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Norberg, Anna
Publications (10 of 11) Show all publications
Hirvonen, E. A. M., Peuhkuri, S., Norberg, A., Degerman, S., Hannula-Jouppi, K., Välimaa, H., . . . Wartiovaara-Kautto, U. (2019). Characterization of an X-chromosome-linked telomere biology disorder in females with DKC1 mutation. Leukemia, 33(1), 275-278
Open this publication in new window or tab >>Characterization of an X-chromosome-linked telomere biology disorder in females with DKC1 mutation
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2019 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, no 1, p. 275-278Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-155772 (URN)10.1038/s41375-018-0243-5 (DOI)000455200900028 ()30185935 (PubMedID)
Available from: 2019-01-28 Created: 2019-01-28 Last updated: 2019-01-28Bibliographically approved
Trotta, L., Norberg, A., Taskinen, M., Beziat, V., Degerman, S., Wartiovaara-Kautto, U., . . . Martelius, T. (2018). Diagnostics of rare disorders: whole-exome sequencing deciphering locus heterogeneity in telomere biology disorders. Orphanet Journal of Rare Diseases, 13, Article ID 139.
Open this publication in new window or tab >>Diagnostics of rare disorders: whole-exome sequencing deciphering locus heterogeneity in telomere biology disorders
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2018 (English)In: Orphanet Journal of Rare Diseases, ISSN 1750-1172, E-ISSN 1750-1172, Vol. 13, article id 139Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
telomere biology disorders, telomeropathies, next-generation sequencing, whole-exome quencing, dyskeratosis congenita, DKC1, TERT, RTEL1
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-151557 (URN)10.1186/s13023-018-0864-9 (DOI)000442134700001 ()30115091 (PubMedID)
Available from: 2018-09-10 Created: 2018-09-10 Last updated: 2018-09-10Bibliographically approved
Norberg, A., Rosén, A., Raaschou-Jensen, K., Kjeldsen, L., Moilanen, J. S., Paulsson-Karisson, Y., . . . Hultdin, M. (2018). Novel variants in Nordic patients referred for genetic testing of telomere-related disorders. European Journal of Human Genetics, 26(6), 858-867
Open this publication in new window or tab >>Novel variants in Nordic patients referred for genetic testing of telomere-related disorders
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2018 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 6, p. 858-867Article in journal (Refereed) Published
Abstract [en]

Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes. We identified pathogenic or likely pathogenic variants in 10 index patients, all of which had short telomeres compared to age-matched healthy controls. Six of the 10 variants were novel; three in TERC (n.69_74dupAGGCGC, n.122_125delGCGG, and n.407_408delinsAA) and three in TERT (p.(D684G), p.(R774*), and p.(*1133Wext*39)). The high proportion of novel variants identified in our study highlights the need for solid interpretation of new variants that may be detected. Measurement of telomere length is a useful approach for evaluating pathogenicity of genetic variants associated with telomere-related disorders.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-149013 (URN)10.1038/s41431-018-0112-8 (DOI)000433424200010 ()29483670 (PubMedID)2-s2.0-85042538231 (Scopus ID)
Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2018-06-15Bibliographically approved
Winbo, A., Stattin, E.-L., Westin, I. M., Norberg, A., Persson, J., Jensen, S. M. & Rydberg, A. (2017). Sex is a moderator of the association between NOS1AP sequence variants and QTc in two long QT syndrome founder populations: a pedigree-based measured genotype association analysis. BMC Medical Genetics, 18, Article ID 74.
Open this publication in new window or tab >>Sex is a moderator of the association between NOS1AP sequence variants and QTc in two long QT syndrome founder populations: a pedigree-based measured genotype association analysis
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2017 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 18, article id 74Article in journal (Refereed) Published
Abstract [en]

Background: Sequence variants in the NOS1AP gene have repeatedly been reported to influence QTc, albeit with moderate effect sizes. In the long QT syndrome (LQTS), this may contribute to the substantial QTc variance seen among carriers of identical pathogenic sequence variants. Here we assess three non-coding NOS1APsequence variants, chosen for their previously reported strong association with QTc in normal and LQTS populations, for association with QTc in two Swedish LQT1 founder populations.

Methods: This study included 312 individuals (58% females) from two LQT1 founder populations, whereof 227 genotype positive segregating either Y111C (n = 148) or R518* (n = 79) pathogenic sequence variants in the KCNQ1 gene, and 85 genotype negatives. All were genotyped for NOS1AP sequence variants rs12143842, rs16847548 and rs4657139, and tested for association with QTc length (effect size presented as mean difference between derived and wildtype, in ms), using a pedigree-based measured genotype association analysis. Mean QTc was obtained by repeated manual measurement (preferably in lead II) by one observer using coded 50 mm/s standard 12-lead ECGs.

Results: A substantial variance in mean QTc was seen in genotype positives 476 ± 36 ms (Y111C 483 ± 34 ms; R518* 462 ± 34 ms) and genotype negatives 433 ± 24 ms. Female sex was significantly associated with QTc prolongation in all genotype groups (p < 0.001). In a multivariable analysis including the entire study population and adjusted for KCNQ1 genotype, sex and age, NOS1AP sequence variants rs12143842 and rs16847548 (but not rs4657139) were significantly associated with QT prolongation, +18 ms (p = 0.0007) and +17 ms (p = 0.006), respectively. Significant sex-interactions were detected for both sequent variants (interaction term r = 0.892, p < 0.001 and r = 0.944, p < 0.001, respectively). Notably, across the genotype groups, when stratified by sex neither rs12143842 nor rs16847548 were significantly associated with QTc in females (both p = 0.16) while in males, a prolongation of +19 ms and +8 ms (p = 0.002 and p = 0.02) was seen in multivariable analysis, explaining up to 23% of QTc variance in all males.

Conclusions: Sex was identified as a moderator of the association between NOS1AP sequence variants and QTc in two LQT1 founder populations. This finding may contribute to QTc sex differences and affect the usefulness of NOS1AP as a marker for clinical risk stratification in LQTS.

Keywords
Long QT syndrome, Sequence variants, Sex, Risk stratification, Modifier genes, QT prolongation, xsequence-variant interaction, Genotype-phenotype interactions, Founder populations
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-138033 (URN)10.1186/s12881-017-0435-2 (DOI)000405695100001 ()
Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2019-05-20Bibliographically approved
Stattin, E.-L., Westin, I. M., Cederquist, K., Jonasson, J., Jonsson, B.-A., Mörner, S., . . . Wisten, A. (2016). Genetic screening in sudden cardiac death in the young can save future lives. International journal of legal medicine (Print), 130(1), 59-66
Open this publication in new window or tab >>Genetic screening in sudden cardiac death in the young can save future lives
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2016 (English)In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 130, no 1, p. 59-66Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Autopsy of sudden cardiac death (SCD) in the young shows a structurally and histologically normal heart in about one third of cases. Sudden death in these cases is believed to be attributed in a high percentage to inherited arrhythmogenic diseases. The purpose of this study was to investigate the value of performing post-mortem genetic analysis for autopsy-negative sudden unexplained death (SUD) in 1 to 35 year olds.

METHODS AND RESULTS: From January 2009 to December 2011, samples from 15 cases suffering SUD were referred to the Department of Clinical Genetics, Umeå University Hospital, Sweden, for molecular genetic evaluation. PCR and bidirectional Sanger sequencing of genes important for long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome type 1 (BrS1), and catecholaminergic polymorphic ventricular tachycardia (CPVT) (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RYR2) was performed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large deletions or duplications in the LQTS genes. Six pathogenic sequence variants (four LQTS and two CPVT) were discovered in 15 SUD cases (40%). Ten first-degree family members were found to be mutation carriers (seven LQTS and three CPVT).

CONCLUSION: Cardiac ion channel genetic testing in autopsy-negative sudden death victims has a high diagnostic yield, with identification of the disease in 40 of families. First-degree family members should be offered predictive testing, clinical evaluation, and treatment with the ultimate goal to prevent sudden death.

Keywords
Sudden unexplained death, Sudden cardiac death, Molecular autopsy, Long QT syndrome, Catecholaminergic polymorphic ventricular tachycardia
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-128555 (URN)10.1007/s00414-015-1237-8 (DOI)000368685400006 ()26228265 (PubMedID)
Available from: 2016-12-07 Created: 2016-12-07 Last updated: 2019-05-10Bibliographically approved
Ueda, Y., Calado, R. T., Norberg, A., Kajigaya, S., Roos, G., Hellstrom-Lindberg, E. & Young, N. S. (2014). A mutation in the H/ACA box of telomerase RNA component gene (TERC) in a young patient with myelodysplastic syndrome. BMC Medical Genetics, 15, 68
Open this publication in new window or tab >>A mutation in the H/ACA box of telomerase RNA component gene (TERC) in a young patient with myelodysplastic syndrome
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2014 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 15, p. 68-Article in journal (Refereed) Published
Abstract [en]

Background: Telomeres are repeated sequences (the hexanucleotide TTAGGG in vertebrates) located at chromosome ends of eukaryotes, protecting DNA from end joining or degradation. Telomeres become shorter with each cell cycle, but telomerase, a ribonucleoprotein complex, alleviates this attrition. The telomerase RNA component (TERC) is an essential element of telomerase, serving as a template for telomere elongation. The H/ACA domain of TERC is indispensable for telomere biogenesis. Mutations in the telomerase components allow accelerated telomere loss, resulting in various disease manifestations, including bone marrow failure. To date, this is the first detailed report of an H-box mutation in TERC that is related to human disease. Case presentation: A 26-year-old man with myelodysplastic syndrome (MDS) had very short telomeres. Sequencing identified a single heterozygous mutation in the H box of the patient's TERC gene. The same mutation was also present in his father and his son, demonstrating that it was germline in origin. The telomere length in the father's blood was shorter compared to age-matched healthy controls, while it was normal in the son and also in the sperm cells of the patient. In vitro experiments suggested that the mutation was responsible for the telomere shortening in the patient's leukocytes and contributed to the pathogenesis of bone marrow failure in our patient. Conclusion: We analyzed a mutation (A377G) in the H box of TERC in a young MDS patient who had significantly short-for-age telomeres. As telomeres protect chromosomes from instability, it is highly plausible that this genetic lesion was responsible for the patient's hematological manifestations, including marrow failure and aneuploidy in the hematopoietic stem cell compartment.

Keywords
Myelodysplastic syndrome (MDS), Telomerase RNA component (TERC), H/ACA box, Southern blotting, Single Telomere Elongation Length Analysis (STELA), RNA fluorescence in situ hybridization (RNA FISH)
National Category
Hematology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-91275 (URN)10.1186/1471-2350-15-68 (DOI)000338265000001 ()
Available from: 2014-07-28 Created: 2014-07-28 Last updated: 2018-06-07Bibliographically approved
Jonsson, F., Burstedt, M. S., Sandgren, O., Norberg, A. & Golovleva, I. (2014). Genetic heterogeneity and clinical outcome in a Swedish family with retinal degeneration caused by mutations in CRB1 and ABCA4 genes. In: Retinal Degenerative Diseases: Mechanisms and Experimental Therapy. Paper presented at 15th International Symposium on Retinal Degeneration (RD) Location: GERMANY Date: JUL 16-21, 2012 (pp. 177-183). Springer Berlin/Heidelberg, 801
Open this publication in new window or tab >>Genetic heterogeneity and clinical outcome in a Swedish family with retinal degeneration caused by mutations in CRB1 and ABCA4 genes
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2014 (English)In: Retinal Degenerative Diseases: Mechanisms and Experimental Therapy, Springer Berlin/Heidelberg, 2014, Vol. 801, p. 177-183Conference paper, Published paper (Refereed)
Abstract [en]

Genetic mechanisms underlying severe retinal dystrophy in a large Swedish family presenting two distinct phenotypes, Leber congenital amaurosis and Stargardt disease were investigated. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was a compound heterozygous for c.5461-10T>C and a novel ABCA4 mutation c.4773+3 A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants.Our results provide evidence of genetic complexity causative of different clinical features present in the same family, which is an obvious challenge for ophthalmologists, molecular geneticists and genetic counsellors.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2014
Series
Advances in Experimental Medicine and Biology, ISSN 0065-2598 ; 801
Keywords
applanation resonance tonometry, ART, glaucoma, intraocular pressure, ISO standard, tonometry
National Category
Ophthalmology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-101488 (URN)10.1007/978-1-4614-3209-8_23 (DOI)000350418200024 ()24664696 (PubMedID)978-1-4614-3209-8 (ISBN)978-1-4614-3208-1 (ISBN)
Conference
15th International Symposium on Retinal Degeneration (RD) Location: GERMANY Date: JUL 16-21, 2012
Available from: 2015-03-31 Created: 2015-03-31 Last updated: 2018-06-07Bibliographically approved
Liljeholm, M., Irvine, A. F., Vikberg, A.-L., Norberg, A., Month, S., Sandström, H., . . . Golovleva, I. (2013). Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23.. Blood
Open this publication in new window or tab >>Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23.
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2013 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020Article in journal (Refereed) Published
Abstract [en]

Haplotype analysis and targeted next-generation resequencing allowed us to identify a mutation in the KIF23 gene and to show its association with an autosomal dominant form of congenital dyserythropoietic anemia type III (CDA III). The region at 15q23 where CDA III was mapped in a large Swedish family was targeted by array-based sequence capture in a female diagnosed with CDA III and her healthy sister. Prioritization of all detected sequence changes revealed 10 variants unique for the CDA III patient. Among those variants, a novel mutation c.2747C>G (p.P916R) was found in KIF23, which encodes mitotic kinesin-like protein 1 (MKLP1). This variant segregates with CDA III in the Swedish and American families but was not found in 356 control individuals. RNA expression of the 2 known splice isoforms of KIF23 as well as a novel one lacking the exons 17 and 18 was detected in a broad range of human tissues. RNA interference-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23/MKLP1, a conserved mitotic kinesin crucial for cytokinesis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-70201 (URN)10.1182/blood-2012-10-461392 (DOI)000321895700025 ()23570799 (PubMedID)
Available from: 2013-05-07 Created: 2013-05-07 Last updated: 2018-06-08Bibliographically approved
Jonsson, F., Burstedt, M. S., Sandgren, O., Norberg, A. & Golovleva, I. (2013). Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family. European Journal of Human Genetics, 21(11), 1266-1271
Open this publication in new window or tab >>Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family
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2013 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 11, p. 1266-1271Article in journal (Refereed) Published
Abstract [en]

This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.

Place, publisher, year, edition, pages
Nature Publishing Group, 2013
Keywords
CRB1, ABCA4, SNP-array, Stargardt disease, Leber congenital amaurosis
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-82275 (URN)10.1038/ejhg.2013.23 (DOI)000325861500015 ()23443024 (PubMedID)
Available from: 2013-10-29 Created: 2013-10-29 Last updated: 2018-06-08Bibliographically approved
Stattin, E.-L., Boström, I. M., Winbo, A., Cederquist, K., Jonasson, J., Jonsson, B.-A., . . . Norberg, A. (2012). Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing. BMC Cardiovascular Disorders, 12, 95
Open this publication in new window or tab >>Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing
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2012 (English)In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 12, p. 95-Article in journal (Refereed) Published
Abstract [en]

Background: Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterised by prolongation of the QT interval on ECG, presence of syncope and sudden death. The symptoms in LQTS patients are highly variable, and genotype influences the clinical course. This study aims to report the spectrum of LQTS mutations in a Swedish cohort.

Methods: Between March 2006 and October 2009, two hundred, unrelated index cases were referred to the Department of Clinical Genetics, Umea University Hospital, Sweden, for LQTS genetic testing. We scanned five of the LQTS-susceptibility genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) for mutations by DHPLC and/or sequencing. We applied MLPA to detect large deletions or duplications in the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes. Furthermore, the gene RYR2 was screened in 36 selected LQTS genotype-negative patients to detect cases with the clinically overlapping disease catecholaminergic polymorphic ventricular tachycardia (CPVT).

Results: In total, a disease-causing mutation was identified in 103 of the 200 (52%) index cases. Of these, altered exon copy numbers in the KCNH2 gene accounted for 2% of the mutations, whereas a RYR2 mutation accounted for 3% of the mutations. The genotype-positive cases stemmed from 64 distinct mutations, of which 28% were novel to this cohort. The majority of the distinct mutations were found in a single case (80%), whereas 20% of the mutations were observed more than once. Two founder mutations, KCNQ1 p.Y111C and KCNQ1 p.R518*, accounted for 25% of the genotype-positive index cases. Genetic cascade screening of 481 relatives to the 103 index cases with an identified mutation revealed 41% mutation carriers who were at risk of cardiac events such as syncope or sudden unexpected death.

Conclusion: In this cohort of Swedish index cases with suspected LQTS, a disease-causing mutation was identified in 52% of the referred patients. Copy number variations explained 2% of the mutations and 3 of 36 selected cases (8%) harboured a mutation in the RYR2 gene. The mutation panorama is characterised by founder mutations (25%), even so, this cohort increases the amount of known LQTS-associated mutations, as approximately one-third (28%) of the detected mutations were unique.

Place, publisher, year, edition, pages
BioMed Central, 2012
Keywords
Arrhythmia, Long QT syndrome, Ion-channel, Founder mutation, Variant of unknown significance
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-64060 (URN)10.1186/1471-2261-12-95 (DOI)000312312500001 ()
Available from: 2013-01-15 Created: 2013-01-14 Last updated: 2018-06-08Bibliographically approved
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