Showing papers in "European Journal of Human Genetics in 2010"
TL;DR: Beckwith–Wiedemann syndrome is a model disorder for the study of imprinting, growth dysregulation, and tumorigenesis and unique observations point to an important embryonic developmental window relevant to the observations of increased monozygotic twinning and an increased rate of epigenetic errors after subfertility/assisted reproduction.
Abstract: Beckwith–Wiedemann syndrome (BWS) is a model disorder for the study of imprinting, growth dysregulation, and tumorigenesis. Unique observations in this disorder point to an important embryonic developmental window relevant to the observations of increased monozygotic twinning and an increased rate of epigenetic errors after subfertility/assisted reproduction.
467 citations
TL;DR: Identification and characterization of this case provide unequivocal evidence for a critical role for the SNORD116 snoRNA molecules in PWS pathogenesis and Array CGH testing for genomic copy-number changes in cases with complex phenotypes is proving to be invaluable in detecting novel alterations and enabling better genotype–phenotype correlations.
Abstract: Prader–Willi syndrome (PWS) is a neurobehavioral disorder manifested by infantile hypotonia and feeding difficulties in infancy, followed by morbid obesity secondary to hyperphagia. It is caused by deficiency of paternally expressed transcript(s) within the human chromosome region 15q11.2. PWS patients harboring balanced chromosomal translocations with breakpoints within small nuclear ribonucleoprotein polypeptide N (SNRPN) have provided indirect evidence for a role for the imprinted C/D box containing small nucleolar RNA (snoRNA) genes encoded downstream of SNRPN. In addition, recently published data provide strong evidence in support of a role for the snoRNA SNORD116 cluster (HBII-85) in PWS etiology. In this study, we performed detailed phenotypic, cytogenetic, and molecular analyses including chromosome analysis, array comparative genomic hybridization (array CGH), expression studies, and single-nucleotide polymorphism (SNP) genotyping for parent-of-origin determination of the 15q11.2 microdeletion on an 11-year-old child expressing the major components of the PWS phenotype. This child had an ∼236.29 kb microdeletion at 15q11.2 within the larger Prader–Willi/Angelman syndrome critical region that included the SNORD116 cluster of snoRNAs. Analysis of SNP genotypes in proband and mother provided evidence in support of the deletion being on the paternal chromosome 15. This child also met most of the major PWS diagnostic criteria including infantile hypotonia, early-onset morbid obesity, and hypogonadism. Identification and characterization of this case provide unequivocal evidence for a critical role for the SNORD116 snoRNA molecules in PWS pathogenesis. Array CGH testing for genomic copy-number changes in cases with complex phenotypes is proving to be invaluable in detecting novel alterations and enabling better genotype–phenotype correlations.
287 citations
TL;DR: The proposed new paradigm for GWAS not only identified the genes that include significant SNPs found by single-SNP analysis, but also detected new genes in which each single SNP conferred a small disease risk; however, their joint actions were implicated in the development of diseases.
Abstract: Despite the great success of genome-wide association studies (GWAS) in identification of the common genetic variants associated with complex diseases, the current GWAS have focused on single-SNP analysis. However, single-SNP analysis often identifies only a few of the most significant SNPs that account for a small proportion of the genetic variants and offers only a limited understanding of complex diseases. To overcome these limitations, we propose gene and pathway-based association analysis as a new paradigm for GWAS. As a proof of concept, we performed a comprehensive gene and pathway-based association analysis of 13 published GWAS. Our results showed that the proposed new paradigm for GWAS not only identified the genes that include significant SNPs found by single-SNP analysis, but also detected new genes in which each single SNP conferred a small disease risk; however, their joint actions were implicated in the development of diseases. The results also showed that the new paradigm for GWAS was able to identify biologically meaningful pathways associated with the diseases, which were confirmed by a gene-set-rich analysis using gene expression data.
244 citations
TL;DR: This study demonstrates that epigenetic perturbations of the 6th CTCF site of the H19 DMR might be a relevant biomarker for quantitative defects of spermatogenesis in humans and defined a methylation threshold sustaining the classification of patients in two groups, unmethylated and methylated.
Abstract: DNA methylation marks, a key modification of imprinting, are erased in primordial germ cells and sex specifically re-established during gametogenesis. Abnormal epigenetic programming has been proposed as a possible mechanism compromising male fertility. We analysed by pyrosequencing the DNA methylation status of 47 CpGs located in differentially methylated regions (DMRs), the DMR0 and DMR2 of the IGF2 gene and in the 3rd and 6th CTCF-binding sites of the H19 DMR in human sperm from men with normal semen and patients with teratozoospermia (T) and/or oligo-astheno-teratozoospermia (OAT). All normal semen samples presented the expected high global methylation level for all CpGs analysed. In the teratozoospermia group, 11 of 19 patients presented a loss of methylation at variable CpG positions either in the IGF2 DMR2 or in both the IGF2 DMR2 and the 6th CTCF of the H19 DMR. In the OAT group, 16 of 22 patients presented a severe loss of methylation of the 6th CTCF, closely correlated with sperm concentration. The methylation state of DMR0 and of the 3rd CTCF was never affected by the pathological status of sperm samples. This study demonstrates that epigenetic perturbations of the 6th CTCF site of the H19 DMR might be a relevant biomarker for quantitative defects of spermatogenesis in humans. Moreover, we defined a methylation threshold sustaining the classification of patients in two groups, unmethylated and methylated. Using this new classification of patients, the observed intrinsic imprinting defects of spermatozoa appear not to impair significantly the outcome of assisted reproductive technologies.
229 citations
TL;DR: The key clinical features of septo-optic dysplasia (SOD), the significant inroads that progress in genetics has made into the understanding of the aetiology of the condition over the last decade, and the pitfalls and challenges that the authors face in the management of these phenotypically variable patients are summarized.
Abstract: This review summarises the key clinical features of septo-optic dysplasia (SOD), the significant inroads that progress in genetics has made into our understanding of the aetiology of the condition over the last decade, and the pitfalls and challenges that we face in the management of these phenotypically variable patients.
199 citations
TL;DR: Research on triple X syndrome may yield more insight into brain and behaviour relations, developmental psychopathology, auditory-processing disorders, EEG disorders, personality and psychotic disorders, etc.
Abstract: The developmental and clinical aspects in the literature on triple X syndrome are reviewed. Prenatal diagnosis depends on karyotyping. The incidence is 1 of 1000 females. At birth, 47,XXX girls have a lower mean birth weight and a smaller head circumference. Triple X diagnosis was not suspected at birth. The maternal age seems to be increased. Toddlers with triple X syndrome show delayed language development. The youngest girls show accelerated growth until puberty. EEG abnormalities seem to be rather common. Many girls show motor-coordination problems and auditory-processing disorders are not rare. Scoliosis is probably more common in adolescent cases. The IQ levels are 20 points below that of controls, and verbal IQ is lowest. The girls struggle with low self-esteem and they need psychological, behavioural and educational support. They perform best in stable families. After leaving school they seem to feel better. In adults, premature ovarian failure seems to be more prevalent than in controls. MRIs of the brain seem to show decreased brain volumes. The 47,XXX women most often find jobs that reflect their performance abilities. Psychotic illness seems to be more prevalent in triple X adult women than in controls. Psychotic disorders respond well to psychotropic drugs. Triple X adults suffer more frequently from cyclothymic and labile personality traits. Research on triple X syndrome may yield more insight into brain and behaviour relations, developmental psychopathology, auditory-processing disorders, EEG disorders, personality and psychotic disorders, etc.
198 citations
TL;DR: The results suggest that gene-specific hypomethylation may be a common phenomenon in EOPet placentas, and that TIMP3 could serve as a potential prenatal diagnostic marker for EOPET.
Abstract: Preeclampsia and intrauterine growth restriction (IUGR) are two of the most common adverse pregnancy outcomes, but their underlying causes are mostly unknown. Although multiple studies have investigated gene expression changes in these disorders, few studies have examined epigenetic changes. Analysis of the DNA methylation pattern associated with such pregnancies provides an alternative approach to identifying cellular changes involved in these disorders. We analyzed methylation of 1505 CpG sites associated with 807 genes in 26 placentas from early-onset preeclampsia (EOPET), late-onset preeclampsia, IUGR and control subjects using an Illumina GoldenGate Methylation panel. Thirty-four loci were hypomethylated (false discovery rate 10%) in the early-onset preeclamptic placentas while no and only five differentially methylated loci were found in late-onset preeclamptic and IUGR placentas, respectively. Hypomethylation of 4 loci in EOPET was further confirmed by bisulfite pyrosequencing of 26 independent placental samples. The promoter of TIMP3 was confirmed to be significantly hypomethylated in EOPET placentas (P=0.00001). Our results suggest that gene-specific hypomethylation may be a common phenomenon in EOPET placentas, and that TIMP3 could serve as a potential prenatal diagnostic marker for EOPET.
194 citations
TL;DR: The principles of validation and verification in the context of clinical human molecular genetic testing are outlined, including implementation processes, types of tests and their key validation components, and some relevant statistical approaches that can be used by individual laboratories to ensure that tests are conducted to defined standards.
Abstract: The validation and verification of laboratory methods and procedures before their use in clinical testing is essential for providing a safe and useful service to clinicians and patients. This paper outlines the principles of validation and verification in the context of clinical human molecular genetic testing. We describe implementation processes, types of tests and their key validation components, and suggest some relevant statistical approaches that can be used by individual laboratories to ensure that tests are conducted to defined standards.
184 citations
TL;DR: This review will address caveolin-3 biological functions in muscle cells and will describe the muscle and heart disease phenotypes associated with caveolae, a protein which leads to skeletal muscle pathology through multiple pathogenetic mechanisms.
Abstract: In muscle tissue the protein caveolin-3 forms caveolae--flask-shaped invaginations localized on the cytoplasmic surface of the sarcolemmal membrane. Caveolae have a key role in the maintenance of plasma membrane integrity and in the processes of vesicular trafficking and signal transduction. Mutations in the caveolin-3 gene lead to skeletal muscle pathology through multiple pathogenetic mechanisms. Indeed, caveolin-3 deficiency is associated to sarcolemmal membrane alterations, disorganization of skeletal muscle T-tubule network and disruption of distinct cell-signaling pathways. To date, there have been 30 caveolin-3 mutations identified in the human population. Caveolin-3 defects lead to four distinct skeletal muscle disease phenotypes: limb girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. In addition, one caveolin-3 mutant has been described in a case of hypertrophic cardiomyopathy. Many patients show an overlap of these symptoms and the same mutation can be linked to different clinical phenotypes. This variability can be related to additional genetic or environmental factors. This review will address caveolin-3 biological functions in muscle cells and will describe the muscle and heart disease phenotypes associated with caveolin-3 mutations.
174 citations
TL;DR: This review compares the key characteristics of β-thalassaemia carrier screening programmes implemented in countries across the world so that the differences and similarities between the programmes can be assessed and identifies a paucity of research into the outcomes of thalASSaemia screening programmes.
Abstract: β-thalassaemia is one of the most common single-gene inherited conditions in the world, and thalassaemia carrier screening is the most widely performed genetic screening test, occurring in many different countries. β-thalassaemia carrier screening programmes provide a unique opportunity to compare the delivery of carrier screening programmes carried out in different cultural, religious and social contexts. This review compares the key characteristics of β-thalassaemia carrier screening programmes implemented in countries across the world so that the differences and similarities between the programmes can be assessed. The manner in which thalassaemia carrier screening programmes are structured among different populations varies greatly in several aspects, including whether the programmes are mandatory or voluntary, the education and counselling provided and whether screening is offered pre-pregnancy or antenatally. National and international guidelines make recommendations on the most appropriate ways in which genetic carrier screening programmes should be conducted; however, these recommendations are not followed in many programmes. We discuss the implications for the ethical and acceptable implementation of population carrier screening and identify a paucity of research into the outcomes of thalassaemia screening programmes, despite the fact that thalassaemia screening is so commonly conducted.
173 citations
Stanford University1, Sorenson Molecular Genealogy Foundation2, Estonian Biocentre3, University of Tartu4, Russian Academy of Sciences5, University of Pavia6, Wellcome Trust Sanger Institute7, Shifa College of Medicine8, Sindh Institute of Urology and Transplantation9, University of Calcutta10, University of Massachusetts Medical School11, Russian Academy12, Comenius University in Bratislava13, Florida International University14, Centre for Cellular and Molecular Biology15, Indian Statistical Institute16, University of Cambridge17
TL;DR: The diversity and frequency profiles of M458 suggest its origin during the early Holocene and a subsequent expansion likely related to a number of prehistoric cultural developments in the region, and the virtual absence of M 458 chromosomes outside Europe speaks against substantial patrilineal gene flow from East Europe to Asia, including to India, at least since the mid-Holocene.
Abstract: Human Y-chromosome haplogroup structure is largely circumscribed by continental boundaries. One notable exception to this general pattern is the young haplogroup R1a that exhibits post-Glacial coalescent times and relates the paternal ancestry of more than 10% of men in a wide geographic area extending from South Asia to Central East Europe and South Siberia. Its origin and dispersal patterns are poorly understood as no marker has yet been described that would distinguish European R1a chromosomes from Asian. Here we present frequency and haplotype diversity estimates for more than 2000 R1a chromosomes assessed for several newly discovered SNP markers that introduce the onset of informative R1a subdivisions by geography. Marker M434 has a low frequency and a late origin in West Asia bearing witness to recent gene flow over the Arabian Sea. Conversely, marker M458 has a significant frequency in Europe, exceeding 30% in its core area in Eastern Europe and comprising up to 70% of all M17 chromosomes present there. The diversity and frequency profiles of M458 suggest its origin during the early Holocene and a subsequent expansion likely related to a number of prehistoric cultural developments in the region. Its primary frequency and diversity distribution correlates well with some of the major Central and East European river basins where settled farming was established before its spread further eastward. Importantly, the virtual absence of M458 chromosomes outside Europe speaks against substantial patrilineal gene flow from East Europe to Asia, including to India, at least since the mid-Holocene.
TL;DR: If broad NIPD testing includes later-onset diseases, the ‘right not to know’ of the future child will become a new issue in the debate about prenatal screening and challenge the notion of prenatal screening as serving reproductive autonomy.
Abstract: This paper explores the ethical implications of introducing non-invasive prenatal diagnostic tests (NIPD tests) in prenatal screening for foetal abnormalities. NIPD tests are easy and safe and can be performed early in pregnancy. Precisely because of these features, it is feared that informed consent may become more difficult, that both testing and selective abortion will become 'normalized', and that there will be a trend towards accepting testing for minor abnormalities and non-medical traits as well. In our view, however, the real moral challenge of NIPD testing consists in the possibility of linking up a technique with these features (easy, safe and early) with new genomic technologies that allow prenatal diagnostic testing for a much broader range of abnormalities than is the case in current procedures. An increase in uptake and more selective abortions need not in itself be taken to signal a thoughtless acceptance of these procedures. However, combining this with considerably enlarging the scope of NIPD testing will indeed make informed consent more difficult and challenge the notion of prenatal screening as serving reproductive autonomy. If broad NIPD testing includes later-onset diseases, the 'right not to know' of the future child will become a new issue in the debate about prenatal screening. With regard to the controversial issue of selective abortion, it may make a morally relevant difference that after NIPD testing, abortion can be done early. A lower moral status may be attributed to the foetus at that moment, given the dominant opinion that the moral status of the foetus progressively increases with its development.
TL;DR: An Expert Group working under the auspices of the EuroGentest project and European Society of Human Genetics Education Committee agreed that a pragmatic solution to the need to establish common standards for education and practice in genetic health care was to agree a set of core competences that could apply across Europe.
Abstract: The use of genetics and genomics within a wide range of health-care settings requires health professionals to develop expertise to practise appropriately. There is a need for a common minimum standard of competence in genetics for health professionals in Europe but because of differences in professional education and regulation between European countries, setting curricula may not be practical. Core competences are used as a basis for health professional education in many fields and settings. An Expert Group working under the auspices of the EuroGentest project and European Society of Human Genetics Education Committee agreed that a pragmatic solution to the need to establish common standards for education and practice in genetic health care was to agree to a set of core competences that could apply across Europe. These were agreed through an exhaustive process of consultation with relevant health professionals and patient groups. Sets of competences for practitioners working in primary, secondary and tertiary care have been agreed and were approved by the European Society of Human Genetics. The competences provide an appropriate framework for genetics education of health professionals across national boundaries, and the suggested learning outcomes are available to guide development of curricula that are appropriate to the national context, educational system and health-care setting of the professional involved. Collaboration between individuals from many European countries and professions has resulted in an adaptable framework for both pre-registration and continuing professional education. This competence framework has the potential to improve the quality of genetic health care for patients globally.
TL;DR: The data suggest that increased expression of FTO is associated with increased body mass, and that skewed allelic expression of the RPGRIP1L gene in blood was independent of the FTO genotype.
Abstract: As shown by genome-wide association studies single-nucleotide polymorphisms (SNPs) within intron 1 of the FTO gene are associated with the body mass index and type II diabetes, although the functional significance of these SNPs has remained unclear. Using primer extension assays, we have determined the ratio of allelic FTO transcript levels in unspliced heterogeneous nuclear RNA preparations from blood of individuals heterozygous for SNP rs9939609. Allelic expression ratios of the neighboring RPGRIP1L gene were investigated in individuals who were heterozygous for SNP rs4784319 and heterozygous or homozygous for rs9939609. In each of five individuals, the FTO transcripts containing the A (risk) allele of rs9939609 were more abundant than those with T allele (mean 1.38; 95% confidence interval 1.31-1.44). Similar results were obtained in a fibroblast sample. We also observed skewed allelic expression of the RPGRIP1L gene in blood, but skewing was independent of the FTO genotype. Our data suggest that increased expression of FTO is associated with increased body mass.
Ghent University1, Johns Hopkins University2, Children's Hospital of Wisconsin3, University of Sydney4, University of Gaziantep5, University of Kansas6, University of Erlangen-Nuremberg7, University of Zurich8, Medical College of Wisconsin9, Oregon Health & Science University10, Johns Hopkins University School of Medicine11
TL;DR: Patients with recessive FBLN4 mutations are predominantly characterized by aortic aneurysms, arterial tortuosity and stenosis, which confirms the important role of fibulin-4 in vascular elastic fiber assembly and provides the first evidence for the involvement of altered TGFβ signaling in the pathogenesis of FBLn4 mutations in humans.
Abstract: Fibulin-4 is a member of the fibulin family, a group of extracellular matrix proteins prominently expressed in medial layers of large veins and arteries. Involvement of the FBLN4 gene in cardiovascular pathology was shown in a murine model and in three patients affected with cutis laxa in association with systemic involvement. To elucidate the contribution of FBLN4 in human disease, we investigated two cohorts of patients. Direct sequencing of 17 patients with cutis laxa revealed no FBLN4 mutations. In a second group of 22 patients presenting with arterial tortuosity, stenosis and aneurysms, FBLN4 mutations were identified in three patients, two homozygous missense mutations (p.Glu126Lys and p.Ala397Thr) and compound heterozygosity for missense mutation p.Glu126Val and frameshift mutation c.577delC. Immunoblotting analysis showed a decreased amount of fibulin-4 protein in the fibroblast culture media of two patients, a finding sustained by diminished fibulin-4 in the extracellular matrix of the aortic wall on immunohistochemistry. pSmad2 and CTGF immunostaining of aortic and lung tissue revealed an increase in transforming growth factor (TGF)β signaling. This was confirmed by pSmad2 immunoblotting of fibroblast cultures. In conclusion, patients with recessive FBLN4 mutations are predominantly characterized by aortic aneurysms, arterial tortuosity and stenosis. This confirms the important role of fibulin-4 in vascular elastic fiber assembly. Furthermore, we provide the first evidence for the involvement of altered TGFβ signaling in the pathogenesis of FBLN4 mutations in humans.
TL;DR: In this paper, mutations in the angiopoietin receptor TIE2/TEK have been identified as the cause for autosomal dominantly inherited cutaneomucosal venous malformation (VMCM).
Abstract: Mutations in the angiopoietin receptor TIE2/TEK have been identified as the cause for autosomal dominantly inherited cutaneomucosal venous malformation (VMCM). Thus far, two specific germline substitutions (R849W and Y897S), located in the kinase domain of TIE2, have been reported in five families. The mutations result in a fourfold increase in ligand-independent phosphorylation of the receptor. Here, we report 12 new families with TEK mutations. Although the phenotype is primarily characterized by small multifocal cutaneous vascular malformations, many affected members also have mucosal lesions. In addition, cardiac malformations are observed in some families. Six of the identified mutations are new, with three located in the tyrosine kinase domain, two in the kinase insert domain, and another in the carboxy terminal tail. The remaining six are R849W substitutions. Overexpression of the new mutants resulted in ligand-independent hyperphosphorylation of the receptor, suggesting this is a general feature of VMCM-causative TIE2 mutations. Moreover, variation in the level of activation demonstrates, to the best of our knowledge for the first time, that widely differing levels of chronic TIE2 hyperphosphorylation are tolerated in the heterozygous state, and are compatible with normal endothelial cell function except in the context of highly localized areas of lesion pathogenesis.
TL;DR: Clinical utility of a genetic test shall be an essential criterion for deciding to offer this test to a person or a group of persons and nationally approved guidelines considering all the above-mentioned aspects should be made and followed.
Abstract: Many private companies offer direct-to-consumer (DTC) genetic testing services. Some tests may detect severe and highly penetrant monogenic disorders, while other tests are for genetic variants found associated with increased susceptibility for common and complex diseases in large-scale population studies. Through its Public and Professional Policy committee followed by member and expert consultation, the European Society of Human Genetics has developed the following policy on advertising and provision of predictive genetic tests by such DTC companies: (1) clinical utility of a genetic test shall be an essential criterion for deciding to offer this test to a person or a group of persons; (2) laboratories providing genetic tests should comply with accepted quality standards, including those regarding laboratory personnel qualifications; (3) information about the purpose and appropriateness of testing should be given before the test is done; (4) genetic counselling appropriate to the type of test and disease should be offered; and for some tests psychosocial evaluation and follow-up should be available; (5) privacy and confidentiality of sensitive genetic information should be secured and the data safely guarded; (6) special measures should be taken to avoid inappropriate testing of minors and other legally incapacitated persons; (7) all claims regarding genetic tests should be transparent; advertisement should be unbiased and marketing of genetic tests should be fair; (8) in biomedical research, health care and marketing, respect should be given to relevant ethical principles, as well as international treaties and recommendations regarding genetic testing; and (9) nationally approved guidelines considering all the above-mentioned aspects should be made and followed.
TL;DR: The contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes, as other sequence variants showing a weaker association with asthma compared with that of rs 7216389 were more strongly associated with the expression with both genes.
Abstract: A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N=4917 cases N=34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0–5 years OR=1.51, P=6.89·10−9) and adolescence (age: 14–17 years OR=1.71, P=5.47·10−9). A weaker association was observed for onset between 6 and 13 years of age (OR=1.17, P=0.035), but none for adult-onset asthma (OR=1.07, P=0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P=0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n=743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.
TL;DR: The genetic and clinical data showing the role of CATSPER mutation in human forms of NSMI and SMI are summarized and how the CATSPEER channel could be used as a target for development of a male contraceptive is described.
Abstract: A clinically significant proportion of couples experience difficulty in conceiving a child. In about half of these cases male infertility is the cause and often genetic factors are involved. Despite advances in clinical diagnostics ∼50% of male infertility cases remain idiopathic. Based on this, further analysis of infertile males is required to identify new genetic factors involved in male infertility. This review focuses on cation channel of sperm (CATSPER)-related male infertility. It is based on PubMed literature searches using the keywords 'CATSPER', 'male infertility', 'male contraception', 'immunocontraception' and 'pharmacologic contraception' (publication dates from January 1979 to December 2009). Previously, contiguous gene deletions including the CATSPER2 gene implicated the sperm-specific CATSPER channel in syndromic male infertility (SMI). Recently, we identified insertion mutations of the CATSPER1 gene in families with recessively inherited nonsyndromic male infertility (NSMI). The CATSPER channel therefore represents a novel human male fertility factor. In this review we summarize the genetic and clinical data showing the role of CATSPER mutation in human forms of NSMI and SMI. In addition, we discuss clinical management and therapeutic options for these patients. Finally, we describe how the CATSPER channel could be used as a target for development of a male contraceptive.
TL;DR: It is shown that cognitive impairment is a part of the phenotype of individuals with deletions of 17q12 and that reciprocal duplications manifest with cognitive impairment and behavioral abnormalities, but not with seizures.
Abstract: Deletions in chromosome 17q12 encompassing the HNF1β gene cause cystic renal disease and maturity onset diabetes of the young, and have been recently described as the first recurrent genomic deletion leading to diabetes. Earlier reports of patients with this microdeletion syndrome have suggested an absence of cognitive impairment, differentiating it from most other contiguous gene deletion syndromes. The reciprocal duplication of 17q12 is rare and has been hypothesized to be associated with an increased risk of epilepsy and mental retardation. We conducted a detailed clinical and molecular characterization of four patients with a deletion and five patients with a reciprocal duplication of this region. Our patients with deletion of 17q12 presented with cognitive impairment, cystic renal disease, seizures, and structural abnormalities of the brain. Patients with reciprocal duplications manifest with cognitive impairment and behavioral abnormalities, but not with seizures. Our findings expand the phenotypic spectrum associated with rearrangements of 17q12 and show that cognitive impairment is a part of the phenotype of individuals with deletions of 17q12.
TL;DR: This publication develops three statistics for testing association of genes and pathways with disease: linear combination test, quadratic test and decorrelation test, which take correlations among SNPs within a gene or genes within a pathway into account.
Abstract: Current GWAS have primarily focused on testing association of single SNPs To only test for association of single SNPs has limited utility and is insufficient to dissect the complex genetic structure of many common diseases To meet conceptual and technical challenges raised by GWAS, we suggest gene and pathway-based GWAS as complementary to the current single SNP-based GWAS This publication develops three statistics for testing association of genes and pathways with disease: linear combination test, quadratic test and decorrelation test, which take correlations among SNPs within a gene or genes within a pathway into account The null distribution of the suggested statistics is examined and the statistics are applied to GWAS of rheumatoid arthritis in the Wellcome Trust Case–Control Consortium and the North American Rheumatoid Arthritis Consortium studies The preliminary results show that the suggested gene and pathway-based GWAS offer several remarkable features First, not only can they identify the genes that have large genetic effects, but also they can detect new genes in which each single SNP conferred a small amount of disease risk, and their joint actions can be implicated in the development of diseases Second, gene and pathway-based analysis can allow the formation of the core of pathway definition of complex diseases and unravel the functional bases of an association finding Third, replication of association findings at the gene or pathway level is much easier than replication at the individual SNP level
TL;DR: Overall, few of the numerous genetic associations proposed in the candidate gene era have been replicated in GWASs, but those that have been conclusively replicated have large genetic effects that should not be discarded.
Abstract: Genome-wide association studies (GWASs) have created a paradigm shift in discovering genetic associations for common diseases and phenotypes, but it is unclear whether the thousands of candidate genetic association studies performed in the pre-GWAS era had found any reliable associations for common diseases and phenotypes. We aimed to systematically evaluate whether loci proposed to harbor candidate associations before the advent of GWASs are replicated in GWASs. The GWAS data published through August, 2008 and included in the NHGRI catalog were screened and variants in candidate loci were selected on the basis of statistical significance (P<0.05) to create a list of independent, non-redundant associations. Altogether, 159 articles on GWASs were evaluated, 100 of which addressed past proposed candidate loci. A total of 291 independent, nominally significant (P<0.05) candidate gene associations were assembled after keeping only the SNP with lowest P-value for each locus and each phenotype; 108 of those had P<10−3 for association and 41 had P<10−7. A total of 22 of these 41 candidate gene associations pertained to binary phenotypes with a median odds ratio=2.91 (IQR: 1.82–4.6) and median minor allele frequency=0.17 (IQR: 0.12–0.29) in Caucasians; for comparison, 60 new associations of binary outcomes with P<10−7 discovered in the same GWASs had much smaller effects (median odds ratio 1.30, IQR: 1.18–1.58) and modestly larger minor allele frequencies (median 0.27, IQR: 0.15–0.43). Overall, few of the numerous genetic associations proposed in the candidate gene era have been replicated in GWASs, but those that have been conclusively replicated have large genetic effects that should not be discarded.
Ghent University Hospital1, University of Southern Denmark2, Karolinska University Hospital3, Necker-Enfants Malades Hospital4, VU University Medical Center5, University College Dublin6, University College London7, University of Amsterdam8, Leiden University Medical Center9, Radboud University Nijmegen Medical Centre10, Children's Hospital at Westmead11, University of Sydney12, Guy's Hospital13, Helsinki University Central Hospital14, Radboud University Nijmegen15, Hospital Sant Joan de Déu Barcelona16, St George's, University of London17, St. Michael's GAA, Sligo18, University of Southampton19, Erasmus University Rotterdam20, Casa Sollievo della Sofferenza21, Boston Children's Hospital22
TL;DR: It is confirmed that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsense-mediated decay.
Abstract: Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P 90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome.
TL;DR: An overview of some of the key ethical issues around GWAS: consent, feedback of results, privacy, and the governance of research are provided.
Abstract: The use of genome-wide association studies (GWAS) in medical research and the increased ability to share data give a new twist to some of the perennial ethical issues associated with genomic research. GWAS create particular challenges because they produce fine, detailed, genotype information at high resolution, and the results of more focused studies can potentially be used to determine genetic variation for a wide range of conditions and traits. The information from a GWA scan is derived from DNA that is a powerful personal identifier, and can provide information not just on the individual, but also on the individual's relatives, related groups, and populations. Furthermore, it creates large amounts of individual-specific digital information that is easy to share across international borders. This paper provides an overview of some of the key ethical issues around GWAS: consent, feedback of results, privacy, and the governance of research. Many of the questions that lie ahead of us in terms of the next generation sequencing methods will have been foreshadowed by GWAS and the debates around ethical and policy issues that these have created.
TL;DR: Coffin–Lowry syndrome is a syndromic form of X-linked mental retardation, which is characterized in male patients by psychomotor and growth retardation and various skeletal anomalies.
Abstract: Coffin–Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation, which is characterized in male patients by psychomotor and growth retardation and various skeletal anomalies. Typical facial changes and specific clinical and radiological signs in the hand are useful aids in the diagnosis. CLS is caused by mutations in the RPS6KA3 gene located at Xp22.2, which encodes RSK2, a growth-factor-regulated protein kinase. RPS6KA3 mutations are extremely heterogeneous and lead to loss of phosphotransferase activity in the RSK2 kinase, most often because of premature termination of translation.
TL;DR: The importance of widening the epigenetic investigation to include multiple imprinted loci and highlights potential involvement of the IGF2R locus in patients with growth restriction is highlighted.
Abstract: This study was an investigation of 79 patients referred to the Wessex Regional Genetics Laboratory with suspected Russell–Silver Syndrome or unexplained short stature/intra uterine growth restriction, warranting genetic investigation Methylation status was analysed at target sequences within eleven imprinted loci (PLAGL1, IGF2R, PEG10, MEST1, GRB10, KCNQ1OT1, H19, IGF2P0, DLK1, PEG3, NESPAS) Thirty seven percent (37%) (29 of 79) of samples were shown to have a methylation abnormality The commonest finding was a loss of methylation at H19 (23 of 29), as previously reported in Russell–Silver Syndrome In addition, four of these patients had methylation anomalies at other loci, of whom two showed hypomethylation of multiple imprinted loci, and two showed a complete gain of methylation at IGF2R This latter finding was also present in five other patients who did not have demonstrable changes at H19 In total, 7 of 79 patients showed a gain of methylation at IGF2R and this was significantly different from a normal control population of 267 individuals (P=0002) This study in patients with growth restriction shows the importance of widening the epigenetic investigation to include multiple imprinted loci and highlights potential involvement of the IGF2R locus
TL;DR: It is shown how the proportion of sporadic cases depends on disease prevalence (K) and heritability on the underlying liability scale (hL2) and it is shown that this proportion is typically large.
Abstract: The results of genome-wide association studies have revealed that most human complex diseases (for example, cancer, diabetes and psychiatric disorders) are affected by a large number of variants, each of which explains a small increase in disease risk, suggesting a pattern of polygenic inheritance. At the same time, it has been argued that most complex diseases are genetically heterogeneous because many sporadic cases are observed, as well as cases with a family history. In this study, under the assumption of polygenic inheritance, we derive the expected proportion of sporadic cases using analytical methods and simulation. We show how the proportion of sporadic cases depends on disease prevalence (K) and heritability on the underlying liability scale (hL2). We predict the underlying heritability and the proportion of sporadic cases for a range of human complex diseases, and show that this proportion is typically large. For a disease with hL2=63% and K=0.4%, such as schizophrenia, >83% of proband cases are predicted to be sporadic (no affected first-, second- and third-degree relatives) in typical families (on an average, two children per couple). For the majority of these diseases, a large proportion of sporadic cases is expected under the polygenic model, implying that the observed large proportion of sporadic cases is not informative to the causal mechanism of a complex genetic disease.
TL;DR: The phenotypic spectrum is defined and it is demonstrated that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.
Abstract: Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.
TL;DR: The findings indicate that fathers contribute significantly stronger to the telomere length of the offspring compared with mothers, but the father–child correlations diminished with increasing age, suggesting that nonheritable factors have an impact on telomeres length dynamics during life.
Abstract: Telomere length is documented to have a hereditary component, and both paternal and X-linked inheritance have been proposed. We investigated blood cell telomere length in 962 individuals with an age range between 0 and 102 years. Telomere length correlations were analyzed between parent–child pairs in different age groups and between grandparent–grandchild pairs. A highly significant correlation between the father's and the child's telomere length was observed (r=0.454, P<0.001), independent of the sex of the offspring (father–son: r=0.465, P<0.001; father–daughter: r=0.484, P<0.001). For mothers, the correlations were weaker (mother–child: r=0.148, P=0.098; mother–son: r=0.080, P=0.561; mother–daughter: r=0.297, P=0.013). A positive telomere length correlation was also observed for grandparent–grandchild pairs (r=0.272, P=0.013). Our findings indicate that fathers contribute significantly stronger to the telomere length of the offspring compared with mothers (P=0.012), but we cannot exclude a maternal influence on the daughter's telomeres. Interestingly, the father–child correlations diminished with increasing age (P=0.022), suggesting that nonheritable factors have an impact on telomere length dynamics during life.
TL;DR: Owing to its close association with 25-OHD3, the results lend further support to the role of vitamin D in MS pathology.
Abstract: Multiple sclerosis, MS (OMIM No. 126200), is a complex inflammatory disease that is characterized by lesions in the central nervous system. Both genes and other environmental factors influence disease susceptibility. One of the environmental factors that has been implicated in MS and autoimmune disease, such as type 1 diabetes, is vitamin D deficiency, in which patients have lower levels of 25-hydroxyvitamin D3 (25-OHD3) in blood than do controls. Previtamin D3 is produced in the skin, and turned into 25-OHD3 in the liver. In the kidney, skin and immune cells, 25-OHD3 is turned into bioactive 1,25(OH)2D3 by the enzyme coded by CYP27B1 (cytochrome P450 family 27 subfamily B peptide 1) on chromosome 12q13.1–3. 1,25(OH)2D3 binds to the vitamin D receptor, expressed in T cells and antigen-presenting cells. 1,25(OH)2D3 has a suppressive role in the adaptive immune system, decreasing T-cell and dendritic cell maturation, proliferation and differentiation, shifting the balance between T-helper 1 (Th1) and Th2 cells in favor of Th2 cells and increasing the suppressive function of regulatory T cells. Rs703842 in the 12q13–14 region was associated with MS in a recent study by the Australian and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene). We show associations with three SNPs in this region in our Swedish materials (2158 cases, 1759 controls) rs4646536, rs10877012 and rs10877015 (P=0.01, 0.01 and 3.5 × 10−3, respectively). We imputed rs703842 SNP and performed a joint analysis with the ANZgene results, reaching a significant association for rs703842 (P=5.1 × 10−11; odds ratio 0.83; 95% confidence interval 0.79–0.88). Owing to its close association with 25-OHD3, our results lend further support to the role of vitamin D in MS pathology.