المؤلفون: Kalman, LV, Agundez, JAG, Appell, ML, Black, JL, Bell, GC, Boukouvala, S, Bruckner, C, Bruford, E, Caudle, K, Coulthard, SA, Daly, AK, Del Tredici, AL, den Dunnen, JT, Drozda, K, Everts, RE, Flockhart, D, Freimuth, RR, Gaedigk, A, Hachad, H, Hartshorne, T, Ingelman-Sundberg, M, Klein, TE, Lauschke, VM, Maglott, DR, McLeod, HL, McMillin, GA, Meyer, UA, Muller, DJ, Nickerson, DA, Oetting, WS, Pacanowski, M, Pratt, VM, Relling, MV, Roberts, A, Rubinstein, WS, Sangkuhl, K, Schwab, M, Scott, SA, Sim, SC, Thirumaran, RK, Toji, LH, Tyndale, RF, van Schaik, RHN, Whirl-Carrillo, M, Yeo, KTJ, Zanger, UM

المصدر: Clinical pharmacology and therapeutics. 99(2):172-185

مصطلحات موضوعية: Medicin och hälsovetenskap

الوصول الحر: http://kipublications.ki.se/Default.aspx?queryparsed=id:132892333Test

المؤلفون: Out, AA, Tops, CMJ, Nielsen, M, Weiss, MM, van Minderhout, IJHM, Fokkema, IFAC, Buisine, MP, Claes, K, Colas, C, Fodde, R, Fostira, F, Franken, PF, Gaustadnes, M, Heinimann, K, Hodgson, SV, Hogervorst, FBL, Holinski-Feder, E, Lagerstedt-Robinson, K, Olschwang, S, van den Ouweland, AMW, Redeker, EJW, Scott, RJ, Vankeirsbilck, B, Gronlund, RV, Wijnen, JT, Wikman, FP, Aretz, S, Sampson, JR, Devilee, P, den Dunnen, JT, Hes, FJ

المصدر: Human mutation. 31(11):1205-1215

مصطلحات موضوعية: Medicin och hälsovetenskap

الوصول الحر: http://kipublications.ki.se/Default.aspx?queryparsed=id:121523340Test

المؤلفون: Kohonen-Corish, MRJ, Al-Aama, JY, Auerbach, AD, Axton, M, Barash, CI, Bernstein, I, Beroud, C, Burn, J, Cunningham, F, Cutting, GR, den Dunnen, JT, Greenblatt, MS, Kaput, J, Katz, M, Lindblom, A, Macrae, F, Maglott, D, Moslein, G, Povey, S, Ramesar, R, Richards, S, Seminara, D, Sobrido, MJ, Tavtigian, S, Taylor, G, Vihinen, M, Winship, I, Cotton, RGH

المصدر: Human mutation. 31(12):1374-1381

مصطلحات موضوعية: Medicin och hälsovetenskap

الوصول الحر: http://kipublications.ki.se/Default.aspx?queryparsed=id:121937048Test

المؤلفون: Bruder, CEG, Piotrowski, A, Gijsbers, AACJ, Andersson, R, Erickson, S, de Stahl, TD, Menzel, U, Sandgren, J, von Tell, D, Poplawski, A, Crowley, M, Crasto, C, Partridge, EC, Tiwari, H, Allison, DB, Komorowski, J, van Ommen, GJB, Boomsma, DI, Pedersen, NL, den Dunnen, JT, Wirdefeldt, K, Dumanski, JP

المصدر: American journal of human genetics. 82(3):763-771

مصطلحات موضوعية: Medicin och hälsovetenskap

الوصول الحر: http://kipublications.ki.se/Default.aspx?queryparsed=id:116704812Test

المؤلفون: Boycott, K. M., Rath, A., Chong, J. X., Hartley, T., Alkuraya, F. S., Baynam, G., Brookes, Anthony J., Brudno, M., Carracedo, A., den Dunnen, JT, Dyke, S. O. M., Estivill, X., Goldblatt, J., Gonthier, C., Groft, SC, Gut, I., Hamosh, A., Hieter, P., Höhn, S., Hurles, M. E., Kaufmann, P., Knoppers, B. M., Krischer, J. P., Macek, M., Matthijs, G., Olry, A., Parker, S., Paschall, J., Philippakis, A .A., Rehm, H. L., Robinson, P. N., Sham, P-C., Stefanov, R., Taruscio, D., Unni, D., Vanstone, M. R., Zhang, F., Brunner, H., Bamshad, M. J., Lochmüller, H.

مصطلحات موضوعية: IRDiRC, Matchmaker Exchange, disease modeling, gene discovery, genome sequencing, ontologies, rare diseases, solving the unsolved, transcriptome sequencing, Databases, Factual, Exome, Genome, Human, Humans, International Cooperation

الوصف: Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population. ; Peer-reviewed ; Publisher Version

العلاقة: https://www.ncbi.nlm.nih.gov/pubmed/28475856Test; American Journal of Human Genetics, 2017, 100 (5), pp. 695-705; https://www.sciencedirect.com/science/article/pii/S0002929717301477?via%3DihubTest; http://hdl.handle.net/2381/42090Test; S0002-9297(17)30147-7

الإتاحة: https://doi.org/10.1016/j.ajhg.2017.04.003Test
https://www.sciencedirect.com/science/article/pii/S0002929717301477?via%3DihubTest
http://hdl.handle.net/2381/42090Test

المؤلفون: Shvetsova, E, Sofronova, A, Monajemi, R, Gagalova, K, Draisma, HHM, White, SJ, Santen, GWE, Lopes, SMCDS, Heijmans, BT, Van Meurs, J, Jansen, R, Franke, L, Kielbasa, SM, Den Dunnen, JT, 't Hoen, PAC, Boomsma, DI, Pool, R, Van Dongen, J, Hottenga, JJ, Van Greevenbroek, MMJ, Da Stehouwer, C, Van der Kallen, CJH, Schalkwijk, CG, Wijmenga, C, Zhernakova, S, Tigchelaar, EF, Slagboom, PE, Beekman, M, Deelen, J, Van Heemst, D, Veldink, JH, Van den Berg, LH, Van Duijn, CM, Hofman, BA, Uitterlinden, AG, Jhamai, PM, Verbiest, M, Suchiman, HED, Verkerk, M, Van der Breggen, R, Van Rooij, J, Lakenberg, N, Mei, H, Bot, J, Zhernakova, DV, 't Hof, PV, Deelen, P, Nooren, I, Moed, M, Vermaat, M, Luijk, R, Bonder, MJ, Van Iterson, M, Van Dijk, F, Van Galen, M, Arindrarto, W, Swertz, MA, Van Zwet, EW, Isaacs, A, Francioli, LC, Menelaou, A, Pulit, SL, Palamara, PF, Elbers, CC, Neerincx, PB, Ye, K, Guryev, V, Kloosterman, WP, Abdellaoui, A, Van Leeuwen, EM, Van Oven, M, Li, M, Laros, JF, Karssen, LC, Kanterakis, A, Amin, N, Lameijer, EW, Kattenberg, M, Dijkstra, M, Byelas, H, Van Setten, J, Van Schaik, BD, Nijman, IJ, Renkens, I, Marschall, T, Schonhuth, A, Hehir-Kwa, JY, Handsaker, RE, Polak, P, Sohail, M, Vuzman, D, Hormozdiari, F, Van Enckevort, D, Koval, V, Moed, MH, Van der Velde, KJ, Rivadeneira, F, Estrada, K, Medina-Gomez, C, McCarroll, SA, De Craen, AJ, Suchiman, HE, Oostra, B, Willemsen, G, Platteel, M, Pitts, SJ, Potluri, S, Sundar, P, Cox, DR, Sunyaev, SR, Stoneking, M, De Knijff, P, Kayser, M, Li, Q, Li, Y, Du, Y, Chen, R, Cao, H, Li, N, Cao, S, Wang, J, Bovenberg, JA, Pe'er, I, Van Ommen, GJ, De Bakker, PI

المصدر: 465 ; 455

مصطلحات موضوعية: Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Genetics & Heredity, DUCHENNE MUSCULAR-DYSTROPHY, CHROMOSOME-INACTIVATION, DMD LOCUS, EXPRESSION, PATTERNS, TRANSLOCATION, ADRENOLEUKODYSTROPHY, CARRIERS, CONSEQUENCES, VARIABILITY, Calcium-Binding Proteins, Female, Humans, Intracellular Signaling Peptides and Proteins, Male, Membrane Glycoproteins, Netherlands, Polymorphism, Single Nucleotide, Population, Receptors, Cytoplasmic and Nuclear, Peptide, Septins, X Chromosome Inactivation, BIOS consortium

الوصف: X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.

العلاقة: European Journal of Human Genetics; http://hdl.handle.net/10044/1/75694Test

الإتاحة: https://doi.org/10.1038/s41431-018-0291-3Test
http://hdl.handle.net/10044/1/75694Test

المؤلفون: Oliveira, J, Gruber, A, Cardoso, M, Taipa, R, Fineza, I, Gonçalves, A, Laner, A, Winder, TL, Schroeder, J, Rath, J, Oliveira, ME, Vieira, E, Sousa, AP, Vieira, JP, Lourenço, T, Almendra, L, Negrão, L, Santos, M, Melo-Pires, M, Coelho, T, den Dunnen, JT, Santos, R, Sousa, M

مصطلحات موضوعية: Alleles, Biomarkers, Brain, Computational Biology, Databases, Nucleic Acid, Gene Frequency, Genetic Variation, Genotype, Humans, Immunohistochemistry, Laminin, Magnetic Resonance Imaging, Muscular Dystrophies, Genetic Association Studies, Mutation, Phenotype, HDE GEN, HDE NEU PED

الوصف: Congenital muscular dystrophy type 1A (MDC1A) is one of the main subtypes of early-onset muscle disease, caused by disease-associated variants in the laminin-α2 (LAMA2) gene. MDC1A usually presents as a severe neonatal hypotonia and failure to thrive. Muscle weakness compromises normal motor development, leading to the inability to sit unsupported or to walk independently. The phenotype associated with LAMA2 defects has been expanded to include milder and atypical cases, being now collectively known as LAMA2-related muscular dystrophies (LAMA2-MD). Through an international multicenter collaborative effort, 61 new LAMA2 disease-associated variants were identified in 86 patients, representing the largest number of patients and new disease-causing variants in a single report. The collaborative variant collection was supported by the LOVD-powered LAMA2 gene variant database (https://www.LOVD.nl/LAMA2Test), updated as part of this work. As of December 2017, the database contains 486 unique LAMA2 variants (309 disease-associated), obtained from direct submissions and literature reports. Database content was systematically reviewed and further insights concerning LAMA2-MD are presented. We focus on the impact of missense changes, especially the c.2461A > C (p.Thr821Pro) variant and its association with late-onset LAMA2-MD. Finally, we report diagnostically challenging cases, highlighting the relevance of modern genetic analysis in the characterization of clinically heterogeneous muscle diseases. ; info:eu-repo/semantics/publishedVersion

العلاقة: Hum Mutat . 2018 Oct;39(10):1314-1337; http://hdl.handle.net/10400.17/3495Test

الإتاحة: https://doi.org/10.1002/humu.23599Test
http://hdl.handle.net/10400.17/3495Test

المؤلفون: Thompson, BA, Spurdle, AB, Plazzer, JP, Greenblatt, MS, Akagi, K, Al-Mulla, F, Bapat, B, Bernstein, I, Capella, G, den Dunnen, JT, du Sart, D, Fabre, A, Farrell, MP, Farrington, SM, Frayling, IM, Frebourg, T, Goldgar, DE, Heinen, CD, Holinski-Feder, E, Kohonen-Corish, M, Robinson, KL, Leung, SY, Martins, A, Moller, P, Morak, M, Nystrom, M, Peltomaki, P, Pineda, M, Qi, M, Ramesar, R, Rasmussen, LJ, Royer-Pokora, B, Scott, RJ, Sijmons, R, Tavtigian, SV, Tops, CM, Weber, T, Wijnen, J, Woods, MO, Macrae, F, Genuardi, M

المصدر: Nature genetics. 46(2):107

مصطلحات موضوعية: Medicin och hälsovetenskap

الوصول الحر: http://kipublications.ki.se/Default.aspx?queryparsed=id:128358261Test

المؤلفون: Leigh, S, Futema, M, Whittall, R, Taylor-Beadling, A, Williams, M, den Dunnen, JT, Humphries, SE

المصدر: Journal of Medical Genetics , 54 (4) pp. 217-223. (2017)

الوصف: BACKGROUND: Familial hypercholesterolaemia (OMIM 143890) is most frequently caused by variations in the low-density lipoprotein receptor (LDLR) gene. Predicting whether novel variants are pathogenic may not be straightforward, especially for missense and synonymous variants. In 2013, the Association of Clinical Genetic Scientists published guidelines for the classification of variants, with categories 1 and 2 representing clearly not or unlikely pathogenic, respectively, 3 representing variants of unknown significance (VUS), and 4 and 5 representing likely to be or clearly pathogenic, respectively. Here, we update the University College London (UCL) LDLR variant database according to these guidelines. METHODS: PubMed searches and alerts were used to identify novel LDLR variants for inclusion in the database. Standard in silico tools were used to predict potential pathogenicity. Variants were designated as class 4/5 only when the predictions from the different programs were concordant and as class 3 when predictions were discordant. RESULTS: The updated database (http://www.lovd.nl/LDLRTest) now includes 2925 curated variants, representing 1707 independent events. All 129 nonsense variants, 337 small frame-shifting and 117/118 large rearrangements were classified as 4 or 5. Of the 795 missense variants, 115 were in classes 1 and 2, 605 in class 4 and 75 in class 3. 111/181 intronic variants, 4/34 synonymous variants and 14/37 promoter variants were assigned to classes 4 or 5. Overall, 112 (7%) of reported variants were class 3. CONCLUSIONS: This study updates the LDLR variant database and identifies a number of reported VUS where additional family and in vitro studies will be required to confirm or refute their pathogenicity.

وصف الملف: text

العلاقة: https://discovery.ucl.ac.uk/id/eprint/1529012/1/Leigh_UCL_low-density_lipoprotein.pdfTest; https://discovery.ucl.ac.uk/id/eprint/1529012/7/Leigh_UCL_low-density_lipoprotein_S1.pdfTest; https://discovery.ucl.ac.uk/id/eprint/1529012/8/Leigh_UCL_low-density_lipoprotein_S2.pdfTest; https://discovery.ucl.ac.uk/id/eprint/1529012/9/Leigh_UCL_low-density_lipoprotein_S3.pdfTest; https://discovery.ucl.ac.uk/id/eprint/1529012Test/

الإتاحة: https://discovery.ucl.ac.uk/id/eprint/1529012/1/Leigh_UCL_low-density_lipoprotein.pdfTest
https://discovery.ucl.ac.uk/id/eprint/1529012/7/Leigh_UCL_low-density_lipoprotein_S1.pdfTest
https://discovery.ucl.ac.uk/id/eprint/1529012/8/Leigh_UCL_low-density_lipoprotein_S2.pdfTest
https://discovery.ucl.ac.uk/id/eprint/1529012/9/Leigh_UCL_low-density_lipoprotein_S3.pdfTest
https://discovery.ucl.ac.uk/id/eprint/1529012Test/

المؤلفون: Kohonen-Corish, MRJ, Macrae, F, Genuardi, M, Aretz, S, Bapat, B, Bernstein, IT, Burn, J, Cotton, RGH, den Dunnen, JT, Frebourg, T, Greenblatt, MS, Hofstra, R, Holinski-Feder, E, Lappalainen, I, Lindblom, A, Maglott, D, Moller, P, Morreau, H, Moslein, G, Sijmons, R, Spurdle, AB, Tavtigian, S, Tops, CMJ, Weber, TK, de Wind, N, Woods, MO

المصدر: Human mutation. 32(4):491-494

مصطلحات موضوعية: Medicin och hälsovetenskap

الوصول الحر: http://kipublications.ki.se/Default.aspx?queryparsed=id:122228159Test