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In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide an update of selected topics that have evolved since 2005. [ABSTRACT FROM AUTHOR]

The arrival of new genetic technologies that allow efficient examination of the whole human genome (microarray, next-generation sequencing) will impact upon both laboratories (cytogenetic and molecular genetics in the first instance) and clinical/medical genetic services. The interpretation of analytical results in terms of their clinical relevance and the predicted health status poses a challenge to both laboratory and clinical geneticists, due to the wealth and complexity of the information obtained. There is a need to discuss how to best restructure the genetic services logistically and to determine the clinical utility of genetic testing so that patients can receive appropriate advice and genetic testing. To weigh up the questions and challenges of the new genetic technologies, the European Society of Human Genetics (ESHG) held a series of workshops on 10 June 2010 in Gothenburg. This was part of an ESHG satellite symposium on the 'Changing landscape of genetic testing', co-organized by the ESHG Genetic Services Quality and Public and Professional Policy Committees. The audience consisted of a mix of geneticists, ethicists, social scientists and lawyers. In this paper, we summarize the discussions during the workshops and present some of the identified ways forward to improve and adapt the genetic services so that patients receive accurate and relevant information. This paper covers ethics, clinical utility, primary care, genetic services and the blurring boundaries between healthcare and research. [ABSTRACT FROM AUTHOR]

Women with a family history of breast cancer dominate referrals for cancer genetic risk counselling across Europe. Given limited health care resources, managing this demand, while achieving good value for money for health services, is a major challenge. The paper reports the benefits and associated costs of moving from a traditional system of deriving family history of cancer during the patient's initial clinic attendance, to a protocol-driven system with pre-counselling assessment of family history. The evaluation was based on retrospective clinical data and a clinical audit. Changes in risk between referral and final risk assessment were ascertained and the cost difference between the two systems estimated. The study results showed that 14% of women assessed as ‘low’ genetic risk at referral were reassessed as ‘moderate’ or ‘high’ genetic risk for breast cancer following verification of family history. Sixteen per cent of those assessed as ‘moderate’ or ‘high’ genetic risk at referral were reassessed as ‘low’ genetic risk for breast cancer. Compared to the traditional system, the new protocol-driven system of risk assessment was more consistent, which reduced the number of return appointments and created time for clinicians to spend with other patients. The estimated cost of family history verification and genetic clinic appointment was calculated as £91.68 (\[euro]132.53) per family history, compared to £104.00 (\[euro]150.34) for the traditional system, representing a slight reduction in health service costs. Finally, the protocol-driven system can be used as part of ongoing audit for planning future genetics services in Scotland.European Journal of Human Genetics (2007) 15, 1139–1144; doi:10.1038/sj.ejhg.5201895; published online 18 July 2007 [ABSTRACT FROM AUTHOR]

Gaps in regulations pertaining to the collection and storage of biological materials in a biobank, at least in the European context, have made the writing of local guidelines essential from an ethical point of view. Nevertheless, until recently, the elaboration of local guidelines for the collection, use and storage of biological materials in a biobank has been the exception in Italy and all European countries. In this context, it is of value to know the policies, even if they are unwritten, of local ethics committees (ECs) engaged in the evaluation of research protocols involving biobanks and biological materials. This paper presents the results of a survey carried out among local Italian ECs (229) to document their attitudes and policies regarding the management of the ethical issues related to biobanks and the use of biological materials. A questionnaire was developed to investigate the areas regarded as critical from an ethical-legal point of view: informed consent and information to the subjects; protection of confidentiality; communication of research results; access/transfer of biological materials and related data; ownership of samples and data and intellectual property rights; and subjects' remuneration and benefit sharing. Twenty-six ECs from the Italian Institutes for Research and Care (62%) and 26 other ECs (14%) participated in the survey. [ABSTRACT FROM AUTHOR]

The paper focuses on the fundamental debate that is going on in Europe and the United States about whether genes and genetic diagnostic methods are to be regarded as inventions or subject matter eligible for patent protection, or whether they are discoveries or principles of nature and thus excluded from patentability. The study further explores some possible scenarios of American influences on European patent applications with respect to genetic diagnostic methods. Our analysis points out that patent eligibility for genes and genetic diagnostic methods, as discussed in the United States in the Association of Molecular Pathology versus US Patent and Trademark Office decision, is based on a different reasoning compared with the European Patent Convention. [ABSTRACT FROM AUTHOR]

Migraine is a common neurological disorder with a genetically complex background. This paper describes a meta-analysis of genome-wide association (GWA) studies on migraine, performed by the Dutch-Icelandic migraine genetics (DICE) consortium, which brings together six population-based European migraine cohorts with a total sample size of 10 980 individuals (2446 cases and 8534 controls). A total of 32 SNPs showed marginal evidence for association at a P-value<10−5. The best result was obtained for SNP rs9908234, which had a P-value of 8.00 × 10−8. This top SNP is located in the nerve growth factor receptor (NGFR) gene. However, this SNP did not replicate in three cohorts from the Netherlands and Australia. Of the other 31 SNPs, 18 SNPs were tested in two replication cohorts, but none replicated. In addition, we explored previously identified candidate genes in the meta-analysis data set. This revealed a modest gene-based significant association between migraine and the metadherin (MTDH) gene, previously identified in the first clinic-based GWA study (GWAS) for migraine (Bonferroni-corrected gene-based P-value=0.026). This finding is consistent with the involvement of the glutamate pathway in migraine. Additional research is necessary to further confirm the involvement of glutamate. [ABSTRACT FROM AUTHOR]

Over the past decade, research on the genetic variants underlying susceptibility to autism and autism spectrum disorders (ASDs) has focused on linkage and candidate gene studies. This research has implicated various chromosomal loci and genes. Candidate gene studies have proven to be particularly intractable, with many studies failing to replicate previously reported associations. In this paper, we investigate previously implicated genomic regions for a role in ASD susceptibility, using four cohorts of European ancestry. Initially, a 384 SNP Illumina GoldenGate array was used to examine linkage at six previously implicated loci. We identify linkage approaching genome-wide suggestive levels on chromosome 2 (rs2885116, MLOD=1.89). Association analysis showed significant associations in MKL2 with ASD (rs756472, P=4.31 × 10−5) and between SND1 and strict autism (rs1881084, P=7.76 × 10−5) in the Finnish and Northern Dutch populations, respectively. Subsequently, we used a second 384 SNP Illumina GoldenGate array to examine the association in seven candidate genes, and evidence for association was found in RELN (rs362780, P=0.00165). Further increasing the sample size strengthened the association with RELN (rs362780, P=0.001) and produced a second significant result in GRIK2 (rs2518261, P=0.008). Our results strengthen the case for a more detailed study of the role of RELN and GRIK2 in autism susceptibility, as well as identifying two new potential candidate genes, MKL2 and SND1. [ABSTRACT FROM AUTHOR]

Within Europe, there is currently no uniform regulatory system that applies to human biobanks used for genetic research purposes. This has resulted in considerable variation in the national law that applies to the use of DNA samples, personal information and medical records in the countries across Europe. This could result in a situation where researchers collaborating across Europe may be operating unlawfully if they share research data and samples across borders where different laws are in operation. There are also concerns that the lack of standardised guidelines inhibits cooperation among researchers across Europe but also restricts the sharing of DNA samples and information across national borders, which is problematic for multinational companies and institutions carrying out collaborative research. Ultimately, the lack of a uniform regulatory system may have implications for the viability and long-term competitiveness of collaborative European research. The purpose of this paper is to discuss some of the preliminary issues that would need to be considered before such a regulatory system for biobanks could be developed within Europe.European Journal of Human Genetics (2006) 14, 245–248. doi:10.1038/sj.ejhg.5201530; published online 23 November 2005 [ABSTRACT FROM AUTHOR]

This paper reports a European pilot External Quality Assessment (EQA) scheme for the molecular diagnosis of Huntington's disease (HD). The European Molecular Genetics Quality Network (EMQN) chose HD as a relatively simple assay that allows a range of difficulty in terms of technical competence and interpretation. Fourteen centres from 12 different countries participated. The scheme organiser provided five cases together with mock clinical information. The participating laboratories were asked to complete the analyses and return the reports in English to their normal laboratory format within a fixed period. The scheme demonstrates a level of potential misdiagnosis in molecular analysis of HD as well as a wide variety in way of reporting laboratory results. Overall 9/146 (6.2%) of alleles fell outside the set limits, and the rate of misdiagnosis was 1/78 (1.3%). A closer estimate of diagnostic accuracy will require expansion of the scheme. [ABSTRACT FROM AUTHOR]

This European study involving seven genetic centres from six countries — Aberdeen, Cardiff (UK), Leiden (Netherlands), Leuven (Belgium), Paris (France), Rome (Italy), Athens (Greece) has gathered information on prenatal testing by direct mutation analysis and exclusion testing for Huntington's disease (HD) from the six European countries during the period 1993-1998. Data describing the parent belonging to the HD family was collected; this included their sex and age as well as their risk of developing HD. Information about previous pregnancies, the rank of the pregnancy being tested and its outcome was also gathered. In addition the number of previous prenatal tests for HD was recorded. Three hundred and five results were recorded by the participating countries between 1993 and 1998. The largest groups came from the UK (157) and the Netherlands (90). The mean age for the parent from the HD family was 30.8 years. In half of the tests the prospective parent was an asymptomatic gene carrier, 42% remained at risk, and 6% of the prospective parents were already showing clinical features of HD. 65% of tests performed used mutation analysis. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to formulate a professional and scientific view on the social, ethical, and legal issues that impact on data storage and DNA banking practices for biomedical research in Europe. Many aspects have been considered, such as the requirements for data storage and DNA banking in the public and private sectors in Europe and the issues relating to DNA banking, that is to say the consent requirements for the banking and further uses of DNA samples, their control and ownership, and the return of benefit derived from DNA exploitation to the community. The methods comprise primarily the review of the existing professional guidelines, legal frameworks and other documents related to the data storage and DNA banking practices in public and private sectors in Europe. Then, the issues related to DNA banking were examined during an international workshop organized by the European Society of Human Genetics Public and Professional Policy Committee in Paris, France, 07-08, April, 2000. A total of 50 experts from 12 European countries attended this workshop. It came out that DNA banking for medical and research purposes is indispensable. It facilitates the constitution of large collections, sharing of samples, multiple testing on the same samples, and repeating testing over the years. However, banking organization is complex, requires multiple actors, and concerns are expressed in various countries. International standardization of ethical requirements and policies with regard to DNA banking has been recommended. Such standardization would facilitate a greater protection of individuals as well as future international cooperation in biomedical research.European Journal of Human Genetics (2003) 11, Suppl 2, S88-S122. doi:10.1038/sj.ejhg.5201114 [ABSTRACT FROM AUTHOR]

One of the more complex policy issues accompanying developments in genetic knowledge relates to how personal genetic information, such as the results of genetic tests, are to be used. To discuss these issues as they relate to insurance and employment and produce recommendations from the professional point of view, the Public and Professional Policy Committee (PPPC) of the European Society of Human Genetics (ESHG) organized a workshop in February, 2000 in Manchester, England, to which 47 experts from 14 European countries were invited. They received, prior to the meeting, a working paper developed by the PPPC, which was revised after the meeting to take into account the points of view expressed by the participants. Following the workshop, the ESHG issued statements and recommendations that are expected to reflect the views of the scientific community and that were endorsed by the ESHG membership.

Focuses on the genome sequencing project introduced by research institutes for human genome laboratories in Europe. Steps in genome sequencing; Protocols of traditional DNA sequencing; Methods of library construction and sequencing of genomes.

3D analysis of facial morphology has delineated facial phenotypes in many medical conditions and detected fine grained differences between typical and atypical patients to inform genotype-phenotype studies. Next-generation sequencing techniques have enabled extremely detailed genotype-phenotype correlative analysis. Such comparisons typically employ control groups matched for age, sex and ethnicity and the distinction between ethnic categories in genotype-phenotype studies has been widely debated. The phylogenetic tree based on genetic polymorphism studies divides the world population into nine subpopulations. Here we show statistically significant face shape differences between two European Caucasian populations of close phylogenetic and geographic proximity from the UK and The Netherlands. The average face shape differences between the Dutch and UK cohorts were visualised in dynamic morphs and signature heat maps, and quantified for their statistical significance using both conventional anthropometry and state of the art dense surface modelling techniques. Our results demonstrate significant differences between Dutch and UK face shape. Other studies have shown that genetic variants influence normal facial variation. Thus, face shape difference between populations could reflect underlying genetic difference. This should be taken into account in genotype-phenotype studies and we recommend that in those studies reference groups be established in the same population as the individuals who form the subject of the study. [ABSTRACT FROM AUTHOR]

Oculo-auriculo-vertebral spectrum is a complex developmental disorder characterised mainly by anomalies of the ear, hemifacial microsomia, epibulbar dermoids and vertebral anomalies. The aetiology is largely unknown, and the epidemiological data are limited and inconsistent. We present the largest population-based epidemiological study to date, using data provided by the large network of congenital anomalies registries in Europe. The study population included infants diagnosed with oculo-auriculo-vertebral spectrum during the 1990-2009 period from 34 registries active in 16 European countries. Of the 355 infants diagnosed with oculo-auriculo-vertebral spectrum, there were 95.8% (340/355) live born, 0.8% (3/355) fetal deaths, 3.4% (12/355) terminations of pregnancy for fetal anomaly and 1.5% (5/340) neonatal deaths. In 18.9%, there was prenatal detection of anomaly/anomalies associated with oculo-auriculo-vertebral spectrum, 69.7% were diagnosed at birth, 3.9% in the first week of life and 6.1% within 1 year of life. Microtia (88.8%), hemifacial microsomia (49.0%) and ear tags (44.4%) were the most frequent anomalies, followed by atresia/stenosis of external auditory canal (25.1%), diverse vertebral (24.3%) and eye (24.3%) anomalies. There was a high rate (69.5%) of associated anomalies of other organs/systems. The most common were congenital heart defects present in 27.8% of patients. The prevalence of oculo-auriculo-vertebral spectrum, defined as microtia/ear anomalies and at least one major characteristic anomaly, was 3.8 per 100 000 births. Twinning, assisted reproductive techniques and maternal pre-pregnancy diabetes were confirmed as risk factors. The high rate of different associated anomalies points to the need of performing an early ultrasound screening in all infants born with this disorder. [ABSTRACT FROM AUTHOR]

For over four decades, it has been possible to offer prenatal diagnostic testing for fetal abnormalities. Prenatal testing is now available for a wide range of monogenic disorders as well as chromosomal abnormalities and should be provided within the ethical framework of informed consent and autonomous choice. However, there are no published guidelines for health professionals from varied disciplines who offer prenatal diagnosis (PND) in a range of possible settings including departments of maternity, obstetrics and clinical genetics. We used an Expert Group technique to develop a set of guidelines for provision of prenatal diagnostic services. Thirteen European health professionals, all experts in PND, participated in a workshop to develop the guidelines, which were then subjected to a wide consultation process. The objective of PND was defined as providing prenatal diagnostic testing services (for genetic conditions) that enable families to make informed choices consistent with their individual needs and values and which support them in dealing with the outcome of such testing. General principles, logistical considerations, clinical care and counselling topics are all described and are equally applicable to invasive and non-invasive testing. These guidelines provide a framework for ethical clinical care; however, they are flexible enough to enable practitioners to adapt them to their particular setting. Ideally, an individualised approach to each family is required to ensure autonomous choice and informed consent regarding prenatal diagnostic testing within the local ethical and legal framework. [ABSTRACT FROM AUTHOR]

The study reported here presents a detailed description of what it is like to parent a child with juvenile Huntington's disease in families across four European countries. Its primary aim was to develop and extend findings from a previous UK study. The study recruited parents from four European countries: Holland, Italy, Poland and Sweden,. A secondary aim was to see the extent to which the findings from the UK study were repeated across Europe and the degree of commonality or divergence across the different countries. Fourteen parents who were the primary caregiver took part in a semistructured interview. These were analyzed using an established qualitative methodology, interpretative phenomenological analysis. Five analytic themes were derived from the analysis: the early signs of something wrong; parental understanding of juvenile Huntington's disease; living with the disease; other people's knowledge and understanding; and need for support. These are discussed in light of the considerable convergence between the experiences of families in the United Kingdom and elsewhere in Europe. [ABSTRACT FROM AUTHOR]

The article discusses the guidelines by the Quality Committee of the European Society of Human Genetics (ESHG) on whole-genome sequencing (WGS) in health care. It states that WGS is used for diagnosing severely-ill infants who are in neonatal intensive care. It highlights the role of the Public and Professional Policy Committee (PPPC) and the recommendations by ESHG on minors' genetic testing.

Human Y chromosomes belonging to the haplogroup R1b1-P25, although very common in Europe, are usually rare in Africa. However, recently published studies have reported high frequencies of this haplogroup in the central-western region of the African continent and proposed that this represents a 'back-to-Africa' migration during prehistoric times. To obtain a deeper insight into the history of these lineages, we characterised the paternal genetic background of a population in Equatorial Guinea, a Central-West African country located near the region in which the highest frequencies of the R1b1 haplogroup in Africa have been found to date. In our sample, the large majority (78.6%) of the sequences belong to subclades in haplogroup E, which are the most frequent in Bantu groups. However, the frequency of the R1b1 haplogroup in our sample (17.0%) was higher than that previously observed for the majority of the African continent. Of these R1b1 samples, nine are defined by the V88 marker, which was recently discovered in Africa. As high microsatellite variance was found inside this haplogroup in Central-West Africa and a decrease in this variance was observed towards Northeast Africa, our findings do not support the previously hypothesised movement of Chadic-speaking people from the North across the Sahara as the explanation for these R1b1 lineages in Central-West Africa. The present findings are also compatible with an origin of the V88-derived allele in the Central-West Africa, and its presence in North Africa may be better explained as the result of a migration from the south during the mid-Holocene. [ABSTRACT FROM AUTHOR]

This study examines trends and geographical differences in total and live birth prevalence of trisomies 21, 18 and 13 with regard to increasing maternal age and prenatal diagnosis in Europe. Twenty-one population-based EUROCAT registries covering 6.1 million births between 1990 and 2009 participated. Trisomy cases included live births, fetal deaths from 20 weeks gestational age and terminations of pregnancy for fetal anomaly. We present correction to 20 weeks gestational age (ie, correcting early terminations for the probability of fetal survival to 20 weeks) to allow for artefactual screening-related differences in total prevalence. Poisson regression was used. The proportion of births in the population to mothers aged 35+ years in the participating registries increased from 13% in 1990 to 19% in 2009. Total prevalence per 10 000 births was 22.0 (95% CI 21.7-22.4) for trisomy 21, 5.0 (95% CI 4.8-5.1) for trisomy 18 and 2.0 (95% CI 1.9-2.2) for trisomy 13; live birth prevalence was 11.2 (95% CI 10.9-11.5) for trisomy 21, 1.04 (95% CI 0.96-1.12) for trisomy 18 and 0.48 (95% CI 0.43-0.54) for trisomy 13. There was an increase in total and total corrected prevalence of all three trisomies over time, mainly explained by increasing maternal age. Live birth prevalence remained stable over time. For trisomy 21, there was a three-fold variation in live birth prevalence between countries. The rise in maternal age has led to an increase in the number of trisomy-affected pregnancies in Europe. Live birth prevalence has remained stable overall. Differences in prenatal screening and termination between countries lead to wide variation in live birth prevalence. [ABSTRACT FROM AUTHOR]

This article examines public perceptions of biobanks in Europe using a multi-method approach combining quantitative and qualitative data. It is shown that public support for biobanks in Europe is variable and dependent on a range of interconnected factors: people's engagement with biobanks; concerns about privacy and data security, and trust in the socio-political system, key actors and institutions involved in biobanks. We argue that the biobank community needs to acknowledge the impact of these factors if they are to successfully develop and integrate biobanks at a pan-European level. [ABSTRACT FROM AUTHOR]

In the 2000s, a number of initiatives were taken internationally to improve quality in genetic testing services. To contribute to and update the limited literature available related to this topic, we surveyed 910 human molecular genetic testing laboratories, of which 291 (32%) from 29 European countries responded. The majority of laboratories were in the public sector (81%), affiliated with a university hospital (60%). Only a minority of laboratories was accredited (23%), and 26% was certified. A total of 22% of laboratories did not participate in external quality assessment (EQA) and 28% did not use reference materials (RMs). The main motivations given for accreditation were to improve laboratory profile (85%) and national recognition (84%). Nearly all respondents (95%) would prefer working in an accredited laboratory. In accredited laboratories, participation in EQA (P<0.0001), use of RMs (P=0.0014) and availability of continuous education (CE) on medical/scientific subjects (P=0.023), specific tasks (P=0.0018), and quality assurance (P<0.0001) were significantly higher than in non-accredited laboratories. Non-accredited laboratories expect higher restriction of development of new techniques (P=0.023) and improvement of work satisfaction (P=0.0002) than accredited laboratories. By using a quality implementation score (QIS), we showed that accredited laboratories (average score 92) comply better than certified laboratories (average score 69, P<0.001), and certified laboratories better than other laboratories (average score 44, P<0.001), with regard to the implementation of quality indicators. We conclude that quality practices vary widely in European genetic testing laboratories. This leads to a potentially dangerous situation in which the quality of genetic testing is not consistently assured. [ABSTRACT FROM AUTHOR]

The ability of humans to digest the milk component lactose after weaning requires persistent production of the lactose-converting enzyme lactase. Genetic variation in the promoter of the lactase gene (LCT) is known to be associated with lactase production and is therefore a genetic determinant for either lactase deficiency or lactase persistence during adulthood. Large differences in this genetic trait exist between populations in Africa and the Middle-East on the one hand, and European populations on the other; this is thought to be due to evolutionary pressures exerted by consumption of dairy products in Neolithic populations in Europe. In this study, we have investigated lactase persistence of 26 out of 46 individuals from Late Neolithic through analysis of ancient South-West European DNA samples, obtained from two burials in the Basque Country originating from 5000 to 4500 YBP. This investigation revealed that these populations had an average frequency of lactase persistence of 27%, much lower than in the modern Basque population, which is compatible with the concept that Neolithic and post-Neolithic evolutionary pressures by cattle domestication and consumption of dairy products led to high lactase persistence in Southern European populations. Given the heterogeneity in the frequency of the lactase persistence allele in ancient Europe, we suggest that in Southern Europe the selective advantage of lactose assimilation in adulthood most likely took place from standing population variation, after cattle domestication, at a post-Neolithic time when fresh milk consumption was already fully adopted as a consequence of a cultural influence. [ABSTRACT FROM AUTHOR]

The purpose of this article is to give an overview and discuss the relevant regulations in place, or under consideration, regarding healthcare-related personal genetics services in Europe - this is a rapidly evolving field and in most European Union (EU) countries the regulatory framework is not yet clear. The review will be framed from the perspective of potential service providers (companies, health services and practitioners, including medical, nutritional, complementary, etc), the growing number of which will need to be aware of potential regulatory hurdles existing now and that may arise in the future. The main conclusion from the survey is that strict regulations regarding practitioner-delivered personal genetic-testing services are unlikely to be enforced over the next 5 years in most EU countries, with the exception of Germany. There is broad-based, but by no means universal, support for a strong voluntary code of practice as an alternative to government regulations to protect consumers and to enable all stakeholders to recognise serious and reputable service providers. On the other hand, there are influential bodies calling for strict regulation. As genotyping costs rapidly fall, it is likely that it will become routine and a major challenge that does not seem to be addressed by current debate on regulations is the emergence of companies offering/selling personal genetic services based on a customer's pre-existing genetic results and therefore no actual laboratory testing involved. [ABSTRACT FROM AUTHOR]

This study aims to assess prevalence and pregnancy outcome for sex chromosome trisomies (SCTs) diagnosed prenatally or in the first year of life. Data held by the European Surveillance of Congenital Anomalies (EUROCAT) database on SCT cases delivered 2000-2005 from 19 population-based registries in 11 European countries covering 2.5 million births were analysed. Cases included were livebirths diagnosed to 1 year of age, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly (TOPFA). In all, 465 cases of SCT were diagnosed between 2000 and 2005, a prevalence of 1.88 per 10,000 births (95% CI 1.71-2.06). Prevalence of XXX, XXY and XYY were 0.54 (95% CI 0.46-0.64), 1.04 (95% CI 0.92-1.17) and 0.30 (95% CI 0.24-0.38), respectively. In all, 415 (89%) were prenatally diagnosed and 151 (36%) of these resulted in TOPFA. There was wide country variation in prevalence (0.19-5.36 per 1000), proportion prenatally diagnosed (50-100%) and proportion of prenatally diagnosed resulting in TOPFA (13-67%). Prevalence of prenatally diagnosed cases was higher in countries with high prenatal detection rates of Down syndrome. The EUROCAT prevalence rate for SCTs diagnosed prenatally or up to 1 year of age represents 12% of the prevalence expected from cytogenetic studies of newborn babies, as the majority of cases are never diagnosed or are diagnosed later in life. There is a wide variation between European countries in prevalence, prenatal detection and TOPFA proportions, related to differences in screening policies as well as organizational and cultural factors. [ABSTRACT FROM AUTHOR]

Family-based research in genetically isolated populations is an effective approach for identifying loci influencing variation in disease traits. In common with all studies in humans, those in genetically isolated populations need ethical approval; however, existing ethical frameworks may be inadequate to protect participant privacy and confidentiality and to address participants’ information needs in such populations. Using the ethical–legal guidelines of the Council for International Organizations of Medical Sciences (CIOMS) as a template, we compared the participant information leaflets and consent forms of studies in five European genetically isolated populations to identify additional information that should be incorporated into information leaflets and consent forms to guarantee satisfactorily informed consent. We highlight the additional information that participants require on the research purpose and the reasons why their population was chosen; on the potential risks and benefits of participation; on the opportunities for benefit sharing; on privacy; on the withdrawal of consent and on the disclosure of genetic data. This research raises some important issues that should be addressed properly and identifies relevant types of information that should be incorporated into information leaflets for this type of study. [ABSTRACT FROM AUTHOR]

Thiopurine S-methyltransferase (TPMT) is the rate-limiting step in the conversion of thiopurine drugs including azathioprine (AZA) to inactive metabolites. Heritable deficiency of TPMT activity increases risk for adverse events, most notably, myelosuppression leading to leukopenia and neutropenic sepsis. The reported European Commission study was undertaken to identify current evidence for the clinical utility of testing for TPMT status and extent of uptake, by either genotyping or phenotyping, in the clinical setting. Data presented here for the UK and Spain indicate that there has been a considerable increase in the uptake of TPMT testing in recent years. There are some data that support routine TPMT testing before AZA prescribing for reducing AZA-related adverse events. Key data include evidence in favor of TPMT testing in addition to the current practice of routine monitoring for reducing the number of AZA-related episodes of myelosuppression, averting deaths from neutropenic sepsis and improving health-related quality of life. Further data are needed for determining the cost-effectiveness of routine TPMT testing.European Journal of Human Genetics (2009) 17, 991–998; doi:10.1038/ejhg.2009.10; published online 18 February 2009 [ABSTRACT FROM AUTHOR]

Genetic matching potentially provides a means to alleviate the effects of incomplete Mendelian randomization in population-based gene–disease association studies. We therefore evaluated the genetic-matched pair study design on the basis of genome-wide SNP data (309 790 markers; Affymetrix GeneChip Human Mapping 500K Array) from 2457 individuals, sampled at 23 different recruitment sites across Europe. Using pair-wise identity-by-state (IBS) as a matching criterion, we tried to derive a subset of markers that would allow identification of the best overall matching (BOM) partner for a given individual, based on the IBS status for the subset alone. However, our results suggest that, by following this approach, the prediction accuracy is only notably improved by the first 20 markers selected, and increases proportionally to the marker number thereafter. Furthermore, in a considerable proportion of cases (76.0%), the BOM of a given individual, based on the complete marker set, came from a different recruitment site than the individual itself. A second marker set, specifically selected for ancestry sensitivity using singular value decomposition, performed even more poorly and was no more capable of predicting the BOM than randomly chosen subsets. This leads us to conclude that, at least in Europe, the utility of the genetic-matched pair study design depends critically on the availability of comprehensive genotype information for both cases and controls.European Journal of Human Genetics (2009) 17, 967–975; doi:10.1038/ejhg.2008.266; published online 21 January 2009 [ABSTRACT FROM AUTHOR]

The debate concerning the mechanisms underlying the prehistoric spread of farming to Southeast Europe is framed around the opposing roles of population movement and cultural diffusion. To investigate the possible involvement of local people during the transition of agriculture in the Balkans, we analysed patterns of Y-chromosome diversity in 1206 subjects from 17 population samples, mainly from Southeast Europe. Evidence from three Y-chromosome lineages, I-M423, E-V13 and J-M241, make it possible to distinguish between Holocene Mesolithic forager and subsequent Neolithic range expansions from the eastern Sahara and the Near East, respectively. In particular, whereas the Balkan microsatellite variation associated to J-M241 correlates with the Neolithic period, those related to E-V13 and I-M423 Balkan Y chromosomes are consistent with a late Mesolithic time frame. In addition, the low frequency and variance associated to I-M423 and E-V13 in Anatolia and the Middle East, support an European Mesolithic origin of these two clades. Thus, these Balkan Mesolithic foragers with their own autochthonous genetic signatures, were destined to become the earliest to adopt farming, when it was subsequently introduced by a cadre of migrating farmers from the Near East. These initial local converted farmers became the principal agents spreading this economy using maritime leapfrog colonization strategies in the Adriatic and transmitting the Neolithic cultural package to other adjacent Mesolithic populations. The ensuing range expansions of E-V13 and I-M423 parallel in space and time the diffusion of Neolithic Impressed Ware, thereby supporting a case of cultural diffusion using genetic evidence.European Journal of Human Genetics (2009) 17, 820–830; doi:10.1038/ejhg.2008.249; published online 24 December 2008 [ABSTRACT FROM AUTHOR]

To investigate the male genetic legacy of the Arab rule in southern Europe during medieval times, we focused on specific Northwest African haplogroups and identified evolutionary close STR-defined haplotypes in Iberia, Sicily and the Italian peninsula. Our results point to a higher recent Northwest African contribution in Iberia and Sicily in agreement with historical data. southern Italian regions known to have experienced long-term Arab presence also show an enrichment of Northwest African types. The forensic and genomic implications of these findings are discussed.European Journal of Human Genetics (2009) 17, 848–852; doi:10.1038/ejhg.2008.258; published online 21 January 2009 [ABSTRACT FROM AUTHOR]

An investigation into fine-scale European population structure was carried out using high-density genetic variation on nearly 6000 individuals originating from across Europe. The individuals were collected as control samples and were genotyped with more than 300 000 SNPs in genome-wide association studies using the Illumina Infinium platform. A major East–West gradient from Russian (Moscow) samples to Spanish samples was identified as the first principal component (PC) of the genetic diversity. The second PC identified a North–South gradient from Norway and Sweden to Romania and Spain. Variation of frequencies at markers in three separate genomic regions, surrounding LCT, HLA and HERC2, were strongly associated with this gradient. The next 18 PCs also accounted for a significant proportion of genetic diversity observed in the sample. We present a method to predict the ethnic origin of samples by comparing the sample genotypes with those from a reference set of samples of known origin. These predictions can be performed using just summary information on the known samples, and individual genotype data are not required. We discuss issues raised by these data and analyses for association studies including the matching of case-only cohorts to appropriate pre-collected control samples for genome-wide association studies.European Journal of Human Genetics (2008) 16, 1413–1429; doi:10.1038/ejhg.2008.210 [ABSTRACT FROM AUTHOR]

The aim of this article is to review the national regulations and practices of genetic counselling in 38 European countries, and to examine how well they intersect the ideals of genetic counselling defined in international guidelines. Using an electronic survey, representatives of the National Societies of Human Genetics in 29 countries, and appropriate contact persons for the field of genetic counselling in 9 other countries, were asked about the regulations and practices. The answers showed that consent, confidentiality, genetic counselling in the context of prenatal diagnosis, those professionals who may perform genetic counselling, and non-directiveness were the topics most often either agreed upon among professionals or regulated in those countries. These are also among the key aspects of ideal genetic counselling, based on international guidelines. Counselling in the context of susceptibility testing for multifactorial diseases, counselling people from ethnic minorities and recontacting the counsellees, on the contrary, were topics regulated or guided by generally applied practices in only few countries. Many of the answers expressed a desire for more regulation of genetic counselling, and that more uniform practices of education and organization of genetic counselling would be welcome in Europe.European Journal of Human Genetics (2008) 16, 1208–1216; doi:10.1038/ejhg.2008.93; published online 14 May 2008 [ABSTRACT FROM AUTHOR]

We studied how well the European CEU samples used in the Haplotype Mapping Project (HapMap) represent five European populations by analyzing nuclear family samples from the Swedish, Finnish, Dutch, British and Australian (European ancestry) populations. The number of samples from each population (about 30 parent-offspring trios) was similar to that in the HapMap sample sets. A panel of 186 single nucleotide polymorphisms (SNPs) distributed over the 1.5 Mb region of the GRID2 gene on chromosome 4 was genotyped. The genotype data were compared pair-wise between the HapMap sample and the other population samples. Principal component analysis (PCA) was used to cluster the data from different populations with respect to allele frequencies and to define the markers responsible for observed variance. The only sample with detectable differences in allele frequencies was that from Kuusamo, Finland. This sample also separated from the others, including the other Finnish sample, in the PCA analysis. A set of tagSNPs was defined based on the HapMap data and applied to the samples. The tagSNPs were found to capture the genetic variation in the analyzed region at r2>0.8 at levels ranging from 95% in the Kuusamo sample to 87% in the Australian sample. To capture the maximal genetic variation in the region, the Kuusamo, HapMap and Australian samples required 58, 63 and 73 native tagSNPs, respectively. The HapMap CEU sample represents the European samples well for tagSNP selection, with some caution regarding estimation of allele frequencies in the Finnish Kuusamo sample, and a slight reduction in tagging efficiency in the Australian sample.European Journal of Human Genetics (2008) 16, 1142–1150; doi:10.1038/ejhg.2008.77; published online 9 April 2008 [ABSTRACT FROM AUTHOR]

The article discusses the significance of patent institution in Europe. The purpose of the patent institution is to promote research and innovation and to allow the return of new beneficial results to serve the country. Many international and national organisations have addressed the issue of patenting DNA. However, some people are against the principle of the patentability of human genes.

The aim of this study is to gather information from European clinical geneticists about their practices and attitudes with regard to carrier testing in incompetent children. European clinical institutes where genetic counseling is offered to patients have been contacted. One hundred and seventy-seven of the 287 eligible respondents, corresponding to a response rate of 63%, completed the questionnaire. For all autosomal recessive and X-linked disorders studied, the majority of the respondents were very unwilling or unwilling to provide a carrier test to a 6-year-old asymptomatic child on parental request (range 73–91%). The results of the Wilcoxon–Mann–Whitney U test indicated that for almost all disorders, respondents from Eastern and Southern European countries are more willing to provide a carrier test to a 6-year-old asymptomatic child than respondents from Western and Northern European countries. The Spearman's rank correlation coefficients showed that when a clinical geneticist was unwilling to perform such a test, he/she mostly disagreed that parental uncertainty and anxiety was a good reason to perform a carrier test, he/she mostly disagreed that parents should have the right to decide about such a test, he/she mostly agreed that future autonomy and the confidentiality of genetic information is violated if this test is performed. Overall, the survey showed an adherence to existing recommendations and guidelines regarding carrier testing in incompetent minors. However, for every condition studied, a group of clinical geneticists was willing or very willing to provide a carrier test to a 6-year-old child on parental request.European Journal of Human Genetics (2007) 15, 1211–1217; doi:10.1038/sj.ejhg.5201909; published online 22 August 2007 [ABSTRACT FROM AUTHOR]

Beckwith–Wiedemann syndrome (BWS) is an imprinting-related human disease. The frequencies of causative alterations such as loss of methylation (LOM) of KvDMR1, hypermethylation of H19-DMR, paternal uniparental disomy, CDKN1C gene mutation, and chromosome abnormality have been described for North American and European patients, but the corresponding frequencies in Japanese patients have not been measured to date. Analysis of 47 Japanese cases of BWS revealed a significantly lower frequency of H19-DMR hypermethylation and a higher frequency of chromosome abnormality than in North American and European patients. These results suggest that susceptibility to epigenetic and genetic alterations differs between the two groups.European Journal of Human Genetics (2007) 15, 1205–1210; doi:10.1038/sj.ejhg.5201912; published online 15 August 2007 [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the quality of written information for patients and families about genetic testing, from a range of European countries. Written information relating to genetic testing for five conditions was gathered from genetic departments across seven European countries. Written information for each condition from each country was randomly chosen for assessment. Fourteen key issues had been identified by a number of pre-existing tools (in particular the DISCERN-Genetics tool) as being important for inclusion when developing or assessing material relating to genetic testing. Fifty pieces in total were assessed for the inclusion or omission of key issues. Although the majority of information discussed issues relating to the condition including background and effect (n=48, 96%), treatment and management (n=37, 74%) and heredity and risk (n=49, 98%), only half the information discussed where to obtain additional information and support (n=25, 50%). Less than half the information discussed what happens after the test (n=15, 30%), patient rights (n=12, 24%) and shared decision making (n=12, 24). Benefits were more likely to be included (n=41, 82%) than any risks involved (n=24, 48%). The issue discussed least frequently was the possible psychological and social effects of genetic testing (n=9, 18%). Pre-written leaflets tended to provide a more comprehensive discussion of the issues surrounding genetic testing than personal letters did and should therefore routinely be available to patients alongside personal letters. Written information should include risks and limitations of testing as well as discussion of the psychological and social aspects of genetic testing.European Journal of Human Genetics (2007) 15, 1012–1022; doi:10.1038/sj.ejhg.5201874; published online 13 June 2007 [ABSTRACT FROM AUTHOR]

Four full genome scans have been carried out by the partners of the European cluster on coeliac disease as well as follow-up studies of candidate regions. No region outside HLA showed significant linkage to the disease in any single study. We first applied a meta-analysis based on a modification of Genome Screen Meta-Analysis to take into account the different linkage statistics, the arbitrariness of bin cutoff points, as well as the sample size of each study. We then performed a pooled linkage analysis of all families and raw genotypes. Besides the HLA region, already known to harbour a risk factor for coeliac disease, both approaches leave very little doubt on the presence of a genetic risk factor in the 5q31-33 region. This region was suggested by several individual studies, but did not reach statistical values high enough to be conclusive when data sets were analysed separately.European Journal of Human Genetics (2003) 11, 828-834. doi:10.1038/sj.ejhg.5201051 [ABSTRACT FROM AUTHOR]

Y chromosome variation in 457 Croatian samples was studied using 16 SNPs/indel and eight STR loci. High frequency of haplogroup I in Croatian populations and the phylogeographic pattern in its background STR diversity over Europe make Adriatic coast one likely source of the recolonization of Europe following the Last Glacial Maximum. The higher frequency of I in the southern island populations is contrasted with higher frequency of group R1a chromosomes in the northern island of Krk and in the mainland. R1a frequency, while low in Greeks and Albanians, is highest in Polish, Ukrainian and Russian populations and could be a sign of the Slavic impact in the Balkan region. Haplogroups J, G and E that can be related to the spread of farming characterize the minor part (12.5%) of the Croatian paternal lineages. In one of the southern island (Hvar) populations, we found a relatively high frequency (14%) of lineages belonging to P*(xM173) cluster, which is unusual for European populations. Interestingly, the same population also harbored mitochondrial haplogroup F that is virtually absent in European populations - indicating a connection with Central Asian populations, possibly the Avars. [ABSTRACT FROM AUTHOR]

Biobanks correspond to different situations: research and technological development, medical diagnosis or therapeutic activities. Their status is not clearly defined. We aimed to investigate human biobanking in Europe, particularly in relation to organisational, economic and ethical issues in various national contexts. Data from a survey in six EU countries (France, Germany, the Netherlands, Portugal, Spain and the UK) were collected as part of a European Research Project examining human and non-human biobanking (EUROGENBANK, coordinated by Professor JC Galloux). A total of 147 institutions concerned with biobanking of human samples and data were investigated by questionnaires and interviews. Most institutions surveyed belong to the public or private non-profit-making sectors, which have a key role in biobanking. This activity is increasing in all countries because few samples are discarded and genetic research is proliferating. Collections vary in size, many being small and only a few very large. Their purpose is often research, or research and healthcare, mostly in the context of disease studies. A specific budget is very rarely allocated to biobanking and costs are not often evaluated. Samples are usually provided free of charge and gifts and exchanges are the common rule. Good practice guidelines are generally followed and quality controls are performed but quality procedures are not always clearly explained. Associated data are usually computerised (identified or identifiable samples). Biobankers generally favour centralisation of data rather than of samples. Legal and ethical harmonisation within Europe is considered likely to facilitate international collaboration. We propose a series of recommendations and suggestions arising from the EUROGENBANK project. [ABSTRACT FROM AUTHOR]

Congenital deafness accounts for about 1 in 1000 infants and approximately 80% of cases are inherited as an autosomal recessive trait. Recently, it has been demonstrated that connexin 26 (GJB2) gene is a major gene for congenital sensorineural deafness. A single mutation (named 35delG) was found in most recessive families and sporadic cases of congenital deafness, among Caucasoids, with relative frequencies ranging from 28% to 63%. We present here the analysis of the 35delG mutation in 3270 random controls from 17 European countries. We have detected a carrier frequency for 35delG of 1 in 35 in southern Europe and 1 in 79 in central and northern Europe. In addition, 35delG was detected in five out of 376 Jewish subjects of different origin, but was absent in other non-European populations. The study suggests either a single origin for 35delG somewhere in Europe or in the Middle East, and the possible presence of a carrier advantage together with a founder effect. The 35delG carrier frequency of 1 in 51 in the overall European population clearly indicates that this genetic alteration is a major mutation for autosomal recessive deafness in Caucasoids. This finding should facilitate diagnosis of congenital deafness and allow early treatment of the affected subjects. [ABSTRACT FROM AUTHOR]

Hypophosphatasia is an inherited disorder characterised by defective bone mineralisation and deficiency of serum and tissue liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. We report the characterisation of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 13 European families affected by perinatal, infantile or childhood hypophosphatasia. Eighteen distinct mutations were found, only three of which had been reported previously in North American and Japanese populations. Most of the 15 new mutations were missense mutations, but we also found two mutations affecting donor splice sites and a nonsense mutation. A missense mutation in the last codon of the putative signal peptide probably affects the final maturation of the protein. Despite extensive sequencing of the gene and its promotor region, only one mutation was identified in two cases, one of which was compatible with a possible dominant effect of certain mutations and the putative role of polymorphisms of the TNSALP gene. In 12 of the 13 tested families, genetic diagnosis was possible by characterisation of the mutations or by use of polymorphisms as genetic markers. Hypophosphatasia diagnosis was assigned in two families where clinical, laboratory and radiographic data were unclear and prenatal diagnosis was performed in one case. The results also show that severe hypophosphatasia is due to a very large spectrum of mutations in European populations with no prevalent mutation and that genetic diagnosis of the disease must be performed by extensive analysis of the gene. [ABSTRACT FROM AUTHOR]

Within the framework of the European Concerted Action on Cystic Fibrosis (Biomed-2, BMH4-CT96-0462) a quality assessment was set up for 135 European and one Australian laboratory. Six DNA samples were sent to the various laboratories. These samples carried the following CFTR genotypes: dF508/N1303K; dI507/wild; dF508/G551D; dF508/621 + 1 GtoT; R553X/wild and 1717-1 GtoA/wild. Each laboratory was asked to process the samples as they routinely do, whether they checked for all mutations or not. More than 75% of the laboratories screened for at least six of these mutations. Heteroduplex analysis was the most frequently used primary testing method (47%), in many instances followed by restriction enzyme digestion. Only a minority of the laboratories made use of a commercial CFTR mutation detection kit. On average, 91% of the laboratories correctly typed both alleles of a given DNA sample. However, 35% of the laboratories incorrectly typed one or more alleles from a total of 12 alleles included in the trial. One laboratory even failed to identify four of the different alleles correctly. The genotyping error frequency tended to be lower in laboratories which perform more than 200 CFTR mutation analyses per year. The results of this quality control trial suggest that there are many laboratories (35%) which have a percentage of errors unacceptable in a routine testing setting. The development of a consensus testing strategy for routine diagnostic laboratories and centralised mutation analysis facilities for rare or country-specific mutations in a limited number of expert centres, in combination with regular training sessions and quality assessments, should further improve genotyping. [ABSTRACT FROM AUTHOR]

The article reports on Cytogenetic Guidelines and Quality Assurance, a European guide for quality assessment for constitutional and acquired cytogenetic investigations. It is noted that the Permanent Working Group "Cytogenetics and Society" of the European Cytogeneticists Association (ECA) prepared these guidelines as a quality basis for cytogenetic laboratories in Europe. These guidelines are developed to assist in the creation of national standards relative to cytogenetic research.

The article presents a study which aims to determine needs and potential strategies to educate health professionals in genetic competences relevant to their professional role in Europe. The findings of the study highlight the deficiencies in current provision of education and confirm the need for concerted efforts to provide professional education to a range of health professionals who may play a role in providing genetic testing in the future.

The last few years have witnessed an important expansion of human DNA sampling and data collecting. This activity has strategic importance for genetic research, clinical care and future treatments. Collections should be maintained and their use optimized. Human DNA, tissue or cell collections and the attached databases have been extensively exchanged for scientific purposes. However, the status of such collections and databases is not well defined and most institutions have no written policies or agreements regarding this activity. Regulations are at an early stage in most European countries and, with the multiplicity of actors and of rules that regulate them, the situation is difficult to comprehend. The rules for exchanging and sharing of information and material are not clear. The notion of return of benefits to research subjects or communities is fairly recent. Collections and databases are expensive to establish and maintain. They are of high interest to scientists, to industrial partners, to health care professionals and ultimately for the community. It is difficult to separate public and private research, as researchers from both sectors are often involved in the same project. While this enables effective technology transfer, it also gives rise to concerns about conflicts of interest. here is a need to promote confidence in research based on DNA collections.