liu.seSearch for publications in DiVA
Change search
Refine search result
1 - 25 of 25
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Abate Waktola, Ebba Abate
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. EPHI, Ethiopia.
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Belayneh, Meseret
    Univ Addis Abeba, Ethiopia.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Kalmar, Sweden.
    Polymorphisms in CARD8 and NLRP3 are associated with extrapulmonary TB and poor clinical outcome in active TB in Ethiopia2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 3126Article in journal (Refereed)
    Abstract [en]

    Innate immunity is a first line defense against Mycobacterium tuberculosis infection where inflammasome activation and secretion of the pro-inflammatory cytokine IL-1beta, plays a major role. Thus, genetic polymorphisms in innate immunity-related genes such as CARD8 and NLRP3 may contribute to the understanding of why most exposed individuals do not develop infection. Our aim was to investigate the association between polymorphisms in CARD8 and NLRP3 and active tuberculosis (TB) as well as their relationship to treatment outcome in a high-endemic setting for TB. Polymorphisms in CARD8 (C10X) and NLRP3 (Q705K) were analysed in 1190 TB patients and 1990 healthy donors (HD). There was a significant association between homozygotes in the CARD8 polymorphism and extrapulmonary TB (EPTB), which was not the case for pulmonary TB or HDs. Among TB-patients, there was an association between poor treatment outcome and the NLRP3 (Q705K) polymorphism. Our study shows that inflammasome polymorphisms are associated with EPTB and poor clinical outcome in active TB in Ethiopia. The practical implications and determining causal relationships on a mechanistic level needs further study.

  • 2.
    Alkaissi, Hammoudi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Havarinasab, Said
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Nielsen, Jesper Bo
    Univ Southern Denmark, Denmark.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 7, article id e0199979Article in journal (Refereed)
    Abstract [en]

    Systemic autoimmune rheumatic disorders (SARD) represent important causes of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Mercury-induced autoimmunity (HgIA) in mice is an established model to study the mechanisms of the development of antinuclear antibodies (ANA), which is a hallmark in the diagnosis of SARD. A.SW mice with HgIA show a significantly higher titer of antinucleolar antibodies (ANoA) than the B10.S mice, although both share the same MHC class II (H-2). We applied a genome-wide association study (GWAS) to their Hg-exposed F2 offspring to investigate the non-MHC genes involved in the development of ANoA. Quantitative trait locus (QTL) analysis showed a peak logarithm of odds ratio (LOD) score of 3.05 on chromosome 3. Microsatellites were used for haplotyping, and fine mapping was conducted with next generation sequencing. The candidate genes Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkbl (nuclear factor kappa B subunit 1) were identified by additional QTL analysis. Expression of the Bank1 and Nfkb1 genes and their downstream target genes involved in the intracellular pathway (Tlr9,II6, Tnf) was investigated in mercury-exposed A.SW and B10.S mice by real-time PCR. Bank1 showed significantly lower gene expression in the A.SW strain after Hg-exposure, whereas the B10.S strain showed no significant difference. Nfkb1, Tlr9, II6 and Tnf had significantly higher gene expression in the A.SW strain after Hg-exposure, while the B10.S strain showed no difference. This study supports the roles of Bank1 (produced mainly in B-cells) and Nfkbl (produced in most immune cells) as key regulators of ANoA development in HgIA.

  • 3.
    Aslan, Cynthia
    et al.
    Tabriz Univ Med Sci, Iran.
    Maralbashi, Sepideh
    Kermanshah Univ Med Sci, Iran.
    Salari, Farhad
    Kermanshah Univ Med Sci, Iran.
    Kahroba, Houman
    Tabriz Univ Med Sci, Iran.
    Sigaroodi, Faraz
    Tabriz Univ Med Sci, Iran.
    Kazemi, Tohid
    Tabriz Univ Med Sci, Iran.
    Kharaziha, Pedram
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Tumor-derived exosomes: Implication in angiogenesis and antiangiogenesis cancer therapy2019In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 234, no 10, p. 16885-16903Article, review/survey (Refereed)
    Abstract [en]

    Tumor cells utilize different strategies to communicate with neighboring tissues for facilitating tumor progression and invasion, one of these strategies has been shown to be the release of exosomes. Exosomes are small nanovesicles secreted by all kind of cells in the body, especially cancer cells, and mediate cell to cell communications. Exosomes play an important role in cancer invasiveness by harboring various cargoes that could accelerate angiogenesis. Here first, we will present an overview of exosomes, their biology, and their function in the body. Then, we will focus on exosomes derived from tumor cells as tumor angiogenesis mediators with a particular emphasis on the underlying mechanisms in various cancer origins. Also, exosomes derived from stem cells and tumor-associated macrophages will be discussed in this regard. Finally, we will discuss the novel therapeutic strategies of exosomes as drug delivery vehicles against angiogenesis.

  • 4.
    Bengtsson, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Joost, Patrick
    Lund University, Sweden.
    Aravidis, Christos
    Uppsala University, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics. Off Medical Serv, Sweden; Lund University, Sweden.
    Backman, Ann-Sofie
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Melin, Beatrice
    Umeå University, Sweden.
    von Salome, Jenny
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Zagoras, Theofanis
    Sahlgrens University Hospital, Sweden.
    Gebre-Medhin, Samuel
    Lund University, Sweden; Karolinska University Hospital, Sweden.
    Burman, Pia
    Lund University, Sweden.
    Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 11, p. 3928-3932Article in journal (Refereed)
    Abstract [en]

    Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported. Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patients germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS. Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected). Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.

  • 5.
    Chibani, Zohra
    et al.
    Univ Sfax, Tunisia.
    Abid, Imen Zone
    Univ Sfax, Tunisia.
    Molbaek, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Feki, Jamel
    Univ Sfax, Tunisia.
    Hmani-Aifa, Mounira
    Univ Sfax, Tunisia.
    Novel BEST1 gene mutations associated with two different forms of macular dystrophy in Tunisian families2019In: Clinical and Experimental Ophthalmology, ISSN 1442-6404, E-ISSN 1442-9071Article in journal (Refereed)
    Abstract [en]

    Background

    Epidemiological studies of hereditary eye diseases allowed us to identify two Tunisian families suffering from macular dystrophies: Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB). The purpose of the current study was to investigate the clinical characteristics and the underlying genetics of these two forms of macular dystrophy.

    Methods

    Complete ophthalmic examination was performed including optical coherence tomography, electroretinography, electrooculography and autofluoresence imaging in all patients. Genomic DNA was extracted from peripheral blood collected from patients and family members.

    Results

    Sanger sequencing of all exons of the BEST1 gene in both families identified two new mutations: a missense mutation c.C91A [p.L31 M] at the N‐terminal transmembrane domain within the ARB family and a nonsense mutation C1550G (p.S517X) in the C‐terminal domain segregating in the BVMD family.

    Conclusions

    Several mutations of the BEST1 gene have been reported which are responsible for numerous ocular pathologies. To the best of our knowledge, it is the first time we report mutations in this gene in Tunisian families presenting different forms of macular dystrophy. Our report also expands the list of pathogenic BEST1 genotypes and the associated clinical diagnosis.

  • 6.
    Dahlrot, R. H.
    et al.
    Odense Univ Hosp, Denmark.
    Dowsett, J.
    Odense Univ Hosp, Denmark.
    Fosmark, S.
    Odense Univ Hosp, Denmark.
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Henriksson, R.
    Umea Univ, Sweden; Reg Canc Ctr Stockholm Gotland, Sweden.
    Boldt, H.
    Odense Univ Hosp, Denmark.
    de Stricker, K.
    Odense Univ Hosp, Denmark.
    Sorensen, M. D.
    Odense Univ Hosp, Denmark; Univ Southern Denmark, Denmark.
    Poulsen, H. S.
    Rigshosp, Denmark.
    Lysiak, Malgorzata
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Rosell, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Business support and Development, Regional Cancer Center.
    Hansen, S.
    Odense Univ Hosp, Denmark; Univ Southern Denmark, Denmark.
    Kristensen, B. W.
    Odense Univ Hosp, Denmark; Univ Southern Denmark, Denmark.
    Prognostic value of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression in glioblastoma excluding nontumour cells from the analysis2018In: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 44, no 2, p. 172-184Article in journal (Refereed)
    Abstract [en]

    Aims: It is important to predict response to treatment with temozolomide (TMZ) in glioblastoma (GBM) patients. Both MGMT protein expression and MGMT promoter methylation status have been reported to predict the response to TMZ. We investigated the prognostic value of quantified MGMT protein levels in tumour cells and the prognostic importance of combining information of MGMT protein level and MGMT promoter methylation status. Methods: MGMT protein expression was quantified in tumour cells in 171 GBMs from the population-based Region of Southern Denmark (RSD)cohort using a double immunofluorescence approach. Pyrosequencing was performed in 157 patients. For validation we used GBM-patients from a Nordic Study (NS) investigating the effect of radiotherapy and different TMZ schedules. Results: When divided at the median, patients with low expression of MGMT protein (AF-low) had the best prognosis (HR = 1.5, P = 0.01). Similar results were observed in the subgroup of patients receiving the Stupp regimen (HR = 2.0, P = 0.001). In the NS-cohort a trend towards superior survival (HR = 1.6, P = 0.08) was seen in patients with AF-low. Including MGMT promoter methylation status, we found for both cohorts that patients with methylated MGMT promoter and AF-low had the best outcome; median OS 23.1 and 20.0 months, respectively. Conclusion: Our data indicate that MGMT protein expression in tumour cells has an independent prognostic significance. Exclusion of nontumour cells contributed to a more exact analysis of tumour-specific MGMT protein expression. This should be incorporated in future studies evaluating MGMT status before potential integration into clinical practice.

  • 7.
    Devito, Claudia
    et al.
    Swedish Inst Infect Dis Control, Sweden; HD Dept Clin Virol, Sweden.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Falkeborn, Tina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ohlin, Mats
    Lund Univ, Sweden.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Broliden, Kristina
    Karolinska Inst, Sweden.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Human IgM monoclonal antibodies block HIV-transmission to immune cells in cervico-vaginal tissues and across polarized epithelial cells in vitro2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 10180Article in journal (Refereed)
    Abstract [en]

    The importance of natural IgM antibodies in protection against infections is still emerging and these antibodies have a potential role in the maintenance of homeostasis through clearance of apoptotic bodies, complement-dependent mechanisms, inflammation and exclusion of misfolded proteins. Natural IgM act as a first line of defence against unknown hazardous factors and are present in most vertebrates. We investigated the functional capacity of anti-HIV-1 IgM monoclonal antibodies, from a combinatorial Fab library derived from healthy individuals, and evaluated their protective role in inhibiting HIV-1 in vitro when passing across the human mucosal epithelial barrier. Primary HIV-1 isolates were efficiently transmitted over the tight polarized epithelial cells when added to their apical surface. Efficient inhibition of HIV-1 transmission was achieved when anti-HIV-1 IgM monoclonal antibodies were added to the basolateral side of the cells. Two of these human IgM MoAbs had the ability to neutralize HIV and reduced infection of dendritic cells in primary cervico-vaginal tissue biopsies in vitro. This indicates a potential role of natural IgM antibodies in the reduction of HIV-1 transmission in mucosal tissues and improve our understanding of how natural IgM antibodies against a neutralizing epitope could interfere with viral transmission.

  • 8.
    Ellegård, Rada
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Khalid, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. King Khalid Univ, Saudi Arabia.
    Svanberg, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Holgersson, Hanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Thoren, Ylva
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Wittgren, Mirja Karolina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Shankar, Esaki M.
    Univ Malaya, Malaysia; Cent Univ Tamil Nadu, India.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Complement-Opsonized HIV-1 Alters Cross Talk Between Dendritic Cells and Natural Killer (NK) Cells to Inhibit NK Killing and to Upregulate PD-1, CXCR3, and CCR4 on T Cells2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 899Article in journal (Refereed)
    Abstract [en]

    Dendritic cells (DCs), natural killer (NK) cells, and T cells play critical roles during primary HIV-1 exposure at the mucosa, where the viral particles become coated with complement fragments and mucosa-associated antibodies. The microenvironment together with subsequent interactions between these cells and HIV at the mucosal site of infection will determine the quality of immune response that ensues adaptive activation. Here, we investigated how complement and immunoglobulin opsonization influences the responses triggered in DCs and NK cells, how this affects their cross talk, and what T cell phenotypes are induced to expand following the interaction. Our results showed that DCs exposed to complement-opsonized HIV (C-HIV) were less mature and had a poor ability to trigger IFN-driven NK cell activation. In addition, when the DCs were exposed to C-HIV, the cytotolytic potentials of both NK cells and CD8 T cells were markedly suppressed. The expression of PD-1 as well as co-expression of negative immune checkpoints TIM-3 and LAG-3 on PD-1 positive cells were increased on both CD4 as well as CD8 T cells upon interaction with and priming by NK-DC cross talk cultures exposed to C-HIV. In addition, stimulation by NK-DC cross talk cultures exposed to C-HIV led to the upregulation of CD38, CXCR3, and CCR4 on T cells. Together, the immune modulation induced during the presence of complement on viral surfaces is likely to favor HIV establishment, dissemination, and viral pathogenesis.

  • 9.
    Eriksson, Daniel
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Bianchi, Matteo
    Uppsala Univ, Sweden.
    Landegren, Nils
    Karolinska Inst, Sweden; Uppsala Univ, Sweden.
    Dalin, Frida
    Karolinska Inst, Sweden; Uppsala Univ, Sweden.
    Skov, Jakob
    Karolinska Inst, Sweden.
    Hultin-Rosenberg, Lina
    Uppsala Univ, Sweden.
    Mathioudaki, Argyri
    Uppsala Univ, Sweden.
    Nordin, Jessika
    Uppsala Univ, Sweden.
    Hallgren, Asa
    Karolinska Inst, Sweden.
    Andersson, Goran
    Swedish Univ Agr Sci, Sweden.
    Tandre, Karolina
    Uppsala Univ, Sweden.
    Rantapaa Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Hulting, Anna-Lena
    Not Found:[Eriksson, Daniel; Landegren, Nils; Dalin, Frida; Hallgren, Asa; Kampe, Olle] Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; [Eriksson, Daniel; Bensing, Sophie; Kampe, Olle] Karolinska Univ Hosp, Dept Endocrinol Metab and Diabet, Stockholm, Sweden; [Bianchi, Matteo; Hultin-Rosenberg, Lina; Mathioudaki, Argyri; Nordin, Jessika; Meadows, Jennifer R. S.; Lindblad-Toh, Kerstin; Pielberg, Gerli Rosengren] Uppsala Univ, Dept Med Biochem and Microbiol, Sci Life Lab, Uppsala, Sweden; [Landegren, Nils; Dalin, Frida; Tandre, Karolina; Ronnblom, Lars] Uppsala Univ, Dept Med Sci, Sci Life Lab, Uppsala, Sweden; [Skov, Jakob; Bensing, Sophie] Karolinska Inst, Dept Mol Med and Surg, Stockholm, Sweden; [Andersson, Goran] Swedish Univ Agr Sci, Dept Anim Breeding and Genet, Uppsala, Sweden; [Dahlqvist, Solbritt Rantapaa; Dahlqvist, Per] Umea Univ, Dept Publ Hlth and Clin Med, Umea, Sweden; [Soderkvist, Peter; Wahlberg, Jeanette] Linkoping Univ, Dept Clin and Expt Med, Linkoping, Sweden; [Wahlberg, Jeanette] Linkoping Univ, Dept Endocrinol, Linkoping, Sweden; [Wahlberg, Jeanette] Linkoping Univ, Dept Med and Hlth Sci, Linkoping, Sweden; [Ekwall, Olov] Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden; [Ekwall, Olov] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol and Inflammat Res, Gothenburg, Sweden; [Lindblad-Toh, Kerstin] Broad Inst MIT and Harvard, Cambridge, MA USA; [Kampe, Olle] KG Jebsen Ctr Autoimmune Dis, Bergen, Norway;.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Dahlqvist, Per
    Umea Univ, Sweden.
    Ekwall, Olov
    Univ Gothenburg, Sweden; Univ Gothenburg, Sweden.
    Meadows, Jennifer R. S.
    Uppsala Univ, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala Univ, Sweden; Broad Inst MIT and Harvard, MA USA.
    Bensing, Sophie
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Pielberg, Gerli Rosengren
    Uppsala Univ, Sweden.
    Kampe, Olle
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; KG Jebsen Ctr Autoimmune Dis, Norway.
    Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addisons disease in Sweden2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8395Article in journal (Refereed)
    Abstract [en]

    Autoimmune Addisons disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

  • 10.
    Fardell, Camilla
    et al.
    Univ Gothenburg, Sweden.
    Zettergren, Anna
    Univ Gothenburg, Sweden.
    Ran, Caroline
    Karolinska Inst, Sweden.
    Belin, Andrea Carmine
    Karolinska Inst, Sweden.
    Ekman, Agneta
    Univ Gothenburg, Sweden.
    Sydow, Olof
    Karolinska Univ Hosp, Sweden.
    Backman, Lars
    Karolinska Inst, Sweden.
    Holmberg, Bjorn
    Univ Gothenburg, Sweden.
    Dizdar Segrell, Nil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Nissbrandt, Hans
    Univ Gothenburg, Sweden.
    S100B polymorphisms are associated with age of onset of Parkinsons disease2018In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 19, article id 42Article in journal (Refereed)
    Abstract [en]

    Background: In this study we investigated the association between SNPs in the S100B gene and Parkinsons disease (PD) in two independent Swedish cohorts. The SNP rs9722 has previously been shown to be associated with higher S100B concentrations in serum and frontal cortex in humans. S100B is widely expressed in the central nervous system and has many functions such as regulating calcium homeostasis, inflammatory processes, cytoskeleton assembly/disassembly, protein phosphorylation and degradation, and cell proliferation and differentiation. Several of these functions have been suggested to be of importance for the pathophysiology of PD. Methods: The SNPs rs9722, rs2239574, rs881827, rs9984765, and rs1051169 of the S100B gene were genotyped using the KASPar (R) PCR SNP genotyping system in a case-control study of two populations (431 PD patients and 465 controls, 195 PD patients and 378 controls, respectively). The association between the genotype and allelic distributions and PD risk was evaluated using Chi-Square and Cox proportional hazards test, as well as logistic regression. Linear regression and Cox proportional hazards tests were applied to assess the effect of the rs9722 genotypes on age of disease onset. Results: The S100B SNPs tested were not associated with the risk of PD. However, in both cohorts, the T allele of rs9722 was significantly more common in early onset PD patients compared to late onset PD patients. The SNP rs9722 was significantly related to age of onset, and each T allele lowered disease onset with 4.9 years. In addition, allelic variants of rs881827, rs9984765, and rs1051169, were significantly more common in early-onset PD compared to late-onset PD in the pooled population. Conclusions: rs9722, a functional SNP in the 3-UTR of the S100B gene, was strongly associated with age of onset of PD.

  • 11.
    Fernlund, Eva
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Lund University, Sweden.
    Wålinder Österberg, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Kuchinskaya, Ekaterina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Jansson, Kjell
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics. Region Östergötland, Center for Business support and Development.
    Novel Genetic Variants in BAG3 and TNNT2 in a Swedish Family with a History of Dilated Cardiomyopathy and Sudden Cardiac Death2017In: Pediatric Cardiology, ISSN 0172-0643, E-ISSN 1432-1971, Vol. 38, no 6, p. 1262-1268Article in journal (Refereed)
    Abstract [en]

    Familial dilated cardiomyopathy is a rare cause of dilated cardiomyopathy (DCM), especially in childhood. Our aim was to describe the clinical course and the genetic variants in a family where the proband was a four-month-old infant presenting with respiratory problems due to DCM. In the family, there was a strong family history of DCM and sudden cardiac death in four generations. DNA was analyzed initially from the deceased girl using next-generation sequencing including 50 genes involved in cardiomyopathy. A cascade family screening was performed in the family after identification of the TNNT2 and the BAG3 variants in the proband. The first-degree relatives underwent clinical examination including biochemistry panel, cardiac ultrasound, Holter ECG, exercise stress test, and targeted genetic testing. The index patient presented with advanced DCM. After a severe clinical course, the baby had external left ventricular assist as a bridge to heart transplantation. 1.5 months after transplantation, the baby suffered sudden cardiac death (SCD) despite maximal treatment in the pediatric intensive care unit. The patient was shown to carry two heterozygous genetic variants in the TNNT2 gene [TNNT2 c.518G amp;gt; A(p.Arg173Gln)] and BAG3 [BAG3 c.785C amp;gt; T(p.Ala262Val)]. Two of the screened individuals (two females) appeared to carry both the familial variants. All the individuals carrying the TNNT2 variant presented with DCM, the two adult patients had mild or moderate symptoms of heart failure and reported palpitations but no syncope or presyncopal attacks prior to the genetic diagnosis. The female carriers of TNNT2 and BAG3 variants had more advanced DCM. In the family history, there were three additional cases of SCD due to DCM, diagnosed by autopsy, but no genetic analysis was possible in these cases. Our findings suggest that the variants in TNNT2 and BAG3 are associated with a high propensity to life-threatening cardiomyopathy presenting from childhood and young adulthood.

  • 12.
    Karimi, Masoud
    et al.
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    von Salomé, Jenny
    Department of Clinical Genetics, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden; 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Aravidis, Christos
    Department of Clinical Genetics, Akademiska University Hospital, Uppsala, Sweden.
    Silander, Gustav
    Department of Clinical Genetics, Norrlands University Hospital, Umeå, Sweden.
    Stenmark Askmalm, Marie
    Region Östergötland, Center for Diagnostics, Clinical genetics. Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.
    Henriksson, Isabelle
    Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden; 8Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.
    Gebre-Medhin, Samuel
    Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden; 8Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.
    Frödin, Jan-Erik
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Björck, Erik
    Department of Clinical Genetics, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden; 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Lagerstedt-Robinson, Kristina
    Department of Clinical Genetics, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden; 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Lindblom, Annika
    Department of Clinical Genetics, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden; 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Tham, Emma
    Department of Clinical Genetics, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden; 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    A retrospective study of extracolonic, non-endometrial cancer in Swedish Lynch syndrome families2018In: Hereditary Cancer in Clinical Practice, ISSN 1731-2302, E-ISSN 1897-4287, Vol. 16, article id 16Article in journal (Refereed)
    Abstract [en]

    Lynch Syndrome is an autosomal dominant cancer syndrome caused by pathogenic germ-line variants in one of the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. Carriers are predisposed to colorectal and endometrial cancer, but also other cancer types. The purpose of this retrospective study was to characterize the tumour spectrum of the Swedish Lynch syndrome families.

  • 13.
    Kissopoulou, Antheia
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Cty Council Jonkoping, Sweden.
    Trinks, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Gréen, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Karlsson, Jan-Erik
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Cty Council Jonkoping, Sweden.
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics. Region Östergötland, Center for Business support and Development.
    Homozygous missense MYBPC3 Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy2018In: ESC Heart Failure, E-ISSN 2055-5822, Vol. 5, no 4, p. 716-723Article in journal (Refereed)
    Abstract [en]

    Hypertrophic cardiomyopathy (HCM) is a primary autosomal-dominant disorder of the myocardium with variable expressivity and penetrance. Occasionally, homozygous sarcomere genetic variants emerge while genotyping HCM patients. In these cases, a more severe HCM phenotype is generally seen. Here, we report a case of HCM that was diagnosed clinically at 39years of age. Initial symptoms were shortness of breath during exertion. Successively, he developed a wide array of severe clinical manifestations, which progressed to an ominous end-stage heart failure that resulted in heart transplantation. Genotype analysis revealed a missense MYBPC3 variant NM_000256.3:c.2618Camp;gt;A,p.(Pro873His) that presented in the homozygous form. Conflicting interpretations of pathogenicity have been reported for the Pro873His MYBPC3 variant described here. Our patient, presenting with two copies of the variant and devoid of a normal allele, progressed to end-stage heart failure, which supports the notion of a deleterious effect of this variant in the homozygous form.

  • 14.
    Krauss, Tobias
    et al.
    Univ Freiburg, Germany.
    Ferrara, Alfonso Massimiliano
    IRCCS, Italy.
    Links, Thera P.
    Univ Groningen, Netherlands.
    Wellner, Ulrich
    Univ Lubeck, Germany.
    Bancoss, Irina
    Mayo Clin, MN USA.
    Kvachenyuk, Andrey
    NAMS Ukraine, Ukraine.
    Gomez de las Heras, Karim Villar
    Serv Salud Castilla La Mancha SESCAM, Spain.
    Yukina, Marina Y.
    Endocrinol Res Ctr, Russia.
    Petrov, Roman
    Bakhrushin Bros Moscow City Hosp, Russia.
    Bullivant, Garrett
    Univ Hlth Network, Canada.
    von Duecker, Laura
    Albert Ludwigs Univ, Germany.
    Jadhav, Swati
    King Edward Mem Hosp, India.
    Ploeckinger, Ursula
    Charite Univ Med Berlin, Germany.
    Welin, Staffan
    Uppsala Univ Hosp, Sweden.
    Schalin-Jantti, Camilla
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Pfeifer, Marija
    Univ Med Ctr, Slovenia.
    Ngeow, Joanne
    Nanyang Technol Univ, Singapore; Nanyang Technol Univ, Singapore.
    Hasse-Lazar, Kornelia
    MSC Mem Inst, Poland.
    Sanso, Gabriela
    Hosp Ninos Dr Ricardo Gutierrez, Argentina.
    Qi, Xiaoping
    Wenzhou Med Univ, Peoples R China.
    Ugurlu, M. Umit
    Marmara Univ, Turkey.
    Diaz, Rene E.
    Hosp Salvador, Chile.
    Wohllk, Nelson
    Univ Chile, Chile.
    Peczkowska, Mariola
    Inst Cardiol, Poland.
    Aberle, Jens
    Univ Med Ctr Hamburg Eppendorf, Germany.
    Lourenco Jr, Delmar M.
    Univ Sao Paulo, Brazil; Univ Sao Paulo, Brazil.
    Pereira, Maria A. A.
    Univ Sao Paulo, Brazil.
    Fragoso, Maria C. B. V
    Univ Sao Paulo, Brazil; Univ Sao Paulo, Brazil.
    Hoff, Ana O.
    Univ Sao Paulo, Brazil; Univ Sao Paulo, Brazil.
    Almeida, Madson Q.
    Univ Sao Paulo, Brazil; Univ Sao Paulo, Brazil.
    Violante, Alice H. D.
    Univ Fed Rio de Janeiro, Brazil.
    Ouidute, Ana R. P.
    Fed Univ Ceara UFC, Brazil.
    Zhang, Zhewei
    Zhejiang Univ, Peoples R China.
    Recasens, Monica
    Hosp Univ Girona, Spain.
    Robles Diaz, Luis
    Hosp Univ 12 Octubre, Spain.
    Kunavisarut, Tada
    Mahidol Univ, Thailand.
    Wannachalee, Taweesak
    Mahidol Univ, Thailand.
    Sirinvaravong, Sirinart
    Mahidol Univ, Thailand.
    Jonasch, Eric
    Univ Texas MD Anderson Canc Ctr, TX 77030 USA.
    Grozinsky-Glasberg, Simona
    Hadassah Hebrew Univ, Israel.
    Fraenkel, Merav
    Hadassah Hebrew Univ, Israel.
    Beltsevich, Dmitry
    Endocrinol Res Ctr, Russia.
    Egorov, Viacheslav I
    Bakhrushin Bros Moscow City Hosp, Russia.
    Bausch, Dirk
    Univ Lubeck, Germany.
    Schott, Matthias
    Heinrich Heine Univ, Germany.
    Tiling, Nikolaus
    Charite Univ Med Berlin, Germany.
    Pennelli, Gianmaria
    Univ Padua, Italy.
    Zschiedrich, Stefan
    Albert Ludwigs Univ, Germany.
    Daerr, Roland
    Albert Ludwigs Univ, Germany; Univ Freiburg, Germany.
    Ruf, Juri
    Albert Ludwigs Univ, Germany.
    Denecke, Timm
    Charite Univ Med Berlin, Germany.
    Link, Karl-Heinrich
    Asklepios Paulinen Klin, Germany.
    Zovato, Stefania
    IRCCS, Italy.
    von Dobschuetz, Ernst
    Acad Teaching Hosp Univ Hamburg, Germany.
    Yaremchuk, Svetlana
    NAMS Ukraine, Ukraine.
    Amthauer, Holger
    Charite Univ Med Berlin, Germany.
    Makay, Ozer
    Dept Gen Surg, Turkey.
    Patocs, Attila
    Semmelweis Univ, Hungary; Semmelweis Univ, Hungary.
    Walz, Martin K.
    Huyssens Fdn Clin, Germany.
    Huber, Tobias B.
    Univ Med Ctr Hamburg Eppendorf, Germany.
    Seufert, Jochen
    Univ Freiburg, Germany.
    Hellman, Per
    Uppsala Univ, Sweden.
    Ekaterina, Raymond H.
    Univ Toronto, Canada; Mt Sinai Hosp, Canada.
    Kuchinskaya, Ekaterina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Schiavi, Francesca
    IRCCS, Italy.
    Malinoc, Angelica
    Albert Ludwigs Univ, Germany.
    Reisch, Nicole
    Ludwigs Maximilians Univ Munich, Germany.
    Jarzab, Barbara
    MSC Mem Inst, Poland.
    Barontini, Marta
    Hosp Ninos Dr Ricardo Gutierrez, Argentina.
    Januszewicz, Andrzej
    Inst Cardiol, Poland.
    Shah, Nalini
    King Edward Mem Hosp, India.
    Young, William F. Jr.
    Mayo Clin, MN USA.
    Opocher, Giuseppe
    Veneto Inst Oncol IOV IRCCS, Italy.
    Eng, Charis
    Cleveland Clin, OH 44106 USA.
    Neumann, Hartmut P. H.
    Albert Ludwigs Univ, Germany.
    Bausch, Birke
    Univ Freiburg, Germany.
    Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors2018In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 25, no 9, p. 783-793Article in journal (Refereed)
    Abstract [en]

    Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P amp;lt; 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were amp;gt;= 2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off amp;gt;= 2.8 cm, 44% and 91% for TVDT cut-off of amp;lt;= 24 months). In 117 of 273 patients, PanNETs amp;gt; 1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs amp;lt; 2.8 cm vs amp;gt;= 2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

  • 15.
    Nazaryan-Petersen, Lusine
    et al.
    Univ Copenhagen, Denmark.
    Eisfeldt, Jesper
    Karolinska Inst, Sweden; Karolinska Inst Sci Pk, Sweden.
    Pettersson, Maria
    Karolinska Inst, Sweden.
    Lundin, Johanna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Nilsson, Daniel
    Karolinska Inst, Sweden; Karolinska Inst Sci Pk, Sweden; Karolinska Univ Hosp, Sweden.
    Wincent, Josephine
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Lieden, Agne
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Lovmar, Lovisa
    Sahlgrens Univ Hosp, Sweden.
    Ottosson, Jesper
    Sahlgrens Univ Hosp, Sweden.
    Gacic, Jelena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Makitie, Outi
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Univ Helsinki, Finland; Helsinki Univ Hosp, Finland; Folkhalsan Inst Genet, Finland.
    Nordgren, Ann
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Vezzi, Francesco
    Stockholm Univ, Sweden; Devyser AB, Sweden.
    Wirta, Valtteri
    KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Kaller, Max
    KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Hjortshoj, Tina Duelund
    Rigshosp, Denmark.
    Jespersgaard, Cathrine
    Rigshosp, Denmark.
    Houssari, Rayan
    Rigshosp, Denmark.
    Pignata, Laura
    Rigshosp, Denmark.
    Bak, Mads
    Univ Copenhagen, Denmark.
    Tommerup, Niels
    Univ Copenhagen, Denmark.
    Lundberg, Elisabeth Syk
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Tumer, Zeynep
    Rigshosp, Denmark; Univ Copenhagen, Denmark.
    Lindstrand, Anna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization2018In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 11, article id e1007780Article in journal (Refereed)
    Abstract [en]

    Clustered copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) are often reported as germline chromothripsis. However, such cases might need further investigations by massive parallel whole genome sequencing (WGS) in order to accurately define the underlying complex rearrangement, predict the occurrence mechanisms and identify additional complexities. Here, we utilized WGS to delineate the rearrangement structure of 21 clustered CNV carriers first investigated by CMA and identified a total of 83 breakpoint junctions (BPJs). The rearrangements were further sub-classified depending on the patterns observed: I) Cases with only deletions (n = 8) often had additional structural rearrangements, such as insertions and inversions typical to chromothripsis; II) cases with only duplications (n = 7) or III) combinations of deletions and duplications (n = 6) demonstrated mostly interspersed duplications and BPJs enriched with microhomology. In two cases the rearrangement mutational signatures indicated both a breakage-fusion-bridge cycle process and haltered formation of a ring chromosome. Finally, we observed two cases with Alu- and LINE-mediated rearrangements as well as two unrelated individuals with seemingly identical clustered CNVs on 2p25.3, possibly a rare European founder rearrangement. In conclusion, through detailed characterization of the derivative chromosomes we show that multiple mechanisms are likely involved in the formation of clustered CNVs and add further evidence for chromoanagenesis mechanisms in both "simple" and highly complex chromosomal rearrangements. Finally, WGS characterization adds positional information, important for a correct clinical interpretation and deciphering mechanisms involved in the formation of these rearrangements.

  • 16.
    Pestoff, Rebecka
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Johansson, Peter
    Linköping University, Department of Social and Welfare Studies, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Nilsen, Per
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Factors influencing use of telegenetic counseling: perceptions of health care professionals in Sweden2019In: Journal of Community Genetics, ISSN 1868-310X, E-ISSN 1868-6001, Vol. 10, no 3, p. 407-415Article in journal (Refereed)
    Abstract [en]

    Genetic counseling services are increasing in demand and limited in access due to barriers such as lack of professional genetic counselors, vast geographic distances, and physical hurdles. This research focuses on an alternative mode of delivery for genetic counseling in Sweden, in order to overcome some of the mentioned barriers. The aim of this study is to identify factors that influence the implementation and use of telegenetic counseling in clinical practice, according to health care professionals in Southeast Sweden. Telegenetic counseling refers to the use of video-conferencing as a means to provide genetic counseling. Qualitative, semi-structured interviews with 16 genetic counseling providers took place and phenomenographic analysis was applied. Significant excerpts were identified in each transcript, which led to sub-categories that constructed the main findings. Three categories emerged from the data: (1) requirements for optimal use, (2) impact on clinical practice, and (3) patient benefits. Each category consists of two or three sub-categories, in total seven sub-categories. These findings could potentially be used to improve access and uptake of telegenetic counseling in Sweden and in other countries with a similar health care system. This could benefit not only remote patient populations, as described in previous research, but also large family groups and patients experiencing obstacles in accessing genetic counseling, such as those with a psychiatric illness or time constraints, and be a useful way to make genetic counseling available in the new era of genomics.

  • 17.
    Pestoff, Rebecka
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Moldovan, R.
    Babes Bolyai Univ, Romania.
    Cordier, C.
    Synlab Genet, Switzerland.
    Serra-Juhe, C.
    Univ Pompeu Fabra Hosp Mar Res Inst IMIM, Spain; Inst Salud Carlos III, Spain.
    Paneque, M.
    Univ Porto, Portugal; Univ Porto, Portugal.
    Ingvoldstad, C. M.
    Uppsala Univ, Sweden; Karolinska Inst, Sweden; Uppsala Univ, Sweden.
    How practical experiences, educational routes and multidisciplinary teams influence genetic counselors clinical practice in Europe2018In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 93, no 4, p. 891-898Article in journal (Refereed)
    Abstract [en]

    The main objective of our study was to explore whether, and to what extent, genetic counselors characteristics impact on their tasks in practice. Specifically, we explored the complementariness between genetic counselors and medical geneticists and therefore looked at the most relevant tasks of genetic counselors, according to genetic counselors themselves and according to the medical geneticists they work with. A total of 104 genetic counselors and 29 medical geneticists from 15 countries completed a purposefully designed questionnaire. Results showed that most genetic counselors in Europe perform similar tasks, irrespective of their backgrounds. When looking at the factors influencing genetic counselors roles data showed that the type of tasks performed by genetic counselors is associated with the years of experience in the field, not with their background or education. Of particular interest was the consensus between genetic counselors and medical geneticists regarding the genetic counselors role. Not surprisingly, tasks with more psychosocial implications were seen as genetic counselors eligibility while tasks with more medical implications were seen as medical geneticists attribution. Our study shows that most genetic counselors work in tune with international recommendations and seem to be supportive of multidisciplinary teams. Corroborating our data with previous research, we discuss potential implications for practice and training in genetic counseling.

  • 18.
    Rossitti, Hugo
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Extent of surgery for phaeochromocytomas in the genomic era2018In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 105, no 2, p. E84-E98Article, review/survey (Refereed)
    Abstract [en]

    Background

    Germline mutations are present in 20–30 per cent of patients with phaeochromocytoma. For patients who develop bilateral disease, complete removal of both adrenal glands (total adrenalectomy) will result in lifelong adrenal insufficiency with an increased risk of death from adrenal crisis. Unilateral/bilateral adrenal‐sparing surgery (subtotal adrenalectomy) offers preservation of cortical function and independence from steroids, but leaves the adrenal medulla in situ and thus at risk of developing new and possibly malignant disease. Here, present knowledge about how tumour genotype relates to clinical behaviour is reviewed, and application of this knowledge when choosing the extent of adrenalectomy is discussed.

    Methods

    A literature review was undertaken of the penetrance of the different genotypes in phaeochromocytomas, the frequency of bilateral disease and malignancy, and the underlying pathophysiological mechanisms, with emphasis on explaining the clinical phenotypes of phaeochromocytomas and their associated syndromes.

    Results

    Patients with bilateral phaeochromocytomas most often have multiple endocrine neoplasia type 2 (MEN2) or von Hippel–Lindau disease (VHL) with high‐penetrance mutations for benign disease, whereas patients with mutations in the genes encoding SDHB (succinate dehydrogenase subunit B) or MAX (myelocytomatosis viral proto‐oncogene homologue‐associated factor X) are at increased risk of malignancy.

    Conclusion

    Adrenal‐sparing surgery should be the standard approach for patients who have already been diagnosed with MEN2 or VHL when operating on the first side, whereas complete removal of the affected adrenal gland(s) is generally recommended for patients with SDHB or MAX germline mutations. Routine assessment of a patient's genotype, even after the first operation, can be crucial for adopting an appropriate strategy for follow‐up and future surgery.

  • 19.
    Sandestig, Anna
    et al.
    Region Östergötland, Center for Diagnostics, Clinical genetics.
    Gréen, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Vogt, Hartmut
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Wahlström, Johan
    Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Pepler, Alexander
    Department of CeGaT GmbH, Tübingen, Germany.
    Ellnebo, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Biskup, Saskia
    Department of CeGaT GmbH, Tübingen, Germany.
    Stefanova, Margarita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Could Dissimilar Phenotypic Effects of ACTB Missense Mutations Reflect the Actin Conformational Change?: Two Novel Mutations and Literature Review2019In: Molecular Syndromology, ISSN 1661-8769, E-ISSN 1661-8777, Vol. 9, no 5, p. 259-265Article in journal (Refereed)
    Abstract [en]

    The beta-actin gene encodes 1 of 6 different actin proteins. De novo heterozygous missense mutations in ACTB have been identified in patients with Baraitser-Winter syndrome (BRWS) and also in patients with developmental disorders other than BRWS, such as deafness, dystonia, and neutrophil dysfunction. We describe 2 different novel de novo missense ACTB mutations, c.208Camp;gt;G (p.Pro70Ala) and c.511Camp;gt;T (p.Leu171Phe), found by trio exome sequencing analysis of 2 unrelated patients: an 8-year-old boy with a suspected BRWS and a 4-year-old girl with unclear developmental disorder. The mutated residue in the first case is situated in the actin H-loop, which is involved in actin polymerization. The mutated residue in the second case (p.Leu171Phe) is found at the actin barbed end in the W-loop, important for binding to profilin and other actin-binding molecules. While the boy presented with a typical BRWS facial appearance, the girl showed facial features not recognizable as a BRWS gestalt as well as ventricular arrhythmia, cleft palate, thrombocytopenia, and gray matter heterotopia. We reviewed previously published ACTB missense mutations and ascertained that a number of them do not cause typical BRWS. By comparing clinical and molecular data, we speculate that the phenotypic differences found in ACTB missense mutation carriers might supposedly be dependent on the conformational change of ACTB.

  • 20.
    Smol, T.
    et al.
    CHU Lille, France; Univ Lille, France.
    Petit, F.
    Univ Lille, France; CHU Lille, France.
    Piton, A.
    Hop Univ Strasbourg, France.
    Keren, B.
    Grp Hosp Pitie Salpetriere, France.
    Sanlaville, D.
    Hosp Civils Lyon, France.
    Afenjar, A.
    Hop Enfants Armand Trousseau, France.
    Baker, S.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Bedoukian, E. C.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Bhoj, E. J.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Bonneau, D.
    CHU Angers, France.
    Boudry-Labis, E.
    CHU Lille, France.
    Bouquillon, S.
    CHU Lille, France.
    Boute-Benejean, O.
    Univ Lille, France; CHU Lille, France.
    Caumes, R.
    CHU Lille, France.
    Chatron, N.
    Hosp Civils Lyon, France.
    Colson, C.
    Univ Lille, France; CHU Lille, France.
    Coubes, C.
    CHU Montpellier, France.
    Coutton, C.
    CHU Grenoble Alpes, France.
    Devillard, F.
    CHU Grenoble Alpes, France.
    Dieux-Coeslier, A.
    Univ Lille, France; CHU Lille, France.
    Doco-Fenzy, M.
    CHU Reims, France.
    Ewans, L. J.
    Univ New South Wales, Australia.
    Faivre, L.
    CHU Dijon, France; CHU Dijon, France; Univ Bourgogne, France.
    Fassi, E.
    Washington Univ, MO 63110 USA.
    Field, M.
    Genet Learning Disabil Serv, Australia.
    Fournier, C.
    Hop Univ Strasbourg, France.
    Francannet, C.
    CHU Clermont Fernand, France.
    Genevieve, D.
    CHU Montpellier, France.
    Giurgea, I.
    Hop Trousseau, France.
    Goldenberg, A.
    CHU Rouen, France; CHU Rouen, France; Univ Rouen, France.
    Gréen, Anna
    Region Östergötland, Center for Diagnostics, Clinical genetics. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Guerrot, A. M.
    CHU Rouen, France; Univ Rouen, France.
    Heron, D.
    Grp Hosp Pitie Salpetriere, France.
    Isidor, B.
    CHU Nantes, France.
    Keena, B. A.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Krock, B. L.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Kuentz, P.
    Univ Bourgogne, France.
    Lapi, E.
    Anna Meyer Childrens Univ Hosp, Italy.
    Le Meur, N.
    CHU Rouen, France; Univ Rouen, France.
    Lesca, G.
    Hosp Civils Lyon, France.
    Li, D.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Marey, I.
    Grp Hosp Pitie Salpetriere, France.
    Mignot, C.
    Grp Hosp Pitie Salpetriere, France.
    Nava, C.
    Grp Hosp Pitie Salpetriere, France.
    Nesbitt, A.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Nicolas, G.
    CHU Rouen, France; Univ Rouen, France.
    Roche-Lestienne, C.
    CHU Lille, France.
    Roscioli, T.
    Univ New South Wales, Australia.
    Satre, V.
    CHU Grenoble Alpes, Grenoble, France.
    Santani, A.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Stefanova, Margarita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Steinwall Larsen, S.
    Region Östergötland, Center for Diagnostics, Clinical genetics.
    Saugier-Veber, P.
    CHU Rouen, France; Univ Rouen, France.
    Picker-Minh, S.
    Charite Univ Med Berlin, Germany.
    Thuillier, C.
    CHU Lille, France.
    Verloes, A.
    Hop Robert Debre, France.
    Vieville, G.
    CHU Grenoble Alpes, France.
    Wenzel, M.
    Clinical Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.
    Willems, M.
    CHU Montpellier, France.
    Whalen, S.
    Grp Hosp Pitie Salpetriere, France.
    Zarate, Y. A.
    Univ Arkansas Med Sci, AR 72205 USA.
    Ziegler, A.
    CHU Angers, France.
    Manouvrier-Hanu, S.
    Univ Lille, France; CHU Lille, France.
    Kalscheuer, V. M.
    Max Planck Inst Mol Genet, Germany.
    Gerard, B.
    Hop Univ Strasbourg, France.
    Ghoumid, Jamal
    Univ Lille, France; CHU Lille, France.
    MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype2018In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 19, no 2, p. 93-103Article in journal (Refereed)
    Abstract [en]

    Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

  • 21.
    Tababi, Mouna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Hypoxia Signaling and Circadian Disruption in and by Pheochromocytoma2018In: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 9, article id 612Article, review/survey (Refereed)
    Abstract [en]

    Disruption of the daily (i.e., circadian) rhythms of cell metabolism, proliferation and blood perfusion is a hallmark of many cancer types, perhaps most clearly exemplified by the rare but detrimental pheochromocytomas. These tumors arise from genetic disruption of genes critical for hypoxia signaling, such as von Hippel-Lindau and hypoxia-inducible factor-2 or cellular metabolism, such as succinate dehydrogenase, which in turn impacts on the cellular circadian clock function by interfering with the Bmal1 and/or Clock transcription factors. While pheochromocytomas are often nonmalignant, the resulting changes in cellular physiology are coupled to de-regulated production of catecholamines, which in turn disrupt circadian blood pressure variation and therefore circadian entrainment of other tissues. In this review we thoroughly discuss the molecular and physiological interplay between hypoxia signaling and the circadian clock in pheochromocytoma, and how this underlies endocrine disruption leading to loss of circadian blood pressure variation in the affected patients. We furthermore discuss potential avenues for targeting these tumor-specific pathophysiological mechanisms therapeutically in the future.

  • 22.
    von Salome, Jenny
    et al.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Boonstra, Philip S.
    University of Michigan, MI 48109 USA.
    Karimi, Masoud
    Karolinska University Hospital, Sweden.
    Silander, Gustav
    Umeå University, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics. Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.
    Gebre-Medhin, Samuel
    Off Medical Serv, Sweden; Lund University, Sweden.
    Aravidis, Christos
    Uppsala University, Sweden.
    Nilbert, Mef
    Lund University, Sweden; University of Copenhagen, Denmark.
    Lindblom, Annika
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Lagerstedt-Robinson, Kristina
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Genetic anticipation in Swedish Lynch syndrome families2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 10, article id e1007012Article in journal (Refereed)
    Abstract [en]

    Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a large cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linkoping, Uppsala and Umea between the years 1990-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are smaller.

  • 23.
    Welander, Jenny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Lysiak, Malgorzata
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Brauckhoff, Michael
    Haukeland Hosp, Dept Surg, Norway; Univ Bergen, Dept Clin Sci, Norway.
    Brunaud, Laurent
    Department of Digestive, Hepato-Biliary and Endocrine Surgery, CHU Nancy - Hospital Brabois Adultes, University de Lorraine, France.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Activating FGFR1 mutations in sporadic pheochromocytoma2018In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 42, no 2, p. 482-489Article in journal (Refereed)
    Abstract [en]

    Pheochromocytomas are neuroendocrine tumors of the adrenal glands that cause hypertension. More than a third of the cases are associated with hereditary mutations in a growing list of susceptibility genes, some of which are also somatically altered in sporadic pheochromocytomas. However, for the majority of sporadic pheochromocytomas, a genetic explanation is still lacking. Here we investigated the genomic landscape of sporadic pheochromocytomas with whole-exome sequencing of 16 paired tumor and normal DNA samples, and discovered on average 33 non-silent somatic mutations per tumor. One of the recurrently mutated genes was FGFR1, encoding the fibroblast growth factor receptor 1, which was recently revealed as an oncogene in pilocytic astrocytoma and childhood glioblastoma. Including a subsequent analysis of a larger cohort, activating FGFR1  mutations were detected in three of 80 sporadic pheochromocytomas (3.8%). Gene expression microarray profiling showed that these tumors clustered with NF1- RET- and HRAS-mutated pheochromocytomas, indicating activation of the MAPK and PI3K-AKT signal transduction pathways. The results advance our biological understanding of pheochromocytoma and suggest that somatic FGFR1 activation is an important event in a subset of these tumors.

  • 24.
    Wågström, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Yamada, Naomi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Nilsdotter-Augustinsson, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Bengner, Malin
    Ryhov Cty Hosp, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Björkander, Jan Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Fc gamma-receptor polymorphisms associated with clinical symptoms in patients with immunoglobulin G subclass deficiency2018In: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 50, no 11-12, p. 853-858Article in journal (Refereed)
    Abstract [en]

    Background: Immunoglobulin G subclass deficiencies (IgGsd) are associated with recurrent respiratory tract infections. Immunoglobulin substitution therapy may be needed to prevent chronic lung tissue damage but tools for identifying the patients that will benefit from this treatment are still insufficient. Some Fc gamma R polymorphisms seem to predispose for an increased risk for infections. In this study we wanted to evaluate if the Fc gamma R-profile differs between individuals with IgGsd and a control population. Methods: Single nucleotide polymorphisms (SNPs) of Fc gamma RIIa, Fc gamma RIIIa and Fc gamma RIIc in 36 IgGsd patients and 192 controls with similar sex and geographical distribution were analyzed by TaqMan allelic discrimination assay or Sanger sequencing. Results: In the IgGsd-group, homozygous frequency for Fc gamma RIIa-R/R131 (low-binding capacity isoform) was higher (p = .03) as well as for non-classical Fc gamma RIIc-ORF (p = .03) and classical Fc gamma RIIc-ORF tended (p = .07) to be more common compared to the controls. There was no difference between the groups regarding Fc gamma RIIIa. Conclusion: The gene for classical Fc gamma RIIc-ORF tended to be more frequent in individuals with immunoglobulin G subclass deficiency and the genes for non-classical Fc gamma RIIc-ORF as well as low-binding capacity receptor Fc gamma RIIa-R/R131 were more frequent. Further studies on the Fc gamma R polymorphisms may pave way for identifying individuals that will benefit from immunoglobulin substitution.

  • 25.
    Zhao, Jin J.
    et al.
    Uppsala University, Sweden.
    Halvardson, Jonatan
    Uppsala University, Sweden.
    Zander, Cecilia S.
    Uppsala University, Sweden.
    Zaghlool, Ammar
    Uppsala University, Sweden.
    Georgii-Hemming, Patrik
    Uppsala University, Sweden; Karolinska Institute, Sweden.
    Mansson, Else
    Örebro University Hospital, Sweden.
    Brandberg, Göran
    Pediat Clin, Falun, Sweden.
    Savmarker, Helena E.
    Gävle Central Hospital, Sweden.
    Frykholm, Carina
    Uppsala University, Sweden.
    Kuchinskaya, Ekaterina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Thuresson, Ann-Charlotte
    Uppsala University, Sweden.
    Feuk, Lars
    Uppsala University, Sweden.
    Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability2018In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 177, no 1, p. 10-20Article in journal (Refereed)
    Abstract [en]

    Intellectual Disability (ID) is a clinically heterogeneous condition that affects 2-3% of population worldwide. In recent years, exome sequencing has been a successful strategy for studies of genetic causes of ID, providing a growing list of both candidate and validated ID genes. In this study, exome sequencing was performed on 28 ID patients in 27 patient-parent trios with the aim to identify de novo variants (DNVs) in known and novel ID associated genes. We report the identification of 25 DNVs out of which five were classified as pathogenic or likely pathogenic. Among these, a two base pair deletion was identified in the PUF60 gene, which is one of three genes in the critical region of the 8q24.3 microdeletion syndrome (Verheij syndrome). Our result adds to the growing evidence that PUF60 is responsible for the majority of the symptoms reported for carriers of a microdeletion across this region. We also report variants in several genes previously not associated with ID, including a de novo missense variant in NAA15. We highlight NAA15 as a novel candidate ID gene based on the vital role of NAA15 in the generation and differentiation of neurons in neonatal brain, the fact that the gene is highly intolerant to loss of function and coding variation, and previously reported DNVs in neurodevelopmental disorders.

1 - 25 of 25
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf