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In this paper, we propose to use pedigrees of any size and any types of relatives in joint high-resolution linkage disequilibrium (LD) and linkage mapping of quantitative trait loci (QTL) by variance component models. Two or multiple markers can be simultaneously used in modeling association with the trait locus, instead of using one marker a time in the analysis. The proposed method can provide a unified result by using two or multiple markers in the modeling. This may avoid the complications of different results obtained from the separate analysis of marker by marker. The models simultaneously incorporate both linkage and LD information. The measures of LD are modeled by mean coefficients, and linkage information is modeled by variance-covariance matrix. Using analytical formulas to calculate the regression coefficients, the genetic effects are shown to be decomposed into additive and dominance components. The noncentrality parameter approximations of test statistics of LD are provided to make power calculations. Power and type I error rates are explored to investigate the merit of the proposed method by both the analytical formulas and simulations. Comparing with the association between-family and association within-family (‘AbAw’) approach of Fulker and Abecasis et al, it is evident that the method proposed in this article is more powerful. The method is applied to investigate the relation between polymorphisms in the angiotensin 1-converting enzyme (ACE) genes and circulating ACE levels, with a better result than that of the‘AbAw’approach. Moreover, two markers I/D and 4656(CT)3/2 can fully interpret association with the trait locus at a 0.01 significance level, which provides a unique result for the ACE data.European Journal of Human Genetics (2005) 13, 216-231. doi:10.1038/sj.ejhg.5201301 Published online 13 October 2004 [ABSTRACT FROM AUTHOR]

The article highlights the two papers published in the March 2006 issue of the "European Journal of Human Genetics," which searched for genes that influence susceptibility to multiple sclerosis. The first paper identified 1068 single nucleotide polymorphisms from a 13.3 Mb interval including the major histocompatibility complex region. The other paper have shown remarkable foresight and tenacity in establishing the crucial collection of African American cases of with multiple sclerosis.

Height is a highly heritable, complex trait. At present, the genes responsible for the variation in height have not yet been identified. This paper summarizes the results of previous linkage studies and presents results of an additional linkage analysis. Using data from the Netherlands Twin Register, a sib-pair-based linkage analysis for adult height was conducted. For 513 sib-pairs from 174 families complete genome scans and adult height were available. The strongest evidence for linkage was found for a region on chromosome 6, near markers D6S1053 and D6S1031 (LOD=2.32). This replicated previous findings in other data sets. LOD scores ranging from 1.53 to 2.04 were found for regions on chromosomes 1, 5, 8, 10, and 18. The region on chromosome 18 (LOD=1.83) also corresponded with the results of previous studies. Several chromosomal regions are now implied in the variance in height, but further study is needed to draw definite conclusions with regard to the significance of these regions for adult height.European Journal of Human Genetics (2004) 12, 820-828. doi:10.1038/sj.ejhg.5201229 Published online 11 August 2004 [ABSTRACT FROM AUTHOR]

Two recent papers suggest distorted sex and transmission ratios associated with BRCA1 mutations. If real, these would provide novel insights into the normal biological function of this gene and have implications for genetic epidemiologic methods used to estimate penetrance. We addressed these observations in two settings: offspring of 283 mutation carriers and 471 mutation negative subjects from BRCA1/2 mutation-positive families with multiple cases of breast and ovarian cancer (NCI families); and relatives of 115 BRCA1/2 mutation carriers from the Washington Ashkenazi Study (WAS). The male:female ratio was below one in both BRCA1 (0.85, 95% CI 0.7-1.1 in NCI families; 0.90, 95% CI 0.6-1.4 in WAS) and BRCA2 families (0.77, 95% CI 0.5-1.3 and 0.80, 95% CI 0.5-1.2, in the NCI and WAS study groups, respectively). None of the sex ratios deviated significantly from one, and there was no significant difference between BRCA1 and BRCA2 families. The reduced sex ratio was due largely to the offspring of males, a distortion that is probably an artifact of ascertainment biases. Among adult daughters without breast or ovarian cancer born to mutation carriers, as expected, fewer than 50% were mutation carriers (39% in BRCA1 families and 44% in BRCA2 families). It is difficult, due to ascertainment biases, to draw firm conclusions regarding sex ratios in studies of a sex-limited phenotype. Nonetheless, these observations do not support the idea that BRCA1 mutation carriers have a lower ratio of male offspring than BRCA2 mutation carriers.European Journal of Human Genetics (2004) 12, 663-667. doi:10.1038/sj.ejhg.5201210 Published online 28 April 2004 [ABSTRACT FROM AUTHOR]

Many genetic disorders demonstrate mutations that can be traced to a founder, sometimes a person who can be identified. These founder mutations have generated considerable interest, because they facilitate studies of prevalence and penetrance and can be used to quantify the degree of homogeneity within a population. This paper reports on founder mutations among the Dutch and relates their occurrence to the history and demography of the Netherlands. International migration, regional and religious endogamy, and rapid population growth played key roles in shaping the Dutch population. In the first millenniums BC and AD, the Netherlands were invaded by Celts, Romans, Huns, and Germans. In more recent times, large numbers of Huguenots and Germans migrated into the Netherlands. Population growth within the Netherlands was slow until the 19th century, when a period of rapid population growth started. Today, the Dutch population numbers 16 million inhabitants. Several different classes of founder mutations have been identified among the Dutch. Some mutations occur among people who represent genetic isolates within this country. These include mutations for benign familial cholestasis, diabetes mellitus, type I, infantile neuronal ceroid lipofuscinosis, L-DOPA responsive dystonia, and triphalangeal thumb. Although not related to a specific isolate, other founder mutations were identified only within the Netherlands, including those predisposing for hereditary breast-ovarian cancer, familial hypercholesterolemia, frontotemporal dementia, hereditary paragangliomas, juvenile neuronal ceroid lipofuscinosis, malignant melanoma, protein C deficiency, and San Filippo disease. Many of these show a regional distribution, suggesting dissemination from a founder. Some mutations that occur among the Dutch are shared with other European populations and others have been transmitted by Dutch émigrés to their descendents in North America and South Africa. The occurrence of short chromosomal regions that have remained identical by descent has resulted in relatively limited genetic heterogeneity for many genetic conditions among the Dutch. These observations demonstrate the opportunity for gene discovery for other diseases and traits in the Netherlands.European Journal of Human Genetics (2004) 12, 591-600. doi:10.1038/sj.ejhg.5201151 Published online 10 March 2004 [ABSTRACT FROM AUTHOR]

The combination of multiple exostoses (EXT) and enlarged parietal foramina (foramina parietalia permagna, FPP) represent the main features of the proximal 11p deletion syndrome (P11pDS), a contiguous gene syndrome (MIM 601224) caused by an interstitial deletion on the short arm of chromosome 11. Here we present clinical aspects of two new P11pDS patients and the clinical follow-up of one patient reported in the original paper describing this syndrome. Recognised clinical signs include EXT, FPP, mental retardation, facial asymmetry, asymmetric calcification of coronary sutures, defective vision (severe myopia, nystagmus, strabismus), skeletal anomalies (small hands and feet, tapering fingers), heart defect, and anal stenosis. In addition fluorescence in situ hybridisation and molecular analysis were performed to gain further insight in potential candidate genes involved in P11pDS.European Journal of Human Genetics (2004) 12, 400-406. doi:10.1038/sj.ejhg.5201163 Published online 11 February 2004 [ABSTRACT FROM AUTHOR]

Deficiency of the skeletal muscle membrane protein dysferlin causes the related and overlapping neuromuscular disorders limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. This paper describes the preliminary characterisation of the human dysferlin promoter. The transcriptional start site of dysferlin has been mapped using 5' RACE PCR, which extended the length of the known 5' UTR to 914?bp. Promoter elements have been mapped by assessing the ability of fragments from this region to activate the expression of a luciferase reporter gene borne on a plasmid transfected into differentiated and undifferentiated C2C12 mouse myoblast cells. Finally, the core promoter region has been screened for mutations in suspected dysferlinopathy patients.European Journal of Human Genetics (2004) 12, 127-131. doi:10.1038/sj.ejhg.5201092 Published online 22 October 2003 [ABSTRACT FROM AUTHOR]

Public concern about genetic discrimination, particularly access to insurance following genetic testing, has been reported in the literature. This paper aims to separate myths from realities regarding genetic discrimination in life insurance and to underline the positive aspects of allowing insurers access to relevant genetic information for underwriting purposes. We present a review of the literature pertinent to discrimination in life insurance and a comparative analysis of industries guidelines. There are few reported cases in the literature of validated genetic discrimination. However, the benefits to be gained by allowing insurers access to relevant genetic data could justify fostering a more active role in the use of genetic information by insurance companies. [ABSTRACT FROM AUTHOR]

In this paper, we investigate variance component models of both linkage analysis and high resolution linkage disequilibrium (LD) mapping for quantitative trait loci (QTL). The models are based on both family pedigree and population data. We consider likelihoods which utilize flanking marker information, and carry out an analysis of model building and parameter estimations. The likelihoods jointly include recombination fractions, LD coefficients, the average allele substitution effect and allele dominant effect as parameters. Hence, the model simultaneously takes care of the linkage, LD or association and the effects of the putative trait locus. The models clearly demonstrate that linkage analysis and LD mapping are complementary, not exclusive, methods for QTL mapping. By power calculations and comparisons, we show the advantages of the proposed method: (1) population data can provide information for LD mapping, and family pedigree data can provide information for both linkage analysis and LD mapping; (2) using family pedigree data and a sparse marker map, one may investigate the prior suggestive linkage between trait locus and markers to obtain low resolution of the trait loci, because linkage analysis can locate a broad candidate region; (3) with the prior knowledge of suggestive linkage from linkage analysis, both population and family pedigree data can be used simultaneously in high resolution LD mapping based on a dense marker map, since LD mapping can increase the resolution for candidate regions; (4) models of high resolution LD mappings using two flanking markers have higher power than that of models of using only one marker in the analysis; (5) excluding the dominant variance from the analysis when it does exist would lose power; (6) by performing linkage interval mappings, one may get higher power than by using only one marker in the analysis. [ABSTRACT FROM AUTHOR]

The paper reports on a 5-year longitudinal study on psychological distress after predictive testing for Huntington's disease (HD) and on correlates of post-test distress. Psychometric tests and questionnaires were used. The tested persons were invited to participate in the follow-up study; the uptake rate was 75% (24 carriers, 33 non-carriers). Three time points were included: baseline, 1 year and 5 years posttest. Five years after the test, mean distress scores of both carriers and non-carriers were within the normal range. Carriers did not differ from non-carriers with regard to mean general distress. Compared to non-carriers, however, carriers had significantly less positive feelings (P<0.001) and were more consciously avoiding HD-related situations and thoughts (P<0.01). These findings reflect the carriers' conscious and unconscious attempt to escape from pessimism and to minimise negative consequences of the test result. Psychological distress 5 years post-test was significantly associated with ego-strength (P<0.05 to P<0.001). Except for intrusion and avoidance, distress was also associated with test motivation (P<0.05 to P<0.01). Compared with baseline level, mean depression, general and specific anxiety had significantly decreased I year and 5 years post-test (P<0.05 to 0.01). This evolution was independent of the test result. However, based on test motivation, a subgroup of tested persons having long lasting psychological distress could be identified, also irrespective of test result. Persons who asked the test to get rid of the uncertainty, without being able to specify implications for substantial life areas, had more psychological distress before and after the test than those who wanted the test for specific reasons (P<0.001 to P<0.0001). Moreover, the pattern of post-test anxiety differed over time, depending on the test motivation (P<0.05). The findings suggest that pre- and post-test counselling should pay special attention to persons with lower... [ABSTRACT FROM AUTHOR]

Chromosomes involved in reciprocal translocations form quadrivalents at meiosis. These quadrivalents segregate, with or without recombination, to give 32 different meiotic outcomes, only two of which are normal or balanced. This paper presents data collected from 25 cycles of preimplantation genetic diagnosis for 18 couples carrying 15 different reciprocal translocations. Embryos were tested using fluorescence in situ hybridisation with probes for the translocated and centric segments. Overall, 47.7% (71 out of 149) of embryos tested showed signal patterns consistent with alternate segregation, 24.8% adiacent-1 segregation, 10.1% adiacent-2 segregation, 15.4% 3:1 segregation and 2% 4:0 segregation. For most translocations, alternate segregation was apparently the most frequent mode. Alternate and adiacent-1 frequencies were similar in male and female carriers; however, 5.7% of embryos from female translocation carriers showed adjacent-2 segregation and 20.0% showed 3:1 segregation, whilst the corresponding figures for male carriers were 20.5 and 4.5%. Overall, 2.8% of embryos were mosaic and 2.3% of embryos showed chaotic constitutions for the chromosomes tested. The pregnancy success rate for these 25 cycles was 38.8% per embryo transfer and also 38.8% per couple. [ABSTRACT FROM AUTHOR]

Tumour necrosis factor (TNF) alpha affects immune response and airway inflammation, which are characteristics of asthma. Genetic factors may impact TNFα levels, and several polymorphisms in the TNF gene cluster on chromosome 6p21 have been associated with TNFα production and potential increased risk of asthma. The present paper evaluates the relation between two single nucleotide polymorphisms (SNPs) in the TNF gene cluster and asthma risk. The SNPs investigated here are guanine (G) to adenosine (A) substitutions in the TNFα and lymphotoxin alpha (LTα) genes. The TNFα SNP is at position -308 in the promoter region (TNFα-308), while the LTα SNP is in the first intron Ncol recognition sequence (LTα-Ncol). (For both SNPs the G allele is denoted as 1, and the A allele 2.) We determined TNFα-308 and LTα-Ncol genotypes in 511 individuals: 236 asthma cases and 275 non-asthmatic controls. Data were analysed by logistic regression of asthma status on the genotypes and potential confounders. TNFα-308[sup *]2 was positively associated with asthma, and this relation was strengthened when restricting cases to individuals reporting acute asthma: the adjusted odds ratio (OR) comparing carriers of one or two TNFα-308[sup *]2 alleles versus none was 1.86 (95% confidence interval (CI)=1.03-3.34, P=0.04). Further restricting the subjects to those with a family history of asthma, and those of European-American ancestry strengthened the association even more: adjusted OR=3.16 (95% C1=1.04-9.66; P=0.04). LTα-NcoI[sup *]1 was weakly associated with asthma, and analysis of both genes suggests that only the TNFα-308[sup *]2 allele increases risk of asthma. [ABSTRACT FROM AUTHOR]

Glycogen storage disease type IIIA (GSD IIIA) is caused by mutations of the amyloglucosidase gene (AGL). For most populations, none of the AGL mutations described to date is particularly frequent. In this paper, we report that six children with GSD IIIa from the Faroe Islands were found to be homozygous for the novel nonsense mutation c.1222C>T (R408X) of the AGL gene. This mutation is easily detected by restriction enzyme digest with NsiI after mismatch PCR. Investigating five intragenic polymorphisms, we could show that this mutation was always associated with the same haplotype. The c.1222C>T mutation could be detected on two chromosomes of another 50 unselected GSD Ilia patients of other European or North American origin which means that this mutation plays a minor role worldwide. From the fact that we are currently aware of a total of 14 GSD IIIA cases in the Faroese population of 45 000, the observed prevalence is 1:3100. While the novel AGL mutation c.1222C>T was not detectable among 198 German newborns, nine out of 272 children from the Faroese neonatal screening program were found to be heterozygous for this mutation. Thus, the calculated prevalence is 1:3600 (95% CI 1:700-1:6400). We conclude that due to a founder effect, the Faroe Islands have the highest prevalence of GSD IIIA world-wide. The detection of the molecular defect has facilitated the diagnosis and has offered the opportunity for prenatal diagnosis in this patient group. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) exhibits a genetically heterogeneous transmission involving at least three different genes. PKD1 gene linked mutations are responsible for the disease in about 85% of ADPKD cases. The search for mutations is a very important step in understanding the molecular mechanisms underlying ADPKD. We undertook this study using denaturing gradient gel electrophoresis (DGGE), after a stage of long range PCR, to scan for mutations in the duplicated region of the PKD1 gene in French ADPKD families. This allowed us to identify eight novel mutations and several polymorphisms: among the mutations, three are nonsense mutations, two are deletions in the coding sequence leading to frameshift mutations, one is a splice mutation and two are highly probable missense mutations. In this paper, we also provide a review of the mutations reported so far which are widespread throughout the gene. Although no clear hot spot for mutation is apparent, we will focus on some clustering observed. [ABSTRACT FROM AUTHOR]

Since the identification of two breast-ovarian cancer susceptibility genes (BRCA½), predictive testing for hereditary breast/ovarian cancer (HBOC) has been available. Given the complexity and uncertainties of HBOC and the potential impact of predictive testing on psychological well-being, we offer the test applicants a combination of information-oriented and psychological counselling. In this paper, we describe the multidisciplinary approach for predictive testing for HBOC as a clinical service in Leuven, hereby focusing on psychological and decision counselling practice. Attention is paid to the theoretical framework used for pre-test psychological counselling in Leuven. We discuss three important interacting dimensions of psychological counselling: individual emotional support, decision counselling and support of the family communication process. Decision counselling consists of an evaluation of the cognitive and the emotional processing of the information given and strategies and resources for coping. This serves as a starting point to facilitate free informed decision making. Scenario development is used as a decision aid. [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]

Multicolour in situ hybridisation (MFISH) is increasingly applied to karyotyping and detection of chromosomal abnormalities. So far 27 colour analyses have been described using fluorescetly labelled chromosome painting probes in a so-called combinatorial approach. In this paper a new strategy is presented to use efficiently the currently available number of spectrally separated fluorophores in order to increase the multiplicity of MFISH. We introduce the principle of COBRA (COmbined Binary RAtio labelling), which is based on the simultaneous use of combinatorial labelling and ratio labelling. Human chromosome painting in 24 colours is accomplished using four fluorophores only. Three fluorophores are used pair wise for ratio labelling of a set of 12 chromosome painting probes. The second set of 12 probes is labelled identically but is also given a binary label (fourth fluorophore). The COBRA method is demonstrated on normal human chromosomes and on a lymphoma (JVM) cell line, using probes enzymatically labelled with fluorescein, lissamine and cy5 as primary fluorophores, and diethylaminocoumarin (DEAC), a blue dye, as combinatorial fourth label to demonstrate incorporated digoxigenin. In addition, the principle was tested using chemical labelling. The first set of 12 painting probes was therefore labelled by ULS (Universal Linkage System), using DEAC, cy3 and cy5 as primary labels, and the second set was labelled similarly, but also contained a digoxigenin-ULS label, which was indirectly stained with fluorescein. Subsequently, a mathematical analysis is presented and methods are indicated for achieving an MFISH multiplicity of 48, 96 or even higher using existing technology. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth disease type 4B (CMT4B) is a demyelinating autosomal recessive motor and sensory neuropathy characterised by focally folded myelin sheaths in the peripheral nerve. The CMT4B gene has been localised by homozygosity mapping and haplotype sharing in the 11q23 region. A cDNA encoding for the β2 subunit of the human brain sodium channel, SCN2B, has been recently assigned to the same chromosomal interval by FISH. The SCN2B gene has been considered a good candidate for CMT4B on the basis of protein homology, chromosomal localisation, and putative biological function of the coded product. In this paper, we report the genomic structure of the SCN2B gene consisting of 4 exons and 3 introns spanning a region of approximately 12 Kb. In addition, a search for mutations in patients affected with CMT4B as well as a refined physical localisation excludes SCN2B as the CMT4B gene. [ABSTRACT FROM AUTHOR]

Discusses the psychological consequences of predictive genetic testing for late onset disease. Difficulty in making accurate and meaningful comparisons across diverse neurogenetic diseases and hereditary cancers; Problems associated with predictive genetic testing.

Responds to a commentary made by Gerry Evers-Kiebooms regarding the review of psychological consequences of predictive genetic testing. Inclusion of qualitative data in systematic reviews; Ethics issue regarding experimental studies of genetic counselling.

Patients who might benefit from genetic services may be denied access through failure to be referred. To investigate the evidence on barriers to referral to genetic services, we conducted a systematic review of empirical evidence on this topic. Nine studies were included in the review. Barriers related to non-genetic healthcare professionals were: lack of awareness of patient risk factors, failure to obtain adequate family history, lack of knowledge of genetics and genetic conditions, lack of awareness of genetic services, inadequate coordination of referral and lack of genetics workforce. Those related to individuals affected by or at risk of a genetic condition were: lack of awareness of personal risk, lack of knowledge and/or awareness of medical history of family members and lack of knowledge of genetic services. Research on access to genetic services is heterogeneous; stronger empirical evidence is needed on factors that are barriers, and further research is needed to develop 'targeted interventions' for equitable access to genetic services in a range of populations. [ABSTRACT FROM AUTHOR]

Due to the association of coeliac disease and HLA-specificities DQ2 and DQ8, HLA-typing can be used for risk determination of the disease. This study was designed to evaluate the knowledge of parents from coeliac families regarding HLA-typing and the impact of HLA-typing on the perception of the health of their children. A structured questionnaire was sent to the Dutch, Spanish and German parents participating with their child in the European PreventCD study on disease prevention in high-risk families, addressing parents' understanding of and attitude towards HLA-typing, distress related to HLA-typing and perceived health and health-related quality of life of their children. Sixty-eight percent of parents of 515 children returned the questionnaires, with 85% of children being DQ2/DQ8 positive. The majority of all parents answered the questions on knowledge correctly. Forty-eight percent of parents of DQ2/DQ8-negative children thought their child could develop coeliac disease. More distress was reported by parents of DQ2/DQ8-positive children (P<0.001). All parents showed few regrets and would repeat HLA-typing in future children. Perceived health and health-related quality of life were similar. In conclusion, we can say that misinterpretation of DQ2/DQ8-negative results by parents is frequent. DQ2/DQ8-positive results do not affect perceived health and health-related quality of life of children but may cause temporary negative feelings among parents. Parents of coeliac families seem to support HLA-typing. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a worldwide disease that affects a large number of males. Although prostate-specific antigen (PSA) screening is used, the specificity is limited. This study analyzes the sensitivity and specificity of adenomatous polyposis coli (APC) methylation for PCa detection in body fluids and tissues. Combining search results from PubMed and Embase, 19 studies were included, 5 involving body fluids and 14 involving prostate tissue, with 2344 subjects. In body fluid subgroups, the pooled sensitivity and specificity was 0.53 (95% confidence interval (CI): 0.28-0.78) and 0.92 (95% CI: 0.86-0.95), respectively. From tissue studies, the results presented as 0.84 (95% CI: 0.70-0.92) and 0.91 (95% CI: 0.77-0.97). To confirm the results, we conducted a further analysis by removing studies which introduced high heterogeneity due to the type of cases and controls. The same degree of sensitivity and specificity was presented in two subgroups (urine: sensitivity 0.46, 95% CI: 0.39-0.53; specificity 0.87, 95% CI: 0.64-0.96; tissue: sensitivity 0.87, 95% CI: 0.72-0.94; specificity 0.89, 95% CI: 0.68-0.97). In addition, analysis of the interaction between APC methylation and PCa showed strong association in the whole data set (odds ratio (OR)=24.91, 95% CI: 12.86-48.24, I2=72.5%). Pooling the same two main subgroups (tissue/fluid) gave a pooled OR of 33.54 (95% CI: 14.88-75.59; I2=70.7%) and 8.20 (95% CI: 2.84-23.74, I2=64.2%), respectively. From this study, the results suggest that APC promoter methylation may be the potential testing for PCa diagnosis and provide a new viewpoint in the treatment of PCa. [ABSTRACT FROM AUTHOR]

There is uncertainty over the population prevalence of people with Down's syndrome in England and Wales. This study aimed to estimate the population prevalence of Down's syndrome in England and Wales in 2011. A meta-analysis of published survival rates of people with Down's syndrome from 1938 to 2010 was conducted and the results were applied to the estimated numbers of babies born with Down's syndrome since 1938 in England and Wales. An estimated 37 090 people had Down's syndrome in England and Wales in 2011, a population prevalence of 0.66 per 1000 people; 650 under 1, 2673 aged 1-5, 7115 aged 5-18, 12819 aged 19-40, 10 626 aged 41-55 and 3207 aged 56 and older. The average life expectancy for babies with Down's syndrome born in 2011 was 51 years and the median life expectancy was 58 years. This study provides clarity on the number of people with Down's syndrome in England and Wales. Owing to sudden increases in the survival of babies with Down's syndrome in the 1950s there are a large proportion of people with Down's syndrome who are in their 40s. These people have an increased risk of developing dementia in the future and services should be aware of their potential needs. [ABSTRACT FROM AUTHOR]

A correction to the article "CRTAP Mutations in lethal and severe osteogenesis imperfecta: The importance of combining biochemical and molecular genetic analysis," published in the June 24, 2009 issue is presented.

A correction to the article "Caveolinopathies: from the biology of caveolin-3 to human diseases," published in the July 8, 2009 issue is presented.

Twin and family studies are typically used to elucidate the relative contribution of genetic and environmental variation to phenotypic variation. Here, we apply a quantitative genetic method based on hierarchical clustering, to blood plasma lipidomics data obtained in a healthy cohort consisting of 37 monozygotic and 28 dizygotic twin pairs, and 52 of their biological nontwin siblings. Such data are informative of the concentrations of a wide range of lipids in the studied blood samples. An important advantage of hierarchical clustering is that it can be applied to a high-dimensional 'omics' type data, whereas the use of many other quantitative genetic methods for analysis of such data is hampered by the large number of correlated variables. For this study we combined two lipidomics data sets, originating from two different measurement blocks, which we corrected for block effects by 'quantile equating'. In the analysis of the combined data, average similarities of lipidomics profiles were highest between monozygotic (MZ) cotwins, and became progressively lower between dizygotic (DZ) cotwins, among sex-matched nontwin siblings and among sex-matched unrelated participants, respectively. Our results suggest that (1) shared genetic background, shared environment, and similar age contribute to similarities in blood plasma lipidomics profiles among individuals; and (2) that the power of quantitative genetic analyses is enhanced by quantile equating and combination of data sets obtained in different measurement blocks. [ABSTRACT FROM AUTHOR]

Hirschsprung disease (HSCR, aganglionic megacolon) is a complex and heterogeneous disease with an incidence of 1 in 5000 live births. Despite the multifactorial determination of HSCR in the vast majority of cases, there is a monogenic subgroup for which private rare RET coding sequence mutations with high penetrance are found (45% of HSCR familial cases). An asymmetrical parental origin is observed for RET coding sequence mutations with a higher maternal inheritance. A parent-of-origin effect is usually assumed. Here we show that a differential reproductive rate for males and females also leads to an asymmetrical parental origin, which was never considered as a possible explanation till now. In the case of HSCR, we show a positive association between penetrance of the mutation and parental transmission asymmetry: no parental transmission asymmetry is observed in sporadic RET CDS mutation carrier cases for which penetrance of the mutation is low, whereas a parental transmission asymmetry is observed in affected sib-pairs for which penetrance of the mutation is higher. This allows us to conclude that the explanation for this parental asymmetry is that more severe mutations have resulted in a differential reproductive rate between male and female carriers. [ABSTRACT FROM AUTHOR]

Correction to: European Journal of Human Genetics (2006) 14, 207–215. doi:10.1038/sj.ejhg.5201528Since publication of the above paper, the authors have identified an error in one of the equations. In the following equation, published on p 208:the −1 should not be superscript, so the correct equation readsEuropean Journal of Human Genetics (2006) 14, 976. doi:10.1038/sj.ejhg.5201655 [ABSTRACT FROM AUTHOR]

The field of Biobanking requires extensive work to maintain traceability of samples. However, sometimes the necessity to authenticate a sample may arise. To address these circumstances, we herein present a method for authenticating derivatives by using a blood spot from each donor, attached to a sample authentication form, by means of genetic profiling. Blood spots are collected at the time a blood sample is donated at a health centre and before processing the blood sample at the biobank. To test the validity of our approach over time, we analyzed 26 blood spots stored at room temperature in our facilities for more than 15 years. DNA was successfully extracted from the three storage materials tested in this study and 15 STR markers plus amelogenin were subsequently analyzed. The storage of a small blood spot attached to a sample authentication form proved to be efficient for genetic profiling and, therefore, may constitute a long-lasting (at least 15 years), cost-effective and effortless approach for genetic authentication of samples in biobanks. [ABSTRACT FROM AUTHOR]

Mutations in the gene Indian Hedgehog (IHH) that cause Brachydactyly A-1 (BDA1) have been restricted to a specific region of the N-terminal active fragment of Indian Hedgehog involving codons 95, 100, 131, and 154. We describe two novel mutations in codons 128 and 130, not previously implicated in BDA1. Furthermore, we identified an independent mutation at codon 131 and we also describe a New Zealand family, which carries the ‘Farabee’ founder mutation and haplotype. All of the BDA1 mutations occur in a restricted area of the N-terminal active fragment of the IHH and are in contrast to those mutations causing an autosomal recessive acrocapitofemoral dysplasia, whose mutations are located at the distal N- and C-terminal regions of IHH-N and are physically separated from the BDA1-causing mutations. The identification of multiple independent mutations in codons 95, 100, and now in 131, implicate a discrete function for this region of the protein. Finally, we present a clinical review of all reported and confirmed cases of BDA1, highlighting features of the disorder, which add to the spectrum of the IHH mutations.European Journal of Human Genetics (2009) 17, 1112–1120; doi:10.1038/ejhg.2009.18; published online 11 March 2009 [ABSTRACT FROM AUTHOR]

In this article the author highlights the changes introduced to the European Journal of Human Genetics (EJHG). With this issue, EJHG has entered its 12th year. The last year has seen major changes, leading to a strongly increased international visibility. First, EJHG has now been firmly rooted in the stable of Nature Publishing Group publications. Secondly, the manuscript processing has undergone two significant changes as well. Early in 2003, EJHG moved to full electronic submission. Finally, in September the journal initiated Advance Online Publication. This means that the finally accepted manuscripts are now available online, and thus for referencing, four to five weeks after final acceptance.

This paper examines the professional and scientific views on the principles, techniques, practices, and policies that impact on the population genetic screening programmes in Europe. This paper focuses on the issues surrounding potential screening programmes, which require further discussion before their introduction. It aims to increase, among the health-care professions and health policy-makers, awareness of the potential screening programmes as an issue of increasing concern to public health.The methods comprised primarily the review of the existing professional guidelines, regulatory frameworks and other documents related to population genetic screening programmes in Europe. Then, the questions that need debate, in regard to different types of genetic screening before and after birth, were examined. Screening for conditions such as cystic fibrosis, Duchenne muscular dystrophy, familial hypercholesterolemia, fragile X syndrome, hemochromatosis, and cancer susceptibility was discussed. Special issues related to genetic screening were also examined, such as informed consent, family aspects, commercialization, the players on the scene and monitoring genetic screening programmes. Afterwards, these questions were debated by 51 experts from 15 European countries during an international workshop organized by the European Society of Human Genetics Public and Professional Policy Committee in Amsterdam, The Netherlands, 19-20, November, 1999. Arguments for and against starting screening programmes have been put forward. It has been questioned whether genetic screening differs from other types of screening and testing in terms of ethical issues. The general impression on the future of genetic screening is that one wants to 'proceed with caution', with more active impetus from the side of patients' organizations and more reluctance from the policy-makers. The latter try to obviate the potential problems about the abortion and eugenics issues that might be perceived as a greater problem than it is in reality. However, it seems important to maintain a balance between a 'professional duty of care' and 'personal autonomy'.European Journal of Human Genetics (2003) 11, Suppl 2, S49-S87. doi:10.1038/sj.ejhg.5201113 [ABSTRACT FROM AUTHOR]

We evaluated the testing and reporting of Hardy-Weinberg equilibrium (HWE) in recent genetic association studies, detected how frequently HWE was violated and estimated the power for HWE testing in this literature. Genetic association studies published in 2002 in Nature Genetics, American Journal of Human Genetics, and American Journal of Medical Genetics were assessed. Data were analyzed on 239 biallelic associations using 154 distinct genotype distribution data sets where HWE could be tested. Any information on HWE was given only for 150 (62.8%) associations (92 (59.7%) data sets). Reanalysis of the data showed significant deviation from HWE in the disease-free controls of 20 associations (13 data sets), but only four of them (two data sets) were admitted in the published articles. Another four deviations (in two data sets) were observed in the combined sample of cases and controls of studies where both cases and controls were diseased, and none were reported in the papers. In all six tested multiallelic associations (six data sets), there was violation of HWE, but this was not admitted in the published articles. Power calculations showed that most studies conforming to HWE simply were largely underpowered to detect HWE deviation; for example, power to detect an inbreeding of magnitude F=0.10 exceeded 80% in only 11 (7%) of the data sets being tested. This empirical evidence suggests that, even in high profile genetics journals, testing and reporting for HWE is often neglected and deviations are rarely admitted in the published reports. Moreover, power is limited for HWE testing in most current genetic association studies. [ABSTRACT FROM AUTHOR]

Presents a corrected reprint of the article 'Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family,' by David P. Kelsell, Amanda L. Wilgoss, Gabriela Richard, Howard P. Stevens and Colin S. Munro, published in the 2000 issue of the 'European Journal of Human Genetics.'

A combined analysis of genome scans was performed for adult height in the NHLBI Family Blood Pressure Program. Height data were available on 6752 individuals. Linkage analysis was performed first separately for each of the eight ethnic groups in the four networks using the variance component method. To increase the power to detect the common genetic components affecting height for all the individuals, a linkage analysis was performed subsequently for the combined data set by pooling the average allelesharing IBD () for all groups. By combining the data, we replicated evidence for a QTL influencing adult height on chromosome 7 (7q31) (LOD = 2.46), which has been reported in two previous studies. Suggestive linkage (LOD > 1) was found in another six regions in our combined analysis. Evidence for linkage for two of these regions (2p12, 20p11) has also been reported previously. [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]

A reply by Ceroni et al. to a letter to the editor on their study that describes a homozygous exonic microdeletion in ZNF277 in a girl with specific language impairment (SLI) is presented.

Reprints a portion of the paper 'An Integrated Map of Chromosome 18 CAG Trinucleotide Repeat Loci,' by A.J. Grierson and others, published in a 1999 issue of the 'European Journal of Human Genetics.'

The author discusses the model for fair allocation of health-care resources that does not disenfranchise genetic services users, relative to the paper by Rogowski and colleagues on resource allocation. She mentions the disadvantaged situation of several individuals at risk of monogenic disorder as one of the highlights of the paper when considering the criteria of health resources allocation. She says that the ability to meet the and maximize benefit from clinical interventions are often unmet.

DiGeorge syndrome (DGS) is a developmental field defect, characterised by absent/hypoplastic thymus and parathyroid, and conotruncal heart defects, with haploinsufficiency loci at 22q (DGS1) and 10p (DGS2). We performed fluorescence in situ hybridisations (FISH) and polymerase chain reaction (PCR) analyses in 12 patients with 10p deletions, nine of them with features of DGS, and in a familial translocation 10p;14q associated with midline defects. The critical DGS2 region is defined by two DGS patients, and maps within a 1 cM interval including D10S547 and D10S585. The other seven DGS patients are hemizygous for both loci. The breakpoint of the reciprocal translocation 10p;14q maps at a distance of at least 12 cM distal to the critical DGS2 region. Interstitial and terminal deletions described are in the range of 10–50 cM and enable the tentative mapping of loci for ptosis and hearing loss, features which are not part of the DGS clinical spectrum. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Exploration of gene-gene interaction effects using entropy-based methods" published within this issue.

The author comments on the paper of K. C. Wilhelmsen which investigates the linkage to regions of chromosomes two and four for quantitative phenotypes related to alcoholism. His work adds a sample to the developing study on linkage regions for alcoholism. It was stated that increasing studies published regarding such topic support the confirmation that genes in these regions are associated with alcoholism.

The article focuses on cancer genetics. The largest mutation analysis series yet reported for tuberous sclerosis (TSC), on page 731 of this issue, provides insights into the number of genes that underlie this syndrome and sheds light onto several other important questions. In this new study, the Halley-van den Ouweland lab report on mutation analysis of 490 samples from definite or suspect TSC cases summarizing several years of work from their clinical diagnostic laboratory. A combination of detection techniques were used, with a mutation detection rate of 74 percent overall, and 85 percent in patients with definite TSC. This level of mutation detection is strikingly similar to two previous comprehensive studies on somewhat smaller numbers of patients.

Presents a letter to the editor commenting on the research paper of M. La Regina colleagues on familial Mediterranean fever in Italy.

A correction to the article "Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome" that was published in the previous issue is presented.

A correction to the article "European guidance for the molecular diagnosis of pseudohypoparathyroidism not caused by point genetic variants at GNAS: an EQA study" that was published online in the July 9, 2014 issue is presented.

A correction to the article "EMQN Best Practice Guidelines for molecular and haematology methods for carrier identification and prenatal diagnosis of the haemoglobinopathies" that was published online in the July 23, 2014 issue is presented.

Highlights a landmark paper that describes and discusses the finished version of the human genome. Confirmation of the finished human genome sequence as a robust resource for large-scale evolutionary, functional and comparative analyses; Analysis of the gene birth and gene death in humans; Importance of sequencing multiple genomes.