The CAG repeat at the Huntington disease gene in the Portuguese population : insights into its dynamics and to the origin of the mutation

Huntington disease (HD) is caused by an expansion of a CAG repeat. This repeat is a dynamic mutation that tends to undergo intergenerational instability. We report the analysis of the CAG repeat in a large population sample (2,000 chromosomes) covering all regions of Portugal, and a haplotype study of (CAG)n and (CCG)n repeats in 140 HD Portuguese families. Intermediate class 2 alleles represented 3.0% of the population; and two expanded alleles (36 and 40 repeats, 0.11%) were found. There was no evidence for geographical clustering of the intermediate or expanded alleles. The Portuguese families showed three different HD founder haplotypes associated with 7-, 9- or 10-CCG repeats, suggesting the possibility of different origins for theHDmutation among this population. The haplotype carrying the 7-CCG repeat was the most frequent, both in normal and in expanded alleles. In general, we propose that three mechanisms, occurring at different times,may lead to the evolution from normal CAGs to full expansion: first, a mutation bias towards larger alleles; then, a stepwise process that could explain the CAGdistributions observed in themore recent haplotypes; and, finally, a pool of intermediate (class 2) alleles more prone to give rise to expanded HD alleles.Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BD/9759/ 2003.Instituto de Genética Médica Jacinto Magalhães

Molecular diagnosis of Huntington disease in Portugal : implications for genetic counselling and clinical practice

Huntington disease (HD) is a eurodegenerative, autosomal dominant disorder of late-onset, caused by the expansion of a CAG repeat in the coding region of the gene. Ours is the reference laboratory for genetic testing in HD, in Portugal, since 1998; 90.1% of all 158 families known were identified for the first time, including patients with unusual presentation or without family history. A total of 338 genetic tests were performed: 234 for diagnosis, 96 for presymptomatic and four for prenatal testing (four were done for family studies). Most referring physicians were neurologists (90.6%); 82.8% of all clinical diagnosis were confirmed, while 83.1% of those sent for exclusion were in fact excluded. In presymptomatic testing, an excess of female subjects (59.4%) was again verified; 37.5% of the consultands were found to be carriers. None of the foetuses, in four prenatal tests, were mutation carriers. One juvenile case was inherited from her mother. Our patient population is very similar to others described so far, namely in terms of mean age at onset and (CAG)n distribution, except perhaps for a higher frequency of large normal (class 2) alleles (3.7%). We also identify cases posing particular problems for genetic counselling, such as, ‘homozygosity’ that can pose a serious ethical dilemma, carriers of large normal alleles, and ‘homoallelism’ for a normal gene, which will demand further procedures and may delay results in presymptomatic and prenatal testing

Misunderstandings Concerning Genetics Among Patients Confronting Genetic Disease

Critical questions arise about misunderstandings of genetics. We interviewed for 2 h each, 64 individuals who had or were at risk for Huntington's disease (HD), breast cancer or Alpha‐1 antitrypsin deficiency. These individuals revealed various misunderstandings that can affect coping, and testing, treatment and reproductive decisions. A therapeutic misconception about testing appeared: that testing would be helpful in and of itself. Many believed they could control genetic disorders (even HD), yet these beliefs were often incorrect, and could impede coping, testing, and treatment. Misunderstandings about statistics and genetics often fueled each other, and reflected denial, and desires for hope and control. Emotional needs can thus outweigh understandings of genetics and statistics, and providers’ input. Individuals often maintained non‐scientific beliefs, though embarrassed by these. These data have implications for care, and public and professional education. Misunderstandings’ persistence, despite realization of their inaccuracy, suggests that providers need to address not just cognitive facts, but underlying emotional issues

Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

This is the final version. Available from BMC via the DOI in this record. Individual cohort-level data can be obtained from the respective cohort (see Additional file 1: Table S1 and Additional file 2 for cohort details).BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N). CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.Wellcome TrustBiotechnology and Biological Sciences Research Council (BBSRC)Biotechnology and Biological Sciences Research Council (BBSRC)European Union’s Horizon 2020Economic and Social Research Council (ESRC)Medical Research Council (MRC)Medical Research Council (MRC)European UnionSwedish foundation for strategic research (SSF)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Environmental Protection Agency (EPA)National Cancer Institute Cancer CenterNational Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Environmental Protection Agency (EPA)Environmental Protection Agency (EPA)European UnionEuropean UnionEuropean UnionEuropean UnionEuropean Union’s Horizon 2020European Research Council (ERC)German Ministry of Education and ResearchNational Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Autism SpeaksNational Institutes of Health (NIH)National Institutes of Health (NIH)European UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean Research Council (ERC)Flemisch Scientific Research CouncilFlemisch Scientific Research CouncilFlemisch Scientific Research CouncilEuropean UnionFonds de recherche du Québec - Santé (FRQS)Canadian Institute of Health Research (CIHR)Canadian Institute of Health Research (CIHR)Netherlands Organisation for Scientific Research (NWO)National Institute of Child and Human DevelopmentEuropean Union’s Horizon 2020European Union’s Horizon 2020European Union’s Horizon 2020ZonMwZonMwMedical Research Council Integrative Epidemiology Unit (University of Bristol)Netherlands Heart FoundationNetherlands Heart FoundationNetherlands Organisation for Scientific Research (NWO)European UnionNational Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Spanish Ministry of ScienceNational Institute for Health and Care Research (NIHR)Wellcome TrustNorwegian Ministry of Health and the Ministry of Education and ResearchNorwegian Ministry of Health and the Ministry of Education and ResearchNorwegian Ministry of Health and the Ministry of Education and ResearchLithuanian Agency for Science Innovation and TechnologySpanish Ministry of HealthSpanish Ministry of HealthSpanish Ministry of HealthSpanish Ministry of HealthSpanish Ministry of HealthInstituto de Salud Carlos IIIInstituto de Salud Carlos IIIEuropean Research Council (ERC)CDMRP/Department of DefenseNIGMSNational Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Asthma Campaign, UKNational Institutes of Health (NIH)Medical Research Council (MRC)National Institutes of Health (NIH)Norwegian Research CouncilNational Institute of Environmental Health SciencesResearch Council of NorwayNational Institute of Environmental Health SciencesNational Institute of Environmental Health SciencesNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of Environmental Health SciencesNational Institute of Environmental Health SciencesSwedish Research CouncilSwedish Initiative for research on Microdata in the Social And Medical Sciences (SIMSAM)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Medical Research Council Integrative Epidemiology Unit (University of Bristol)Medical Research Council Integrative Epidemiology Unit (University of Bristol)Medical Research Council Integrative Epidemiology Unit (University of Bristol)Swedish Heart-Lung FoundationUniversity of MunichFoundation for Medical Research (FRM)National Agency for ResearchNational Institute for Research in Public HealthFrench Ministry of HealthFrench Ministry of ResearchInserm Bone and Joint Diseases National Research (PRO-A) and Human Nutrition National Research ProgramsParis–Sud UniversityNestléFrench National Institute for Population Health SurveillanceFrench National Institute for Health EducationFrench Agency for Environmental Health SafetyMutuelle Générale de l’Education NationaleFrench National Agency for Food SecurityFrench-speaking association for the study of diabetes and metabolismItalian National Centre for Disease Prevention and ControlItalian Ministry of HealthGreek Ministry of HealthFlemish Government (Department of Economy, Science and Innovations, Agency for Care and Health and Department of Environment)The Research Foundation-FlandersFlemish Institute for Technological ResearchDiabète QuébecErasmus University RotterdamNetherlands Organization for Health Research and Development and the Ministry of Health, Welfare and SportErasmus MCDanish National Research FoundationDanish Regional CommitteesNovo Nordisk FoundationLundbeck FoundationHelmholtz Center for Environmental ResearchGerman Cancer Research CentreAcademy of FinlandEraNetEVOUniversity of Helsinki Research FundsSigne and Ane Gyllenberg foundationEmil Aaltonen FoundationFinnish Medical FoundationJane and Aatos Erkko FoundationJuho Vainio foundationYrjö Jahnsson foundationJalmari and Rauha Ahokas foundationPaivikki and Sakari Sohlberg FoundationSigrid Juselius FoundationSir Jules Thorn Charitable TrustSwedish Asthma and Allergy Association's Research FoundationStiftelsen Frimurare Barnhuset Stockhol

Comparison of genotypic and phenotypic strategies for population screening in hemochromatosis: Assessment of anxiety, depression, and perception of health

Purpose: Hemochromatosis is a treatable disorder with a major genetic predisposition. It provides an example in which genotypic and phenotypic strategies for screening may be compared. We previously showed noninferiority of uptake of a genotypic population screening strategy for hemochromatosis compared with a phenotypic strategy. In this article we present the psychologic effects of each strategy.Methods: A sample of 3000 individuals from primary care were randomly allocated to a phenotypic or genotypic screening strategy for hemochromatosis, and the 939 individuals who accepted screening provide the sample for this article. Standardized assessments of anxiety, general health, and depression were made at invitation, testing, result-giving, and 6 months.Results: Screening did not lead to significant changes in the self-rated assessments of anxiety, depression, and general health over time, and there were no significant differences between the two screening strategies. The unemployed or permanently disabled had lower ratings of health and higher anxiety and depression.Conclusion: The two screening strategies appeared to cause little adverse psychologic disturbance in the short term, and there was no difference between the two strategies This study provides some empiric data to support arguments against "genetic exceptionalism" and suggests that genetic testing when used for population screening for a treatable disease has few adverse effects.<br/