the 126 patients who tested positive, the majority belong to MPS III and IV, unlike in other populations. So far, no MPS VII patient has been identified. The distribution of MPS types, the extent and type of consanguinity among this group, and their community distribution will be discussed. mayasundari@satyam.net.in Novel diversity in human MHC: contiguity between Asian Indians and Orientals Mehra, N.K., Jaini, R. and Kaur, G. All India Institute of Medical Sciences, New Delhi, India The major Histocompatibility Complex (MHC) contains genes that have their primary function in controlling immune responsiveness. We have observed immense diversity in several HLA class I and class II alleles in the North Indian population that suggests gene conversion events and heterozygote advantage in this population. Specific examples include HLA-A2, an ubiquitous allele that occurs fairly frequently in most populations. In the North Indian population, we observed specific reduced occurrence of HLA-A*0201 which occurs predominantly among Western Caucasoid populations. Instead, a novel allele, HLA-A*0211 occurred in 36.5 % of the A2 positive individuals followed by high frequencies of the Oriental alleles A*0207 (31.8%) and A*0206 (7%) and also the Negroid allele A*0205 (14.1%). Further we identified another novel allele designated as A*3306 (accession no. HWS 10000697) that differs from A*3303 at position 228. A*3303 is primarily an Oriental allele and our studies provide evidence that the novel A*3306 allele may have arisen from it by a single nucleotide mutation. Similarly, extensive diversity was observed in HLA-DR4 with *0403 being the most common subtype. This allele also occurs more frequently in the Japanese (~ 13%) but rarely in Caucasians (~3%). These observations suggest that Asian Indians have shared parallel natural selection driving forces and racial admixing with the Oriental populations that has led to analogous influence on HLA diversity. These observations are further supported by the occurrence of multiple HLA-DR3+ve autoimmunity favouring haplotypes (extended) among Asian Indians, some of which (e.g. A26-Cw7, B8-DR3-DQ2) are unique to this population and show strong association with type I diabetes mellitus and celiac disease. These studies have important implications in our understanding of disease pathogenesis, selecting an unrelated donor for BMT or designing MHC-based vaccines. narin98@hotmail.com Genetic disorders in hematological practice in India Mohanty, D. New Delhi, India No abstact submitted Genetic studies in the Sultanate of Oman Patton, M.A.1 and Rajab, A.2 1St. Georges Hospital Medical School, London, U.K. and 2Royal Hospital, Muscat, Oman Oman has a population of 1.5 million Omanis and approximately 0.5 million non-Omanis. The Omani population has a tribal structure with traditional patterns of endogamous marriage. We have carried out a study on consanguinity in Oman using a questionnaire in the antenatal clinic. The consanguinity rates among 60,895 couples (20% of the population of childbearing age) showed 24% of marriages between first cousins, 11.8% between second cousins and a further 20.4% within the tribal group. The validity of the questionnaire was checked by 500 detailed pedigrees. The questionnaire slightly underestimated the rate of consanguinity because of more complex patterns of intermarriage e.g. double first cousins, which were not included in the questionnaire. The mean coefficient of inbreeding (a) was 0.0204. Knowledge of the population structure in Oman has proved useful in a number of studies. With the relatively small population and high standard of healthcare studies a national study of haemoglobinopathies was undertaken, and there have been additional studies on the rate of congenital malformations, such as posterior urethral valves, spina bifida and Hirschsprung's disease. The high rate of consanguinity and the population size has favoured studies for mapping autosomal recessive syndromes, and one such study led to the identification of the gene for Robinow syndrome. mpatton@sghms.ac.uk The cost implications of the transition to a genetic mode of disease Patton, M.A. St. George's Hospital School of Medicine, London, U.K. No abstract submitted mpatton@sghms.ac.uk Infant and child mortality and consanguineous marriages among Palestinians in the West Bank and Gaza Strip, Jordan, Lebanon and Syria Pedersen, J. Fafo Institute for Applied International Studies, Oslo, Norway The paper shows the prevalence of consanguineous marriages among Palestinians in the West Bank, the Gaza Strip, Jordan, Lebanon and Syria. It also estimates the infant and child mortality that can be ascribed to consanguineous marriages when a number of socio-economic factors are controlled for. It also considers some aspects of child morbidity. The analysis is based on birth history data that derives from living conditions surveys of Palestinians living in the five areas. The surveys are very similar, enabling easy comparison across the different areas. The paper uses survival regression techniques, controlling for unobserved heterogeneity that may result from clustering of deaths for particular women. jon.pedersen@fafo.no Castes, migration, infectious diseases and immunogenetics Pitchappan, R.M. Madurai Kamaraj University, Madurai, India The caste system in India is characterized by endogamy and inbreeding. Populations migrated during different time points of history to Tamil Nadu, and lived and bred in isolated groups (sympatrically). The numerical strength and spatial distribution (proximity) of various clans of a caste decides the gene pool. A Y-chromosome study on the Dravidian language Pirmalai Kallars, an ancient population, and the Yadhavas thought to be the descendants of Yadhu tribe of Lord Krishna, and the Sourashtrans of Madurai (IndoEuropean language speaker), who migrated from Gujarat during the Vijayanagar Empire, suggest their origin in central Asia, though at different time points of history. CCR del32 heterozygote frequency is low in all of them, 0.8-1.9%. HLA DRB1*1501 is, however, present in very high frequency in the Dravidian groups when compared with other Indian populations. Pulmonary tuberculosis is associated with HLA-DRB1*1501. The Piramalai Kallars possess the highest frequency of this allele (and the disease?), while the distinction between this susceptible allele and another resistant allele (DRB1*10) is categorical in Sourashtran patients and controls. The high risk alleles have a bearing on BCG vaccination-induced immunity and on cytokine responses. Differences in the distribution of HLA B57 and psoriasis susceptibility have also been observed in south Indian caste groups, with a stronger association in the related Vellala community. Thus Community Genetics and genetic epidemiology have a very important bearing in the epidemiology of infectious diseases and autoimmune disorders in the Indian context. pichappanrm@yahoo.co.uk Outcome of genetic testing for mental retardation in India Radha Rama Devi, A. Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India Mental retardation is the consequence of insults suffered by brain cells due to variety of reasons. A genetic etiology is one of the most important causes of such disability and this usually is inherited. Chromosomal defects in structure and number are an important cause of mental retardation, due to the disruption or over-expression of certain genes. Single gene defects are responsible for large number of inherited metabolic disorders, autosomal recessive, autosomal dominant, and X-linked, as well as mitochondrial gene defects. The availability of facilities for genetic testing has paved the way for a better understanding of disease and its possible intervention and prevention, with high risk families identified through proband screening and genetic counseling offered. CDFD, Hyderabad, offers comprehensive genetic testing to the community, including an expanded newborn screening program, with the objectives of prevention and early intervention. The results of genetic testing carried out at CDFD over a period of 18 months will be discussed. Down syndrome and structural chromosomal anomalies were common cytogenetic anomalies in the study group. CGG triplet repeat expansion in the FMR-1 gene is a common mutation in male mental retardation. MPS and homocysteinemia are common biochemical defects detected in mentally retarded individuals. Altered homocysteine metabolism was responsible for number of clinical states, ranging from behavioural abnormalities and MR, to vascular episodes and NTDs. The role of MTHFR gene mutations in causing homocysteinemia will be presented. Patterns of endogamy and consanguinity in India: theory and empirical evidence of inbreeding effects Reddy, B.M. Indian Statistical Institute, Kolkata, India Due to historical reasons, India presents a unique population structure that is a mosaic not only of diverse ethnic constituents but also of contrasting cultural elements, particularly pertaining to the institution of marriage. This presentation will attempt to provide an overview of the different patterns of endogamy prevalent among populations of the diverse geographic, linguistic and religious backgrounds in India, besides depicting the broad patterns and prevalence of consanguineous marriages in these populations. In-depth analyses of the types and relative frequencies of consanguineous marriages among about 100 populations will also be presented in the light of the backgrounds of these populations, and the nature of study units considered for those studies, especially from the southern Indian regions. The extent of inbreeding effects observed in many of these populations will be gauged in the light of the type of study units, backgrounds of investigators, and intensity of overall inbreeding. Finally, an attempt will be made to assess if the empirical evidence so far obtained conforms to the theoretical expectations and, if not, the probable reasons for these findings. Inherited renal diseases Saggar-Malik, A.K. St George's Hospital Medical School, London, U.K. The hereditary nephropathies have become increasingly important to the practising nephrologist. Economically, they represent a significant burden to the cost of provision of renal replacement therapy for paediatric and adult patients developing end-stage renal failure (ESRF). About 50% of children and over 15% of adult patients requiring dialysis and/or transplantation have diseases with an underlying hereditary basis. Whilst some inherited renal diseases present early and may be fatal in infancy, there are many which present in adolescence or early adult life. This decade has seen many major clinical and scientific advances in the subject of inherited renal diseases. In particular, the isolation of two of the mutant genes responsible for the commonest inherited renal disease - autosomal dominant polycystic kidney disease and the identification of the putative protein, polycystin, has attracted worldwide interest and has provided a very good example of how collaborative effort between academic groups can work. The presentation will be more directly related to the adult onset diseases which have a multisystem nature, or those diseases in which survival is usual and long-term care is involved through paediatric to adult specialists. Where ethnic/population differences occur, these will be highlighted. a.saggar@sghms.ac.uk Fragile X syndrome: a weak founder effect and other novel findings among Indians Thelma, B.K.1, Sharma, D.1 and Gupta, M.2 1University of Delhi South Campus, New Delhi and2Gobind Ballabh Pant Hospital, New Delhi, India Fragile X Syndrome (FXS), the most common cause of inherited mental retardation, is caused primarily by hyperexpansion of the (CGG)n unit in the X-linked FMR1 gene. Our DNA based study revealed an overall frequency of 7.7% for this disorder among the institutionalized MR population in Delhi. Possible origins of this dynamic mutation have been investigated in diverse ethnic groups based on flanking STR (DXS548, FRAXAC1, and FRAXAC2) and SNP (ATL1) polymorphic markers. This has led to the concept of 'founder' effect for FXS indicating a common ancestral origin of the mutation. Comparisons of allele frequency distributions in our population with other major ethnic groups (White Caucasians, Africans, and Mongoloid Asians) show an overall similarity to Western Caucasians. However, significant differences are noted in haplotypic associations with the disease locus. A very high diversity and heterozygosity of haplotypes among mutated X-chromosomes including four new haplotypes and intrapopulation regional variations have been the major findings of this study. Consequently, the weak founder effect which is evident, questions the basic tenet of a shared ancestry of mutated fragile X chromosomes. Besides suggesting an unusually higher rate of STR mutational changes in our population, the results highlight the inappropriateness of using STR-based haplotype data for predicting instability at this locus. humgen@del3.vsnl.net.in The social impact of Genetics Varma, R.M. National Institute of Mental Health and Neurosciences, Bangalore, India No abstract submitted | |
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