99 research outputs found

    Linkage analysis and exome sequencing identify a novel mutation in KCTD7 in patients with progressive myoclonus epilepsy with ataxia

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    Epilepsy affects approximately 1% of the world\u27s population. Genetic factors and acquired etiologies, as well as a range of environmental triggers, together contribute to epileptogenesis.Wehave identified a family with three daughters affected with progressive myoclonus epilepsy with ataxia. Clinical details of the onset and progression of the neurologic presentation, epileptic seizures, and the natural history of progression over a 10-year period are described. Using autozygosity genetic mapping, we identified a high likelihood homozygous region on chromosome 7p12.1-7q11.22. We subsequently applied whole-exome sequencing and employed a rare variant prioritization analysis within the homozygous region. We identified p.Tyr276Cys in the potassium channel tetramerization domain-containing seven gene, KCTD7, which is expressed predominantly in the brain. Mutations in this gene have been implicated previously in epileptic phenotypes due to disturbances in potassium channel conductance. Pathogenicity of the mutation was supported by bioinformatic predictive analyses and variant cosegregation within the family. Further biologic validation is necessary to fully characterize the pathogenic mechanisms that explain the phenotypic causes of epilepsy with ataxia in these patients

    A molecular genetic study of autism and related phenotypes in extended pedigrees

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    Abstract: Background: Efforts to uncover the risk genotypes associated with the familial nature of autism spectrum disorder (ASD) have had limited success. The study of extended pedigrees, incorporating additional ASD-related phenotypes into linkage analysis, offers an alternative approach to the search for inherited ASD susceptibility variants that complements traditional methods used to study the genetics of ASD. Methods: We examined evidence for linkage in 19 extended pedigrees ascertained through ASD cases spread across at least two (and in most cases three) nuclear families. Both compound phenotypes (i.e., ASD and, in non-ASD individuals, the broad autism phenotype) and more narrowly defined components of these phenotypes, e.g., social and repetitive behavior, pragmatic language, and anxiety, were examined. The overarching goal was to maximize the aggregate information available on the maximum number of individuals and to disaggregate syndromic phenotypes in order to examine the genetic underpinnings of more narrowly defined aspects of ASD behavior. Results: Results reveal substantial between-family locus heterogeneity and support the importance of previously reported ASD loci in inherited, familial, forms of ASD. Additional loci, not seen in the ASD analyses, show evidence for linkage to the broad autism phenotype (BAP). BAP peaks are well supported by multiple subphenotypes (including anxiety, pragmatic language, and social behavior) showing linkage to regions overlapping with the compound BAP phenotype. Whereas ‘repetitive behavior’, showing the strongest evidence for linkage (Posterior Probability of Linkage = 62% at 6p25.2-24.3, and 69% at 19p13.3), appears to be linked to novel regions not detected with other compound or narrow phenotypes examined in this study. Conclusions: These results provide support for the presence of key features underlying the complexity of the genetic architecture of ASD: substantial between-family locus heterogeneity, that the BAP appears to correspond to sets of subclinical features segregating with ASD within pedigrees, and that different features of the ASD phenotype segregate independently of one another. These findings support the additional study of larger, even more individually informative pedigrees, together with measurement of multiple, behavioral- and biomarker-based phenotypes, in both affected and non-affected individuals, to elucidate the complex genetics of familial ASD

    Development and evaluation of a new Plasmodium falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies

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    Background: New anti-malarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating anti-malarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. This study aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated. Methods: The 3D7-V2 MCB was expanded in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated. Results: The in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and < 0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable P. falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 h (PMR48) using non-linear mixed effects modelling was 34.6 (95% CI 18.5–64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 11.5 [95% CI 8.5–15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI 3.61–4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI 4.16–4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study. Conclusion: The safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies. Trial Registration: Australian New Zealand Clinical Trials registry numbers: P3487 (3D7-V1): ACTRN12619001085167. P3491 (3D7-MBE-008): ACTRN1261900107913

    The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position statement of the Canadian College of medical geneticists

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    Purpose and scope: The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. Methods of statement development: Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. Results and conclusions: Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely reevaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally

    16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

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    Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65 046 European population controls (5/393 cases versus 32/65 046 controls; Fisher's exact test P = 2.83 × 10−6, odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10−4). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical R
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