Browsing by Subject "MOLECULAR-GENETICS"

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  • Ahonen, Saija J.; Kaukonen, Maria; Nussdorfer, Forrest D.; Harman, Christine D.; Komaromy, Andras M.; Lohi, Hannes (2014)
  • Pussila, Marjaana; Sarantaus, Laura; Dermadi Bebek, Denis; Valo, Satu; Reyhani, Nima; Ollila, Saara; Päivärinta, Essi Mari-Anna; Peltomäki, Päivi T; Mutanen, Marja; Nyström, Minna (2013)
  • Trotta, Luca; Norberg, Anna; Taskinen, Mervi; Beziat, Vivien; Degerman, Sofie; Wartiovaara-Kautto, Ulla; Välimaa, Hannamari; Jahnukainen, Kirsi; Casanova, Jean-Laurent; Seppänen, Mikko; Saarela, Janna; Koskenvuo, Minna; Martelius, Timi (2018)
    Background: The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKQ, the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs. Methods: Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions. Results: In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients. Conclusions: Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.
  • Wendt, Frank R.; Sajantila, Antti; Moura-Neto, Rodrigo S.; Woerner, August E.; Budowle, Bruce (2018)
    CYP2D6 is a critical pharmacogenetic target, and polymorphisms in the gene region are commonly used to infer enzyme activity score and predict resulting metabolizer phenotype: poor, intermediate, extensive/normal, or ultrarapid which can be useful in determining cause and/or manner of death in some autopsies. Current genotyping approaches are incapable of identifying novel and/or rare variants, so CYP2D6 star allele definitions are limited to polymorphisms known a priori. While useful for most predictions, recent studies using massively parallel sequencing data have identified additional polymorphisms in CYP2D6 that are predicted to alter enzyme function but are not considered in current star allele nomenclature. The 1000 Genomes Project data were used to produce full-gene haplotypes, describe their distribution in super-populations, and predict enzyme activity scores. Full-gene haplotypes generated lower activity scores than current approaches due to inclusion of additional damaging polymorphisms in the star allele. These findings are critical for clinical implementation of metabolizer phenotype prediction because a fraction of the population may be incorrectly considered normal metabolizers but actually may be poor or intermediate metabolizers.
  • Gialluisi, Alessandro; Andlauer, Till F. M.; Mirza-Schreiber, Nazanin; Moll, Kristina; Becker, Jessica; Hoffmann, Per; Ludwig, Kerstin U.; Czamara, Darina; St Pourcain, Beate; Brandler, William; Honbolygo, Ferenc; Toth, Denes; Csepe, Valeria; Huguet, Guillaume; Morris, Andrew P.; Hulslander, Jacqueline; Willcutt, Erik G.; DeFries, John C.; Olson, Richard K.; Smith, Shelley D.; Pennington, Bruce F.; Vaessen, Anniek; Maurer, Urs; Lyytinen, Heikki; Peyrard-Janvid, Myriam; Leppanen, Paavo H. T.; Brandeis, Daniel; Bonte, Milene; Stein, John F.; Talcott, Joel B.; Fauchereau, Fabien; Wilcke, Arndt; Francks, Clyde; Bourgeron, Thomas; Monaco, Anthony P.; Ramus, Franck; Landerl, Karin; Kere, Juha; Scerri, Thomas S.; Paracchini, Silvia; Fisher, Simon E.; Schumacher, Johannes; Noethen, Markus M.; Mueller-Myhsok, Bertram; Schulte-Koerne, Gerd (2019)
    Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p <1 x 10(-8)) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 x 10(-9)), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 x 10(-8)). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 x 10(-8)) and with all the cognitive traits tested (p = 3.07 x 10(-8)), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p similar to [10(-5)-10(-7)]) and negatively associated with ADHD PRS (p similar to [10(-8)-10(-17)]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
  • Ahonen, Saija J.; Pietilä (ent.Rusanen), Elina Maria; Mellersh, Cathryn S.; Tiira, Katriina; Hansen, Liz; Johnson, Gary S.; Lohi, Hannes (2013)
  • EAS Familial Hypercholestero; EAS Familial Hypercholesterolaemia (2018)
    Background and aims: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. Methods: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. Results: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in similar to 2/3 countries. Lipoprotein-apheresis is offered in similar to 60% countries, although access is limited. Conclusions: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed.
  • Pelttari, Liisa M.; Nurminen, Riikka; Gylfe, Alexandra; Aaltonen, Lauri A.; Schleutker, Johanna; Nevanlinna, Heli (2012)
  • de Vries, Boukje; Anttila, Verneri; Freilinger, Tobias; Wessman, Maija; Kaunisto, Mari A.; Kallela, Kaarlo Mikko; Artto, Ville; Vijfhuizen, Lisanne S.; Goebel, Hartmut; Dichgans, Martin; Kubisch, Christian; Ferrari, Michel D.; Palotie, Aarno; Terwindt, Gisela M.; van den Maagdenberg, Arn M. J. M.; Int Headache Genetics Consortium (2016)
    BackgroundBefore the genome-wide association (GWA) era, many hypothesis-driven candidate gene association studies were performed that tested whether DNA variants in genes that had been selected based on prior knowledge about migraine pathophysiology were associated with migraine. Most studies involved small sample sets without robust replication, thereby making the risk of false-positive findings high. Genome-wide marker data of thousands of migraine patients and controls from the International Headache Genetics Consortium provide a unique opportunity to re-evaluate key findings from candidate gene association studies (and other non-GWA genetic studies) in a much larger data set. MethodsWe selected 21 genes from published candidate gene association studies and six additional genes from other non-GWA genetic studies in migraine. Single nucleotide polymorphisms (SNPs) in these genes, as well as in the regions 500kb up- and downstream, were inspected in IHGC GWAS data from 5175 clinic-based migraine patients with and without aura and 13,972 controls. ResultsNone of the SNPs in or near the 27 genes, including the SNPs that were previously found to be associated with migraine, reached the Bonferroni-corrected significance threshold; neither when analyzing all migraine patients together, nor when analyzing the migraine with and without aura patients or males and females separately. ConclusionThe available migraine GWAS data provide no clear evidence for involvement of the previously reported most promising candidate genes in migraine.