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Cederquist, Kristina
Publications (7 of 7) Show all publications
Rentoft, M., Svensson, D., Sjödin, A., Olason, P. I., Sjöström, O., Nylander, C., . . . Johansson, E. (2019). A geographically matched control population efficiently limits the number of candidate disease-causing variants in an unbiased whole-genome analysis. PLOS ONE, 14(3), Article ID e0213350.
Open this publication in new window or tab >>A geographically matched control population efficiently limits the number of candidate disease-causing variants in an unbiased whole-genome analysis
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2019 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 3, article id e0213350Article in journal (Refereed) Published
Abstract [en]

Whole-genome sequencing is a promising approach for human autosomal dominant disease studies. However, the vast number of genetic variants observed by this method constitutes a challenge when trying to identify the causal variants. This is often handled by restricting disease studies to the most damaging variants, e.g. those found in coding regions, and overlooking the remaining genetic variation. Such a biased approach explains in part why the genetic causes of many families with dominantly inherited diseases, in spite of being included in whole-genome sequencing studies, are left unsolved today. Here we explore the use of a geographically matched control population to minimize the number of candidate disease-causing variants without excluding variants based on assumptions on genomic position or functional predictions. To exemplify the benefit of the geographically matched control population we apply a typical disease variant filtering strategy in a family with an autosomal dominant form of colorectal cancer. With the use of the geographically matched control population we end up with 26 candidate variants genome wide. This is in contrast to the tens of thousands of candidates left when only making use of available public variant datasets. The effect of the local control population is dual, it (1) reduces the total number of candidate variants shared between affected individuals, and more importantly (2) increases the rate by which the number of candidate variants are reduced as additional affected family members are included in the filtering strategy. We demonstrate that the application of a geographically matched control population effectively limits the number of candidate disease-causing variants and may provide the means by which variants suitable for functional studies are identified genome wide.

Place, publisher, year, edition, pages
Public Library of Science, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-158021 (URN)10.1371/journal.pone.0213350 (DOI)000462465800028 ()30917156 (PubMedID)2-s2.0-85063572524 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2011.0042
Available from: 2019-04-10 Created: 2019-04-10 Last updated: 2023-03-23Bibliographically 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, 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, 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)2-s2.0-84954360690 (Scopus ID)
Available from: 2016-12-07 Created: 2016-12-07 Last updated: 2024-01-17Bibliographically approved
Olsson, M., Jonasson, J., Cederquist, K. & Suhr, O. B. (2014). Frequency of the transthyretin Val30Met mutation in the northern Swedish population. Amyloid: Journal of Protein Folding Disorders, 21(1), 18-20
Open this publication in new window or tab >>Frequency of the transthyretin Val30Met mutation in the northern Swedish population
2014 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 21, no 1, p. 18-20Article in journal (Other academic) Published
Abstract [en]

By genotyping a large number of samples from the Northern Sweden Health and Disease Study cohort, a carrier frequency could be determined for the Skelleftea and Lycksele populations. A previous study of the amyloidogenic transthyretin mutation TTRV30M in Northern Sweden's endemic area has shown a large variation in carrier frequency and penetrance of the trait within the area. However, the estimations have been based on a small sample size within the different regions in the area and therefore, the wide variation in TTRV30M carrier frequency observed between the Lycksele and Skelleftea populations are uncertain. Based on a total of 3460 samples, the estimated overall carrier frequency in the two regions was 1.82% with a carrier frequency in the Skelleftea and Lycksele population of 1.63% and 2.02%, respectively. Thus, the previously reported extremely high frequency in the Lycksele region compared to that of the Skelleftea region could not be substantiated. However, it does not change the previous finding of a surprisingly higher carrier frequency in the population from endemic area of Northern Sweden compared to that reported from endemic areas in Portugal.

Keywords
amyloidosis-hereditary-neuropathic, ATTRV30M (p.ATTRV50M), frequency, genotyping, mutation, transthyretin, TTR c.(Val50Met)
National Category
Medical Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-34124 (URN)10.3109/13506129.2013.860027 (DOI)000335764200003 ()2-s2.0-84896695696 (Scopus ID)
Note

Originally published in dissertation in manuscript form.

Available from: 2010-05-12 Created: 2010-05-12 Last updated: 2023-03-24Bibliographically approved
Andersson, U., Wibom, C., Cederquist, K., Aradottir, S., Borg, Å., Armstrong, G. N., . . . Melin, B. S. (2014). Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer. Paper presented at 11th Congress of the European-Association-of-Neuro-Oncology, Turin, ITALY, OCT 09-12, 2014. Neuro-Oncology, 16(10), 1333-1340
Open this publication in new window or tab >>Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer
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2014 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, no 10, p. 1333-1340Article in journal (Refereed) Published
Abstract [en]

Background: Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers. Methods: Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer. The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma. Results: We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer. Conclusions: Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes.

Place, publisher, year, edition, pages
Oxford University Press, 2014
Keywords
CDKN2A/B, family history, glioma, MLH1, MSH2, TP53
National Category
Cancer and Oncology Neurology
Identifiers
urn:nbn:se:umu:diva-96514 (URN)10.1093/neuonc/nou052 (DOI)000343671000005 ()2-s2.0-84901614478 (Scopus ID)
Conference
11th Congress of the European-Association-of-Neuro-Oncology, Turin, ITALY, OCT 09-12, 2014
Note

Meeting Abstract: P04.02 published in the same journal, Vol. 16, Suppl. 2.

Available from: 2014-11-23 Created: 2014-11-21 Last updated: 2023-03-24Bibliographically 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 ()2-s2.0-84867742520 (Scopus ID)
Available from: 2013-01-15 Created: 2013-01-14 Last updated: 2023-03-24Bibliographically approved
Olsson, M., Norgren, N., Obayashi, K., Plante-Bordeneuve, V., Suhr, O. B., Cederquist, K. & Jonasson, J. (2010). A possible role for miRNA silencing in disease phenotype variation in Swedish transthyretin V30M carriers. BMC Medical Genetics, 11, 130
Open this publication in new window or tab >>A possible role for miRNA silencing in disease phenotype variation in Swedish transthyretin V30M carriers
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2010 (English)In: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 11, p. 130-Article in journal (Refereed) Published
Abstract [en]

Our results are the first to show the presence of a 3'UTR polymorphism on the V30M haplotype in Swedish carriers, which can serve as a miRNA binding site potentially leading to down-regulated expression from the mutated TTR allele. This finding may be related to the low penetrance and high age at onset of the disease observed in the Swedish patient population.

Keywords
Allele Frequency; Amyloidosis; Amyloid Neuropathies, Familial; Humans; MicroRNA; Polymorphism, Single Nucleotide; Transthyretin; 3' Untranslated Regions/genetics
National Category
Medical Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-39677 (URN)10.1186/1471-2350-11-130 (DOI)000283195800001 ()20840742 (PubMedID)2-s2.0-77956470387 (Scopus ID)
Available from: 2011-02-03 Created: 2011-02-03 Last updated: 2024-01-17Bibliographically approved
Cederquist, K., Palmqvist, R., Emanuelsson, M., Golovleva, I. & Grönberg, H. Retained immunohistochemical staining in a large Swedish HNPCC family with a pathogenic MLH1 missense mutation.
Open this publication in new window or tab >>Retained immunohistochemical staining in a large Swedish HNPCC family with a pathogenic MLH1 missense mutation
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Bioscience
Identifiers
urn:nbn:se:umu:diva-4762 (URN)
Available from: 2005-10-19 Created: 2005-10-19 Last updated: 2018-06-09Bibliographically approved
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