Estimating the birth prevalence and pregnancy outcomes of congenital malformations worldwide.

Congenital anomaly registries have two main surveillance aims: firstly to define baseline epidemiology of important congenital anomalies to facilitate programme, policy and resource planning, and secondly to identify clusters of cases and any other epidemiological changes that could give early warning of environmental or infectious hazards. However, setting up a sustainable registry and surveillance system is resource-intensive requiring national infrastructure for recording all cases and diagnostic facilities to identify those malformations that that are not externally visible. Consequently, not all countries have yet established robust surveillance systems. For these countries, methods are needed to generate estimates of prevalence of these disorders which can act as a starting point for assessing disease burden and service implications. Here, we describe how registry data from high-income settings can be used for generating reference rates that can be used as provisional estimates for countries with little or no observational data on non-syndromic congenital malformations.

CONSANGUINITY, GENETICS AND DEFINITIONS OF KINSHIP IN THE UK PAKISTANI POPULATION.

Consanguineous marriage is a controversial topic in many Western societies, with attention mainly focused on the health of immigrant communities from Asia and Africa. In the UK consanguinity is especially prevalent in the Pakistani community, which now numbers over 1.1 million. Less attention has been paid to the influence of hereditary population stratification within Pakistani communities, in particular biraderi (literally brotherhood) membership, which denotes male lineages that largely govern marriage partner choice and hence the transmission of disease genes. The various roles played by biraderi and their relationship to other socio-occupational and kinship terms, such as caste, quom and zat, are often overlooked in health-based studies. The interchangeable use of these different kinship terms without rigorous definition can create identity uncertainty and hinders inter-study comparisons. Where feasible, standardization of terminology would be both desirable and beneficial, with biraderi the preferred default term to identify specific social and genetic relationships within the Pakistani diaspora.

The triple challenges associated with age-related comorbidities in Down syndrome.

BACKGROUND: Major increases in the survival of people with Down syndrome during the last two generations have resulted in extended periods of adulthood requiring specialist care, which in turn necessitates greater understanding of the nature, timing and impact of comorbidities associated with the disorder. METHOD: The prevalence of five comorbidities reported as common in adults with Down syndrome, visual impairment, hearing impairment, epilepsy, thyroid disorders and dementia was assessed by decade of life. RESULTS: From early adulthood, people with Down syndrome are at enhanced risk of developing new comorbidities and they may present with multiple conditions. Three specific challenges are identified and discussed: are comorbidities detected in a timely manner, is the clinical progress of the disorder adequately understood, and who is responsible for the provision of care? CONCLUSIONS: Further detailed investigations into the development and treatment of comorbidities across the lifespan are needed for a successful longitudinal approach to healthcare in people with Down syndrome. Implementation of this approach will better inform healthcare providers to ensure continuity of care with advancing age.

Genetics and global healthcare.

During the course of the last decade there has been extensive discussion on the role of genetics and genomics in global healthcare, with major diagnostic advances regularly announced, such as exome sequencing to identify and classify de novo, autosomal and X-linked mutations in people with severe intellectual disability,1 and whole-genome sequencing for prenatal diagnosis of chromosomal anomalies,2 in the differential diagnosis of acute neonatal disorders,3 and in devising improved treatment protocols.4 There are, however, a number of basic issues that need to be addressed if advances of this nature are to be more widely translated in terms of healthcare.

Delivering genetic education and genetic counseling for rare diseases in rural Brazil.

Brazil is the largest country in Latin America, with an ethnically diverse, Portuguese-speaking and predominantly Roman Catholic population of some 194 million. Universal health care is provided under the Federal Unified Health System (Sistema Único de Saúde) but, as in many other middle and low income countries, access to medical genetics services is limited in rural and remote regions of the country. Since there is no formally recognized Genetic Counseling profession, genetic counseling is provided by physicians, trained either in medical genetics or a related clinical discipline. A comprehensive medical genetics program has been established in Monte Santo, an inland rural community located in the state of Bahia in Northeast Brazil, with high prevalences of a number of autosomal recessive genetic disorders, including non-syndromic deafness, phenyketonuria, congenital hypothyroidism and mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Genetic education, counseling and treatment are locally provided, with a neonatal screening program for MPSVI currently under trial.

Socioeconomic, demographic and legal influences on consanguinity and kinship in northern coastal Sweden 1780-1899.

Most studies on consanguinity have been conducted on contemporary populations and have focused on the prevalence and types of preferred intra-familial marriage. With its comprehensive birth, marriage and deaths records dating back to the late 17th century, and the legal bar on first cousin marriage removed in the mid-19th century, Sweden offers unique opportunities to examine the factors that determine by whom, where and why consanguineous marriages were contracted. The present study covers the period 1780-1899 and presents a detailed portrait of cousin and sibling exchange marriages in the Skellefteå region of northern coastal Sweden. The combined prevalence of first, second and third cousin marriage increased from 2.3% in 1790-1810 to 8.8% in 1880-1899, and multi-generation consanguinity also increased significantly over the study period. The distribution and prevalence of first cousin marriages was strikingly non-random, with a significantly greater propensity for consanguinity among land-owning families, especially involving first-born sons, within specific pedigrees, and in a number of more remote inland communities. Additional factors associated with a greater likelihood of consanguineous marriage included physical or mental disability among males, and among females the prior birth of an illegitimate child. Besides the inherent interest in the social and demographic structure of this region of northern Sweden during the course of the 19th century, in future studies it will be important to determine the degree to which the observed patterns of consanguineous and sibling exchange marriages in these past generations could have influenced present-day genetic structure.

The impact of consanguinity on neonatal and infant health.

Marriage between biological relatives is widely popular in many parts of the world, with over 1000 million people living in countries where 20-50+% of unions are contracted between couples related as second cousins or closer. Consanguinity is, however, a controversial topic, in part due to public misunderstanding, complicated by often exaggerated past estimates of the adverse health outcomes. While some consanguineous couples are at high risk of conceiving a child with a genetic disorder, they are a small minority. Thus a multi-population meta-analysis has indicated an excess infant death rate of 1.1% in the progeny of first cousins, and even this figure may be compromised by inadequate control for non-genetic variables. The benefits as well as the disadvantages of consanguineous marriage are assessed and discussed, with specific consideration given to the health of migrant communities in Western countries, among whom first cousin marriage remains preferential.

A descriptive profile of ß-thalassaemia mutations in India, Pakistan and Sri Lanka.

Thalassaemia is a common and debilitating autosomal recessive disorder affecting many populations in South Asia. To date, efforts to create a regional profile of ß-thalassaemia mutations have largely concentrated on the populations of India. The present study updates and expands an earlier profile of ß-thalassaemia mutations in India, and incorporates comparable data from Pakistan and Sri Lanka. Despite limited data availability, clear patterns of historical and cultural population movements were observed relating to major ß-thalassaemia mutations. The current regional mutation profiles of ß-thalassaemia have been influenced by historical migrations into and from the Indian sub-continent, by the development and effects of Hindu, Buddhist, Muslim and Sikh religious traditions, and by the major mid-twentieth century population translocations that followed the Partition of India in 1947. Given the resultant genetic complexity revealed by the populations of India, Pakistan and Sri Lanka, to ensure optimum diagnostic efficiency and the delivery of appropriate care, it is important that screening and counselling programmes for ß-thalassaemia mutations recognise the underlying patterns of population sub-division throughout the region.

Evolution in health and medicine Sackler colloquium: Consanguinity, human evolution, and complex diseases.

There is little information on inbreeding during the critical early years of human existence. However, given the small founding group sizes and restricted mate choices it seems inevitable that intrafamilial reproduction occurred and the resultant levels of inbreeding would have been substantial. Currently, couples related as second cousins or closer (F >or= 0.0156) and their progeny account for an estimated 10.4% of the global population. The highest rates of consanguineous marriage occur in north and sub-Saharan Africa, the Middle East, and west, central, and south Asia. In these regions even couples who regard themselves as unrelated may exhibit high levels of homozygosity, because marriage within clan, tribe, caste, or biraderi boundaries has been a long-established tradition. Mortality in first-cousin progeny is approximately 3.5% higher than in nonconsanguineous offspring, although demographic, social, and economic factors can significantly influence the outcome. Improving socioeconomic conditions and better access to health care will impact the effects of consanguinity, with a shift from infant and childhood mortality to extended morbidity. At the same time, a range of primarily social factors, including urbanization, improved female education, and smaller family sizes indicate that the global prevalence of consanguineous unions will decline. This shift in marriage patterns will initially result in decreased homozygosity, accompanied by a reduction in the expression of recessive single-gene disorders. Although the roles of common and rare gene variants in the etiology of complex disease remain contentious, it would be expected that declining consanguinity would also be reflected in reduced prevalence of complex diseases, especially in population isolates.

Genetic clinics in arab communities: meeting individual, family and community needs.

Arab societies are characterized by a wide range of family and social structures, religious and legal conventions, and highly variable economic resources. As might be expected under these circumstances, genetic services cannot readily be devised, delivered, and assessed according to a single model. However, in general terms, the provision of genetic services in Arab communities at all population levels is still inadequate given the prevalence and burden of genetic diseases. Improving this situation calls for major educational efforts that include increasing the genetic literacy of the general public, comprehensive courses and campaigns to familiarize primary health care workers with counseling needs and skills and with referral guidelines for high-risk families, updating medical, nursing, and paramedical curricula to incorporate information on community genetics, and training clinical and laboratory genetic specialists to meet the short- and long-term goals of genetic disease prevention and management.

Australia: public health genomics.

Australia has a multicultural society that has arisen from continuing migration. While the population is relatively small, just over 20.7 million, it is genetically diverse and is spread over a large land mass. The federal system of government is democratic, based on states and territories, and there is a socialized healthcare system, in which public and private models operate in parallel. Clinical genetics services are publicly funded by State Departments of Health, rather than by the Commonwealth Government, with the model of service provision varying from state to state. Each of these factors has important implications for the effective delivery of genetic screening programs and clinical genetic services that meet the needs of all Australians. Population genetic screening occurs throughout Australia predominantly as newborn screening programs and to identify pregnancies at risk of chromosomal and neural tube defects, while carrier screening programs are essentially ad hoc. Despite inevitable tensions between federal and state policies, there is increasing evidence of the development of national policy in a range of genetic issues, not least in newborn screening, genetic testing, and health professional education. However, further work is necessary to establish frameworks for the regulation and funding of new genetic tests across state/federal boundaries, which will be crucial to the establishment of a national approach to public health genomics policy.

Profiling ß-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes.

UNLABELLED: Thalassaemia and sickle cell disease have been recognized by the World Health Organization as important inherited disorders principally impacting on the populations of low income countries. To create a national and regional profile of ß-thalassaemia mutations in the population of India, a meta-analysis was conducted on 17 selected studies comprising 8,505 alleles and offering near-national coverage for the disease. At the national level 52 mutations accounted for 97.5% of all ß-thalassaemia alleles, with IVSI-5(G>C) the most common disease allele (54.7%). Population stratification was apparent in the mutation profiles at regional level with, for example, the prevalence of IVSI-5(G>C) varying from 44.8% in the North to 71.4% in the East. A number of major mutations, such as Poly A(T>C), were apparently restricted to a particular region of the country, although these findings may in part reflect the variant test protocols adopted by different centres. Given the size and genetic complexity of the Indian population, and with specific mutations for ß-thalassaemia known to be strongly associated with individual communities, comprehensive disease registries need to be compiled at state, district and community levels to ensure the efficacy of genetic education, screening and counselling programmes. At the same, time appropriately designed community-based studies are required as a health priority to correct earlier sampling inequities which resulted in the under-representation of many communities, in particular rural and socioeconomically under-privileged groups. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11568-010-9132-3) contains supplementary material, which is available to authorized users.

A community genetics perspective on consanguineous marriage.

Consanguineous marriage has long been a controversial topic, with particular attention focused on adverse health outcomes. Unfortunately, the studies that have been conducted on consanguinity to date have usually lacked control for important sociodemographic variables, such as maternal age and birth intervals, and in estimating specific disease gene frequency, they have ignored the influence of population sub-division. Inadequate attention has also been paid to the social benefits associated with intra-familial marriage, resulting in a biased overall cost-benefit assessment. Worldwide, some 1,000 million people live in countries where 20 to more than 50% of marriages are consanguineous, and large migrant communities from these regions are now resident in Western Europe, North America and Oceania. The need for comprehensive and more balanced investigations into all aspects of consanguineous marriage is pressing and merits a substantial international collaborative research effort.

Physical anthropology and ethnicity in Asia: the transition from anthropometry to genome-based studies.

Initial physical anthropology studies into ethnic diversity were largely dependent on comparative whole body and craniometric measurements, and through time assessments of ethnic diversity based on these measures exhibited increasing statistical sophistication. Since the 1990s, in Asia as elsewhere in the world, human diversity studies have increasingly utilized DNA-based analyses, with Y-chromosome and mtDNA markers providing complementary perspectives on the origins and gene pool structures of different ethnic groups. This approach is illustrated in a study of population genetic structure in PR China, in which DNA samples from the Han majority and eight ethnic minorities were analyzed. The Y-chromosome and mtDNA data showed multiple paternal geographical and ethnic origins but restricted maternal ancestries. However, interpretive problems were apparent in the definition of a number of the ethnic study populations, which appear to reflect political as well as genetic influences. In all anthropological studies, whether based on anthropometry or genomic analysis, unambiguous and appropriate community identification is a prerequisite.

The profile and incidence of cancer in Down syndrome.

BACKGROUND: Down syndrome is one of the commonest causes of intellectual disability. As life expectancy improves with early and more intensive surgical and medical treatments, people with the disorder are more likely to exhibit classic morbidity and mortality patterns and be diagnosed with diseases such as cancer. METHODS: A profile of cancer cases among people with Down syndrome has been compiled, based on the analysis of a linked data set that included information from the Disability Services Commission of Western Australian and the State Cancer Registry. RESULTS AND CONCLUSIONS: Although the total age- and sex-standardized incidence ratios (SIRs) for people with Down syndrome were similar to that for the general population, SIRs for leukaemia were significantly higher while the incidence of certain other types of cancers was reduced. Overall, there was a lower incidence of solid tumours in Down syndrome, possibly reflecting the age profile of the study cohort.

A long-term population-based clinical and morbidity profile of Angelman syndrome in Western Australia: 1953-2003.

PURPOSE: To investigate the incidence, clinical presentation and associated comorbidities of Angelman syndrome (AS) in Western Australia, with establishment of an information database for the disorder. METHODS: Data were collected from Disability Services Commission files, supplemented by datasets provided by the Western Australian Data Linkage Unit. The analysis was retrospective and quantitative. RESULTS: Thirty-four individuals (two deceased) were identified (19 F, 15 M), with a mean age of 21.6 years; 52.9% had an IQ < 40, with the remainder of IQ 40-69. The incidence was one in 40,000 births and mean age at diagnosis was 5.8 years. The mean age of the 23 home residents was 20.2 years compared to 27.9 years in the nine individuals in sheltered accommodation. In general, the patients exhibited a typical AS clinical presentation. A median of 5.5 (range 0-20) hospital admissions was recorded per person, with epilepsy, gastrointestinal disorders, and dental work all common reasons for admission. CONCLUSIONS: The estimated incidence was low compared to other reports, as was the proportion of IQ < 40. AS cases required substantial levels of medical care, especially those who were epileptic. An increase in the future numbers of AS patients needing sheltered accommodation is predicted.