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  • 1. Dahlquist, Gisela
    et al.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Rudberg, S
    Urinary albumin excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy; a long-term follow-up study of childhood onset type-1 diabetic patients.2001In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 16, no 7, p. 1382-1386Article in journal (Refereed)
    Abstract [en]

    At a mean diabetes duration of 29 years the cumulative incidence of macroalbuminuria was 12%; however, another 20% had persistent microalbuminuria. A screening value of 24-h AER >15 mg/min was a strong predictor, whereas increased GFR was a weaker but significant predictor for micro and macroalbuminuria.

  • 2.
    Diamant, Ulla-Britt
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Jensen, Steen M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Winbo, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Vectorcardiographic recordings of the Q-T interval in a pediatric long Q-T syndrome population2013In: Pediatric Cardiology, ISSN 0172-0643, E-ISSN 1432-1971, Vol. 34, no 2, p. 245-249Article in journal (Refereed)
    Abstract [en]

    Measurements of the Q-T interval are less reliable in children than in adults. Identification of superior diagnostic tools is warranted. This study aimed to investigate whether a vectorcardiogram (VCG) recorded from three orthogonal leads (X, Y, Z) according to Frank is superior to a 12-lead electrocardiogram (ECG) in providing a correct long Q-T syndrome (LQTS) diagnosis in children. This LQTS group consisted of 35 genetically confirmed carriers of mutations in the KCNQ1 (n = 29) and KCNH2 (n = 6) genes. The control group consisted of 35 age- and gender-matched healthy children. The mean age was 7 years in the LQTS group and 6.7 years in the control group (range, 0.5-16 years). The corrected Q-T interval (QT(c)) was measured manually (QT(man)) by one author (A.W.). The 12-lead ECG automatic measurements (QT(ECG)) and interpretation (QT(Interpret)) of QT(c) were performed with the Mac5000 (GE Medical System), and the VCG automatic measurements (QT(VCG)) were performed with the Mida1000, CoroNet (Ortivus AB, Sweden). By either method, a QT(c) longer than 440 ms was considered prolonged and indicative of LQTS. Of the 35 children with genetically confirmed LQTS, 30 (86 %) received a correct diagnosis using QT(VCG), 29 (82 %) using QT(man), 24 (69 %) using QT(ECG), and 17 (49 %) using QT(Interpret). Specificity was 0.80 for QT(VCG), 0.83 for QT(man), 0.77 for QT(ECG), and 0.83 for QT(Interpret). The VCG automatic measurement of QT(c) seems to be a better predictor of LQTS than automatic measurement and interpretation of 12-lead ECG.

  • 3.
    Diamant, Ulla-Britt
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Vahedi, Farzad
    Sahlgrenska Akademin Göteborgs Universitet.
    Winbo, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Jensen, Steen M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Bergfeldt, Lennart
    Sahlgrenska Akademin Göteborgs Universitet.
    Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene2013In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 115, no 10, p. 1423-1432Article in journal (Refereed)
    Abstract [en]

    Long QT syndrome is the prototypical disorder of ventricular repolarization (VR), and a genotype-phenotype relation is postulated. Furthermore, although increased VR heterogeneity (dispersion) may be important in the arrhythmogenicity in long QT syndrome, this hypothesis has not been evaluated in humans and cannot be tested by conventional electrocardiography. In contrast, vectorcardiography allows assessment of VR heterogeneity and is more sensitive to VR alterations than electrocardiography. Therefore, vectorcardiography was used to compare the electrophysiological phenotypes of two mutations in the LQT1 gene with different in vitro biophysical properties, and with LQT2 mutation carriers and healthy control subjects. We included 99 LQT1 gene mutation carriers (57 Y111C, 42 R518X) and 19 LQT2 gene mutation carriers. Potassium channel function is in vitro most severely impaired in Y111C. The control group consisted of 121 healthy subjects. QRS, QT, and T-peak to T-end (Tp-e) intervals, measures of the QRS vector and T vector and their relationship, and T-loop morphology parameters were compared at rest. Apart from a longer heart rate-corrected QT interval (QT heart rate corrected according to Bazett) in Y111C mutation carriers, there were no significant differences between the two LQT1 mutations. No signs of increased VR heterogeneity were observed among the LQT1 and LQT2 mutation carriers. QT heart rate corrected according to Bazett and Tp-e were longer, and the Tp-e-to-QT ratio greater in LQT2 than in LQT1 and the control group. In conclusion, there was a marked discrepancy between in vitro potassium channel function and in vivo electrophysiological properties in these two LQT1 mutations. Together with previous observations of the relatively low risk for clinical events in Y111C mutation carriers, our results indicate need for cautiousness in predicting in vivo electrophysiological properties and the propensity for clinical events based on in vitro assessment of ion channel function alone.

  • 4.
    Diamant, Ulla-Britt
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Winbo, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Kesek, Milos
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jensen, Steen M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Two automatic QT algorithms compared with manual measurement in identification of long QT syndrome2010In: Journal of Electrocardiology, ISSN 0022-0736, E-ISSN 1532-8430, Vol. 43, no 1, p. 25-30Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Long QT syndrome (LQTS) is an inherited disorder that increases the risk of syncope and malignant ventricular arrhythmias, which may result in sudden death.

    METHODS: We compared manual measurement by 4 observers (QT(manual)) and 3 computerized measurements for QT interval accuracy in the diagnosis of LQTS: 1. QT measured from the vector magnitude calculated from the 3 averaged orthogonal leads X, Y, and Z (QTVCG) and classified using the same predefined QTc cut-points for classification of QT prolongation as in manual measurements; 2. QT measured by a 12-lead electrocardiogram (ECG) program (QTECG) and subsequently classified using the same cut-points as in (1) above; 3. The same QT value as in (2) above, automatically classified by a 12-lead ECG program with thresholds for QT prolongation adjusted for age and sex (QTinterpret). The population consisted of 94 genetically confirmed carriers of KCNQ1 (LQT1) and KCNH2 (LQT2) mutations and a combined control group of 28 genetically confirmed noncarriers and 66 unrelated healthy volunteers.

    RESULTS: QT(VCG) provided the best combination of sensitivity (89%) and specificity (90%) in diagnosing LQTS, with 0.948 as the area under the receiver operating characteristic curve. The evaluation of QT measurement by the 4 observers revealed a high interreader variability, and only 1 of 4 observers showed acceptable level of agreement in LQTS mutation carrier identification (kappa coefficient >0.75).

    CONCLUSION: Automatic QT measurement by the Mida1000/CoroNet system (Ortivus AB, Danderyd, Sweden) is an accurate, efficient, and easily applied method for initial screening for LQTS.

  • 5.
    Entesarian, Miriam
    et al.
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Carlsson, Birgit
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Mansouri, Mahmoud Reza
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Eva
    Department of Clinical Genetics, Sahlgrenska University Hospital/East, Gothenburg, Sweden.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Stefansson, Hreinn
    CNS Division, deCODE Genetics, Reykjavik, Iceland.
    Klar, Joakim
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Dahl, Niklas
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent and frequent in the Swedish population2009In: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 149A, no 3, p. 380-386Article in journal (Refereed)
    Abstract [en]

    We identified a paracentric inversion of chromosome 10 [inv(10)(q11.22q21.1)] in 0.20% of Swedish individuals (15/7,439) referred for cytogenetic analysis. A retrospective analysis of 8,896 karyotypes from amniocenteses in Sweden revealed a carrier frequency of 0.079% (7/8,896) for the inversion. Cloning and detailed analysis of the inversion breakpoint regions show enrichment for interspersed repeat elements and AT-stretches. The centromeric breakpoint coincides with that of a predicted inversion from HapMap data, which suggests that this region is involved in several chromosome 10 variants. No known gene or predicted transcript are disrupted by the inversion which spans approximately 12 Mb. Carriers from four non-related Swedish families have identical inversion breakpoints and haplotype analysis confirmed that the rearrangement is identical by descent. Diagnosis was retrieved in 6 out of the 15 carriers referred for cytogenetic analysis. No consistent phenotype was found to be associated with the inversion. Our study demonstrates that the inv(10)(q11.22q21.1) is a rare and inherited chromosome variant with a broad geographical distribution in Sweden.

  • 6.
    Hannuksela, Matias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Screening for familial thoracic aortic aneurysms with aortic imaging does not detect all potential aarriers of the disease2015In: Aorta, ISSN 2325-4637, Vol. 3, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Background: About 20% of patients with thoracic aortic aneurysm or dissection (TAAD) have a first-degree relative with a similar disease. The familial form (FTAAD) of the disease is inherited in an autosomal-dominant pattern. Current guidelines for thoracic aortic disease recommend screening of first-degree relatives of TAAD patients. In known familial disease, screening of both first- and second-degree relatives is recommended. However, the outcomes of such a screening program are unknown.

    Methods: We screened all first- and second-degree relatives in seven families with known FTAAD with echo- cardiography. No underlying gene defect had been detected in these families.

    Results: Of 119 persons investigated, 13 had known thoracic aortic disease. In the remaining 106 cases, we diagnosed 19 additional individuals with a dilated ascending thoracic aorta; for an autosomal-dominant disease, the expected number of individuals in this group would have been 40 (p<0.0001). Further, only one of the 20 first-degree relatives younger than 40 years had a dilated aorta, although the expected number of individuals with a disease-causing mutation would have been 10.

    Conclusions: In most families with TAAD, a diagnosis still relies on measuring the diameter of the thoracic aorta. We show that a substantial number of previously unknown cases of aortic dilatation can be identified by screening family members. It is, however, not possible to consider anyone free of the condition, even if the aortic diameter is normal, especially at a younger age.

  • 7.
    Hannuksela, Matias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Klar, Joakim
    Ameur, Adam
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Sorensen, Karen
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    A novel variant in MYLK causes thoracic aortic dissections: genotypic and phenotypic description2016In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 17, article id 61Article in journal (Refereed)
    Abstract [en]

    Background: Mutations in MYLK cause non- syndromic familial thoracic aortic aneurysms and dissections (FTAAD). Very little is known about the phenotype of affected families. We sought to characterize the aortic disease and the presence of other vascular abnormalities in FTAAD caused by a deletion in MYLK and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers.

    Methods: We studied FTAAD in a 5-generation family that included 19 living members. Exome sequencing was performed to identify the underlying gene defect. Aortic elastic properties measured by TTE, MRI and pulse wave velocity were then compared between mutation carriers and non-carriers.

    Results: Exome sequencing led to the identification of a 2-bp deletion in MYLK (c3272_ 3273del, p. Ser1091*) that led to a premature stop codon and nonsense-mediated decay. Eleven people were mutation carriers and eight people were non-carriers. Five aortic ruptures or dissections occurred in this family, with two survivors. There were no differences in aortic diameter or stiffness between carriers and non-carriers of the mutation.

    Conclusions: Individuals carrying this deletion in MYLK have a high risk of presenting with an acute aortic dissection or rupture. Aortic events occur over a wide range of ages and are not always preceded by obvious aortic dilatation. Aortic elastic properties do not differ between carriers and non-carriers of this mutation, rendering it uncertain whether and when carriers should undergo elective prophylactic surgery.

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  • 8.
    Hannuksela, Matias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nyberg, Peter
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Familära torakala aortaaneurysm och dissektioner: flera former finns2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 9-10, p. 399-403Article in journal (Refereed)
    Abstract [en]

    Thoracic aortic aneurysms and dissections (TAAD) can be divided into three different main categories. 1. Inherited syndromes predisposing to TAAD such as Marfan syndrome, Ehlers-Danlos syndrome type IV and Loeys-Dietz syndrome (less than 5% of all TAAD). 2. Familial TAAD (FTAAD) with more than one affected family member (20 % of all TAAD). Inheritance shows an autosomal dominant pattern and there are no features of known syndromes. 3. Sporadic forms of TAAD with no family history or features of syndromic forms. FTAAD present earlier in life and dissections occur in smaller diameter than in sporadic cases. The underlying genetic cause can be found in about 20 % of the inherited cases. The pathogenesis seems to be an involvement of the transforming growth factor β (TGFβ) signaling pathway or a dysfunction of the smooth muscle cell contraction. The role of β-blockers for aneurysm prevention is uncertain and there are on-going studies comparing angiotensin receptor blockers and β-blockers.

  • 9. Hilton, Emma N
    et al.
    Manson, Forbes D C
    Urquhart, Jill E
    Johnston, Jennifer J
    Slavotinek, Anne M
    Hedera, Peter
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nordgren, Ann
    Biesecker, Leslie G
    Black, Graeme C M
    Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination.2007In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 16, no 14, p. 1773-1782Article in journal (Refereed)
    Abstract [en]

    Oculofaciocardiodental (OFCD) syndrome is an X-linked male lethal condition encompassing cardiac septal defects, as well as ocular and dental anomalies. The gene mutated in OFCD syndrome, the BCL-6 corepressor (BCOR), is part of a transcriptional repression complex whose transcriptional targets remain largely unknown. We reviewed cases of OFCD syndrome and identified patients exhibiting defective lateralization including dextrocardia, asplenia and intestinal malrotation, suggesting that BCOR is required in normal laterality determination. To study the function of BCOR, we used morpholino oligonucleotides (MOs) to knockdown expression of xtBcor in Xenopus tropicalis, thus creating an animal model for OFCD syndrome. The resulting tadpoles had cardiac and ocular features characteristic of OFCD syndrome. Reversed cardiac orientation and disorganized gut patterning were seen when MOs were injected into the left side of embryos, demonstrating a left-sided requirement for xtBcor in lateral determination in Xenopus. Ocular defects displayed no left-right bias and included anterior and posterior segment disorders such as microphthalmia and coloboma. Expression of xtPitx2c was shown to be downregulated when xtBcor was depleted. This identifies a pathway in which xtBcor is required for lateral specification, a process intrinsically linked to correct cardiac septal development.

  • 10. Hooper, Sean D.
    et al.
    Johansson, Anna C. V.
    Tellgren-Roth, Christian
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Dahl, Niklas
    Cavelier, Lucia
    Feuk, Lars
    Genome-wide sequencing for the identification of rearrangements associated with Tourette syndrome and obsessive-compulsive disorder2012In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 13, p. 123-Article in journal (Refereed)
    Abstract [en]

    Background: Tourette Syndrome (TS) is a neuropsychiatric disorder in children characterized by motor and verbal tics. Although several genes have been suggested in the etiology of TS, the genetic mechanisms remain poorly understood. Methods: Using cytogenetics and FISH analysis, we identified an apparently balanced t(6,22)(q16.2;p13) in a male patient with TS and obsessive-compulsive disorder (OCD). In order to map the breakpoints and to identify additional submicroscopic rearrangements, we performed whole genome mate-pair sequencing and CGH-array analysis on DNA from the proband. Results: Sequence and CGH array analysis revealed a 400 kb deletion located 1.3 Mb telomeric of the chromosome 6q breakpoint, which has not been reported in controls. The deletion affects three genes (GPR63, NDUFA4 and KLHL32) and overlaps a region previously found deleted in a girl with autistic features and speech delay. The proband's mother, also a carrier of the translocation, was diagnosed with OCD and shares the deletion. We also describe a further potentially related rearrangement which, while unmapped in Homo sapiens, was consistent with the chimpanzee genome. Conclusions: We conclude that genome-wide sequencing at relatively low resolution can be used for the identification of submicroscopic rearrangements. We also show that large rearrangements may escape detection using standard analysis of whole genome sequencing data. Our findings further provide a candidate region for TS and OCD on chromosome 6q16.

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  • 11.
    Jensen, Steen
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Stattin, Eva-lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    [Long QT syndrome can be effectively treated. Important to identify mutation carriers]2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 104, no 40, p. 2866-2870Article in journal (Refereed)
  • 12. Lombardi, Maria Paola
    et al.
    Bulk, Saskia
    Celli, Jacopo
    Lampe, Anne
    Gabbett, Michael T
    Ousager, Lillian Bomme
    van der Smagt, Jasper J
    Soller, Maria
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mannens, Marcel A M M
    Smigiel, Robert
    Hennekam, Raoul C
    Mutation update for the PORCN gene2011In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 32, no 7, p. 723-728Article in journal (Refereed)
    Abstract [en]

    Mutations in the PORCN gene were first identified in Goltz-Gorlin syndrome patients in 2007. Since then, several reports have been published describing a large variety of genetic defects resulting in the Goltz-Gorlin syndrome, and mutations or deletions were also reported in angioma serpiginosum, the pentalogy of Cantrell and Limb-Body Wall Complex. Here we present a review of the published mutations in the PORCN gene to date and report on seven new mutations together with the corresponding clinical data. Based on the review we have created a Web-based locus-specific database that lists all identified variants and allows the inclusion of future reports. The database is based on the Leiden Open (source) Variation Database (LOVD) software, and is accessible online at http://www.lovd.nl/porcn. At present, the database contains 106 variants, representing 68 different mutations, scattered along the whole coding sequence of the PORCN gene, and 12 large gene rearrangements, which brings up to 80 the number of unique mutations identified in Goltz-Gorlin syndrome patients.

  • 13. Mansouri, Mahmoud Reza
    et al.
    Schuster, Jens
    Badhai, Jitendra
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lösel, Ralf
    Wehling, Martin
    Carlsson, Birgit
    Hovatta, Outi
    Karlström, Per Olof
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Toniolo, Daniela
    Bione, Silvia
    Peluso, John
    Dahl, Niklas
    Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure.2008In: Human molecular genetics, ISSN 1460-2083, Vol. 17, no 23, p. 3776-3783Article in journal (Refereed)
    Abstract [en]

    Premature ovarian failure (POF) is characterized by hypergonadotropic hypogonadism and amenorrhea before the age of 40. The condition has a heterogeneous background but genetic factors are demonstrated by the occurrence of familial cases. We identified a mother and daughter with POF both of whom carry an X;autosome translocation [t(X;11)(q24;q13)]. RNA expression studies of genes flanking the X-chromosome breakpoint revealed that both patients have reduced expression levels of the gene Progesterone Receptor Membrane Component-1 (PGRMC1). Mutation screening of 67 females with idiopathic POF identified a third patient with a missense mutation (H165R) located in the cytochrome b5 domain of PGRMC1. PGRMC1 mediates the anti-apoptotic action of progesterone in ovarian cells and it acts as a positive regulator of several cytochrome P450 (CYP)-catalyzed reactions. The CYPs are critical for intracellular sterol metabolism, including biosynthesis of steroid hormones. We show that the H165R mutation associated with POF abolishes the binding of cytochrome P450 7A1 (CYP7A1) to PGRMC1. In addition, the missense mutation attenuates PGRMC1's ability to mediate the anti-apoptotic action of progesterone in ovarian cells. These findings suggest that mutant or reduced levels of PGMRC1 may cause POF through impaired activation of the microsomal cytochrome P450 and increased apoptosis of ovarian cells.

  • 14.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Rudberg, Susanne
    Higher intakes of fish protein are related to a lower risk of microalbuminuria in young Swedish type 1 diabetic patients.2001In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 24, no 5, p. 805-810Article in journal (Refereed)
  • 15. Renard, Marjolijn
    et al.
    Callewaert, Bert
    Baetens, Machteld
    Campens, Laurence
    MacDermot, Kay
    Fryns, Jean-Pierre
    Bonduelle, Maryse
    Dietz, Harry C.
    Gaspar, Isabel Mendes
    Cavaco, Diogo
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Schrander-Stumpel, Constance
    Coucke, Paul
    Loeys, Bart
    De Paepe, Anne
    De Backer, Julie
    Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGF beta signaling in FTAAD2013In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 165, no 2, p. 314-321Article in journal (Refereed)
    Abstract [en]

    Background: Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGF beta) signaling (TGF beta receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK).

    Methods and result: In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGF beta signaling pathway.

    Conclusions: MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16% of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGF beta signaling.

    (C) 2011 Elsevier Ireland Ltd. All rights reserved.

  • 16. Rudberg, S
    et al.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Dahlquist, G
    Familial and perinatal risk factors for micro- and macroalbuminuria in young IDDM patients.1998In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 47, no 7, p. 1121-1126Article in journal (Refereed)
    Abstract [en]

    It has been suggested that hereditary risk for hypertension and cardiovascular disease (CVD) as well as intrauterine growth may be involved in the pathogenesis of diabetic nephropathy. In the present study, we investigated the influence of familial and perinatal risk factors on the occurrence of micro- and macroalbuminuria in young IDDM patients. A cohort of 1,150 young patients with > or =5 years' duration of IDDM was screened for microalbuminuria. Data on family history of hypertension, CVD, IDDM, and NIDDM; perinatal factors such as birth weight, gestational age, and duration of breastfeeding; and maternal education, smoking, hypertension, and proteinuria during pregnancy were collected. We identified 75 patients with an albumin excretion rate > or =15 microg/min in more than two overnight urinary samples and compared them in a nested case-control study with three normoalbuminuric control subjects per patient from the same cohort, matched for diabetes duration. Perinatal factors were analyzed in all patients born at term (+/- 2 weeks), 59 of the 75 patients and 155 of the 225 control subjects. In univariate analysis, hypertension in parents (odds ratio [OR] 4.21), CVD in parents and grandparents (OR 1.26), maternal smoking during pregnancy (OR 3.21), and a low level of maternal education (OR 2.33) were significantly associated with the development of micro- and macroalbuminuria. When adjusted for other familial and perinatal factors, current mean blood pressure, HbA1c, smoking, BMI, sex, age, and postpubertal diabetes duration, using logistic regression analyses, only parental hypertension in all patients and maternal smoking during pregnancy and low level of maternal education in full-term patients were independent risk factors. When patients with poor glycemic control were analyzed separately, familial CVD, poor metabolic control, parental hypertension, maternal smoking during pregnancy, and level of maternal education were independent risk factors, with the adjusted OR markedly increased, compared with the matched subgroup with better HbA1c. In conclusion, familial hypertension and CVD, maternal smoking during pregnancy, and low level of maternal education may independently increase the risk for incipient nephropathy in full-term offspring who later develop IDDM. Current poor glycemic control seemed to increase the effect of these risk factors.

  • 17.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Boström, Ida Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Winbo, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Cederquist, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonsson, Björn-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Diamant, Ulla-Britt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Jensen, Steen M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Norberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing2012In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 12, p. 95-Article in journal (Refereed)
    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.

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  • 18.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Henning, Petra
    Klar, Joakim
    McDermott, Emma
    Stecksen-Blicks, Christina
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sandström, Per-Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Kellgren, Therese G
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Lönnerholm, Torsten
    Ameur, Adam
    Helfrich, Miep H
    Coxon, Fraser P
    Dahl, Niklas
    Wikström, Johan
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology. Centre for Bone and Arthritis Research, Department of internal medicine and clinical nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 3012Article in journal (Refereed)
    Abstract [en]

    Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Västerbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro.

  • 19.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Linden, Bjarne
    Department of Orthopedic Surgery, Höglands Hospital, Eksjö, Sweden.
    Lönnerholm, Torsten
    Department of Radiology, Uppsala University, Uppsala, Sweden.
    Schuster, Jens
    Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden..
    Dahl, Niklas
    Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden..
    Brachydactyly type A1 associated with unusual radiological findings and a novel mutation in the Indian Hedgehog (IHH) geneManuscript (Other academic)
  • 20.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindén, Bjarne
    Department of Orthopedic Surgery, Höglands Hospital, Eksjö, Sweden.
    Lönnerholm, Torsten
    Department of Radiology, Uppsala University, Uppsala, Sweden.
    Schuster, Jens
    Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Dahl, Niklas
    Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Brachydactyly type A1 associated with unusual radiological findings and a novel Arg158Cys mutation in the Indian hedgehog (IHH) gene2009In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 52, no 5, p. 297-302Article in journal (Refereed)
    Abstract [en]

    Brachydactyly type A1 (BDA1; MIM 112500) is characterized by shortness or absence of the middle phalanx of the hands and feet. The condition is caused by heterozygous mutations in the Indian hedgehog (IHH) gene or a yet unidentified gene on chromosome 5p13. We investigated six affected members of a large Swedish family segregating autosomal dominant brachymesophalangia. Affected individuals show hypoplasia of the ulnar styloid processes, ulna minus, osteoarthritis, normal length of all distal phalanges and shortening or absence of the middle phalanges. Stationary ossicles or sesamoid bones were observed at the metacarpal heads in all patients. Genetic analysis of the family showed that the IHH-gene was linked to the disease (Z(max) 3.42 at theta 0.00) and sequence analysis of IHH revealed a novel c.472C > T transition in all affected family members. The mutation results in a p.158Arg > Cys substitution located in the highly conserved amino-terminal domain of IHH. This domain is of importance for the interaction between IHH and the Patched receptor. Our combined findings add radiological findings to the BDA1 phenotype and confirm a critical functional domain of IHH.

  • 21.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Rydberg, Annika
    Jensen, Steen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    [Genetic testing for long QT syndrome is used in clinical practice]2006In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 103, no 45, p. 3542-Article in journal (Refereed)
  • 22.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Tegner, Yelverton
    Department of Health Sciences, Luleå Technical University, Sweden.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Dahl, Niklas
    Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Sweden..
    Familial osteochondritis dissecans associated with early osteoarthritis and disproportionate short stature2008In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 16, no 8, p. 890-896Article in journal (Refereed)
    Abstract [en]

    Objective: Familial osteochondritis dissecans (OCD) is a rare disorder characterised by disturbed chondro-skeletal development, disproportionate growth and deformation of the skeleton.

    Design: We identified a five-generation family with 15 living affected members from Northern Sweden. The disorder was diagnosed with a case definition of OCD in at least one joint.

    Results: Main clinical findings consisted of OCD in knees and/or hips and/or elbows, disproportionate short stature and early osteoarthritis (OA). There were no radiological indications of epiphyseal dysplasia. Anthropometric measurements of affected individuals showed short stature, a high ratio between sitting height and total height, a relatively normal arm span and head circumference. In 12 of 15 cases, onset was during late childhood or adolescence and OA had developed in seven of those patients.

    Conclusions: Our observation suggests that OA is a frequent complication in familial OCD even though the lesions appear before closure of physis.

  • 23.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Westin, Ida Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Cederquist, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonsson, Björn-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Norberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Krantz, Peter
    Wisten, Aase
    Genetic screening in sudden cardiac death in the young can save future lives2016In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 130, no 1, p. 59-66Article in journal (Refereed)
    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.

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  • 24.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Wiklund, Fredrik
    Lindblom, Karin
    Onnerfjord, Patrik
    Jonsson, Björn-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tegner, Yelverton
    Sasaki, Takako
    Struglics, André
    Lohmander, Stefan
    Dahl, Niklas
    Heinegård, Dick
    Aspberg, Anders
    A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans2010In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 86, no 2, p. 126-137Article in journal (Refereed)
    Abstract [en]

    Osteochondritis dissecans is a disorder in which fragments of articular cartilage and subchondral bone dislodge from the joint surface. We analyzed a five-generation family in which affected members had autosomal-dominant familial osteochondritis dissecans. A genome-wide linkage analysis identified aggrecan (ACAN) as a prime candidate gene for the disorder. Sequence analysis of ACAN revealed heterozygosity for a missense mutation (c.6907G > A) in affected individuals, resulting in a p.V2303M amino acid substitution in the aggrecan G3 domain C-type lectin, which mediates interactions with other proteins in the cartilage extracellular matrix. Binding studies with recombinant mutated and wild-type G3 proteins showed loss of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M protein. Mass spectrometric analyses of aggrecan purified from patient cartilage verified that V2303M aggrecan is produced and present in the tissue. Our results provide a molecular mechanism for the etiology of familial osteochondritis dissecans and show the importance of the aggrecan C-type lectin interactions for cartilage function in vivo.

  • 25. Sukalo, Maja
    et al.
    Fiedler, Ariane
    Guzman, Celina
    Spranger, Stephanie
    Addor, Marie-Claude
    Mcheik, Jiad N.
    Benavent, Manuel Oltra
    Cobben, Jan M.
    Gillis, Lynette A.
    Shealy, Amy G.
    Deshpande, Charu
    Bozorgmehr, Bita
    Everman, David B.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Liebelt, Jan
    Keller, Klaus-Michael
    Bertola, Debora Romeo
    van Karnebeek, Clara D. M.
    Bergmann, Carsten
    Liu, Zhifeng
    Dueker, Gesche
    Rezaei, Nima
    Alkuraya, Fowzan S.
    Ogur, Gonul
    Alrajoudi, Abdullah
    Venegas-Vega, Carlos A.
    Verbeek, Nienke E.
    Richmond, Erick J.
    Kirbiyik, Ozgur
    Ranganath, Prajnya
    Singh, Ankur
    Godbole, Koumudi
    Ali, Fouad A. M.
    Alves, Cresio
    Mayerle, Julia
    Lerch, Markus M.
    Witt, Heiko
    Zenker, Martin
    Mutations in the Human UBR1 Gene and the Associated Phenotypic Spectrum2014In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 35, no 5, p. 521-531Article in journal (Refereed)
    Abstract [en]

    Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n=29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.

  • 26.
    Timby, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Kristiansen, Ingela
    Pediatric Clinic, Östersund Hospital, Sweden.
    Eriksson, Urban
    Pediatric Clinic, Östersund Hospital, Sweden.
    Erikson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Early onset autosomal dominant spinocerebellar ataxia with miosis: Four cases2008In: European journal of paediatric neurology, ISSN 1090-3798, E-ISSN 1532-2130, Vol. 12, no 1, p. 38-40Article in journal (Other academic)
    Abstract [en]

    Previously, at least 29 different forms of autosomal dominant spinocerebellar ataxias (SCAs) have been described. We describe a family with four members through three generations with autosomal dominant ataxia in combination with miosis and hyperreflexia. This family's ataxia does not match any of the previously described SCAs and is probably a novel form of SCA. To continue with the search for the genetic background of this disease, more cases are needed.

  • 27. Wang, Zheng
    et al.
    Iida, Aritoshi
    Miyake, Noriko
    Nishiguchi, Koji M.
    Fujita, Kosuke
    Nakazawa, Toru
    Alswaid, Abdulrahman
    Albalwi, Mohammed A.
    Kim, Ok-Hwa
    Cho, Tae-Joon
    Lim, Gye-Yeon
    Isidor, Bertrand
    David, Albert
    Rustad, Cecilie F.
    Merckoll, Else
    Westvik, Jostein
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Grigelioniene, Giedre
    Kou, Ikuyo
    Nakajima, Masahiro
    Ohashi, Hirohumi
    Smithson, Sarah
    Matsumoto, Naomichi
    Nishimura, Gen
    Ikegawa, Shiro
    Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0150555Article in journal (Refereed)
    Abstract [en]

    Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point) mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.

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  • 28. Wentzel, C
    et al.
    Lynch, SA
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Sharkey, FH
    Annerén, G
    Thuresson, A-C
    Interstitial deletions at 6q14.1-q15 associated with obesity, developmental delay and a distinct clinical phenotype2010In: Molecular syndromology, ISSN 1661-8777, Vol. 1, no 2, p. 75-81Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Interstitial deletions of the long arm of chromosome 6 have been described in several patients with obesity and a Prader-Willi-like phenotype. Haploinsufficiency of the SIM1 gene located at 6q16.3 is suggested as being responsible for the regulation of body weight. Here we report on 2 patients with interstitial deletions at 6q14.1-q15 presenting with obesity and symptoms strikingly similar to those reported for deletions involving the SIM1 gene despite not having a deletion of this gene.

    METHODS: Array comparative genomic hybridisation was used to diagnose 2 children with obesity and developmental delay, revealing 2 interstitial deletions at 6q14.1-q15 of 8.73 and 4.50 Mb, respectively, and a region of overlap of 4.2-Mb.

    RESULTS: The similar phenotype in the 2 patients was most likely due to a 4.2-Mb common microdeletion at 6q14.1-q15. Another patient has previously been described with an overlapping deletion. The 3 patients share several features, such as developmental delay, obesity, hernia, rounded face with full cheeks, epicanthal folds, short palpebral fissures, bulbous nose, large ears, and syndactyly between toes II and III.

    CONCLUSIONS: Together with a previously reported patient, our study suggests that the detected deletions may represent a novel clinically recognisable microdeletion syndrome caused by haploinsufficiency of dosage-sensitive genes in the 6q14.1-q15 region.

  • 29. Wentzel, Christian
    et al.
    Rajcan-Separovic, Evica
    Ruivenkamp, Claudia A L
    Chantot-Bastaraud, Sandra
    Metay, Corinne
    Andrieux, Joris
    Annerén, Göran
    Gijsbers, Antoinet C J
    Druart, Luc
    Hyon, Capucine
    Portnoi, Marie-France
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Vincent-Delorme, Catherine
    Kant, Sarina G
    Steinraths, Michelle
    Marlin, Sandrine
    Giurgea, Irina
    Thuresson, Ann-Charlotte
    Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p112011In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, no 9, p. 959-964Article in journal (Refereed)
    Abstract [en]

    With the clinical implementation of genomic microarrays, the detection of cryptic unbalanced rearrangements in patients with syndromic developmental delay has improved considerably. Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 to 10.6 Mb. The smallest region of overlap is 306 kb, which includes WAC gene, known to be associated with microtubule function and to have a role in cell division. Another patient has previously been described with a 10 Mb deletion, partially overlapping with our six patients. All seven patients have developmental delay and a majority of the patients have abnormal behaviour and dysmorphic features, including bulbous nasal tip, deep set eyes, synophrys/thick eyebrows and full cheeks, whereas other features varied. All patients also displayed various visual impairments and six out of seven patients had cardiac malformations. Taken together with the previously reported patient, our study suggests that the detected deletions may represent a new contiguous gene syndrome caused by dosage-sensitive genes that predispose to developmental delay.

  • 30.
    Winbo, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Diamant, Ulla-Britt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Persson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jensen, Steen M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Origin of the Swedish long QT syndrome Y111C/KCNQ1 founder mutation2011In: Heart Rhythm, ISSN 1547-5271, E-ISSN 1556-3871, Vol. 8, no 4, p. 541-547Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The Y111C/KCNQ1 mutation causes a dominant-negative effect in vitro albeit a benign clinical phenotype in a Swedish Long QT Syndrome population.

    OBJECTIVE: To investigate the origin (genealogic, geographic, genetic and age) of the Y111C/KCNQ1 mutation in Sweden.

    METHODS: We identified 170 carriers of the Y111C/KCNQ1 mutation in 37 Swedish proband families. Genealogical investigation was performed in all families. Haplotype analysis was performed in 26 probands, 21 family members and 84 healthy Swedish controls, using 15 satellite markers flanking the KCNQ1 gene. Mutation age was estimated using the ESTIAGE and DMLE computer softwares and regional population demographics data.

    RESULTS: All probands were traced back to a northern river valley region. A founder couple born in 1605/1614 connected 26/37 families. Haplotyped probands shared 2-14 (median 10) uncommon alleles, with frequencies ranging between 0.01-0.41 (median 0.16) in the controls. The age of the mutation was estimated to 24 generations (95% CI 18; 34), i.e. 600 years (95% CI 450; 850) if assuming 25 years per generation. The number of now living Swedish Y111C mutation-carriers was estimated to ~200-400 individuals for the mutation age span 22-24 generations and population growth rates 25-27%.

    CONCLUSIONS: The Y111C/KCNQ1 mutation is a Swedish LQTS founder mutation, introduced in the northern population approximately 600 years ago. The enrichment of the mutation was enabled by a mild clinical phenotype and strong regional founder effects during the population development of the northern inland. The Y111C/KCNQ1 founder population constitutes an important asset for future genetic and clinical studies.

  • 31.
    Winbo, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Diamant, Ulla-Britt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Jensen, Steen M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Low incidence of sudden cardiac death in a Swedish Y111C type 1 long-QT syndrome population2009In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 2, no 6, p. 558-564Article in journal (Refereed)
    Abstract [en]

    Background: A 10% cumulative incidence and a 0.3% per year incidence rate of sudden cardiac death in patients younger than 40 years and without therapy have been reported in type 1 long-QT syndrome. The Y111C-KCNQ1 mutation causes a severe phenotype in vitro, suggesting a high-risk mutation. This study investigated the phenotype among Y111C-KCNQ1 mutation carriers in the Swedish population with a focus on life-threatening cardiac events.

    Methods and Results: We identified 80 mutation carriers in 15 index families, segregating the Y111C-KCNQ1 mutation during a national inventory of mutations causing the long-QT syndrome. Twenty-four mutation carriers <40 years experienced syncope (30%). One mutation carrier had an aborted cardiac arrest (1.25%). No case of sudden cardiac death was reported during a mean nonmedicated follow-up of 25±20 years. This corresponds to a low incidence rate of life-threatening cardiac events (0.05%/year versus 0.3%/year, P=0.025). In 8 Y111C families connected by a common ancestor, the natural history of the mutation was assessed by investigating the survival over the age of 40 years for 107 nonmedicated ascertained mutation carriers (n=24) and family members (n=83) born between 1873 and 1968. In total, 4 deaths in individuals younger than 40 years were noted: 1 case of noncardiac death and 3 infant deaths between 1873 and 1915.

    Conclusions: The dominant-negative Y111C-KCNQ1 mutation, associated with a severe phenotype in vitro, presents with a low incidence of life-threatening cardiac events in a Swedish population. This finding of discrepancy emphasizes the importance of clinical observations in the risk stratification of long-QT syndrome.

  • 32.
    Winbo, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Diamant, Ulla-Britt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Persson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jensen, Steen M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Prevalence, mutation spectrum, and cardiac phenotype of the Jervell and Lange-Nielsen syndrome in Sweden2012In: Europace, ISSN 1099-5129, E-ISSN 1532-2092, Vol. 14, no 12, p. 1799-1806Article in journal (Refereed)
    Abstract [en]

    AIMS: To explore the national prevalence, mutation spectrum, cardiac phenotype, and outcome of the uncommon Jervell and Lange-Nielsen syndrome (JLNS), associated with a high risk of sudden cardiac death.

    METHODS AND RESULTS: A national inventory of clinical JLNS cases was performed. Genotype and area of origin were ascertained in index families. Retrospective clinical data were collected from medical records and interviews. We identified 19 cases in 13 Swedish families. A JLNS prevalence >1:200 000 was revealed (five living cases <10 years of age). The mutation spectrum consisted of eight KCNQ1 mutations, whereof p.R518X in 12/24 alleles. Geographic clustering of four mutations (20/24 alleles) and similarities to Norway's mutation spectrum were seen. A high prevalence of heterozygotes was suggested. Three paediatric cases on β-blockers since birth were as yet asymptomatic. Seven symptomatic cases had suffered an aborted cardiac arrest and four had died suddenly. QTc prolongation was significantly longer in symptomatic cases (mean 605 ± 62 vs. 518 ± 50 ms, P = 0.016). β-Blockers reduced, but did not abolish, cardiac events in any previously symptomatic case. β-Blocker type, dosage, and compliance probably affect outcome significantly. Implantable cardioverter-defibrillator therapy (ICD, n = 6) was associated with certain complications; however, no case of sudden death.

    CONCLUSION: Founder effects could explain 83% of the Swedish JLNS mutation spectrum and probably contribute to the high JLNS prevalence found in preadolescent Swedish children. Due to the severe cardiac phenotype in JLNS, the importance of stringent β-blocker therapy and compliance, and consideration of ICD implantation in the case of therapy failure is stressed.

  • 33.
    Winbo, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nordin, Charlotte
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Diamant, Ulla-Britt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Persson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jensen, Steen M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Phenotype, origin and estimated prevalence of a common long QT syndrome mutation: a clinical, genealogical and molecular genetics study including Swedish R518X/KCNQ1 families2014In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 14, p. 22-Article in journal (Refereed)
    Abstract [en]

    Background: The R518X/KCNQ1 mutation is a common cause of autosomal recessive (Jervell and Lange Nielsen Syndrome-JLNS) and autosomal dominant long QT syndrome (LQTS) worldwide. In Sweden p.R518X accounts for the majority of JLNS cases and is the second most common cause of LQTS. Here we investigate the clinical phenotype and origin of Swedish carriers of the p. R518X mutation. Methods: The study included 19 Swedish p. R518X index families, ascertained by molecular genetics methods (101 mutation-carriers, whereof 15 JLNS cases and 86 LQTS cases). In all families analyses included assessment of clinical data (symptoms, medications and manually measured electrocardiograms), genealogy (census records), haplotype (microsatellite markers) as well as assessment of mutation age and associated prevalence (ESTIAGE and DMLE computer software). Results: Clinical phenotype ranged from expectedly severe in JLNS to surprisingly benign in LQTS (QTc 576 +/- 61 ms vs. 462 +/- 34 ms, cumulative incidence of (aborted) cardiac arrest 47% vs. 1%, annual non-medicated incidence rate (aborted) cardiac arrest 4% vs. 0.04%). A common northern origin was found for 1701/1929 ancestors born 1650-1950. Historical geographical clustering in the coastal area of the Pite River valley was shown. A shared haplotype spanning the KCNQ1 gene was seen in 17/19 families. Mutation age was estimated to 28 generations (95% CI 19;41). A high prevalence of Swedish p. R518X heterozygotes was suggested (similar to 1: 2000-4000). Conclusions: R518X/KCNQ1 occurs as a common founder mutation in Sweden and is associated with an unexpectedly benign phenotype in heterozygous carriers.

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  • 34.
    Wisten, Aase
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Boström, Ida Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mutation analysis of cases of sudden unexplained death, 15 years after death: Prompt genetic evaluation after resuscitation can save future lives2012In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 83, no 10, p. 1229-1234Article in journal (Refereed)
    Abstract [en]

    Introduction: The aim of this study is to use genetic mutation analysis to determine the cause of sudden unexpected death in young (SUDY) persons with normal autopsy findings, and to provide relatives with an identified cardiac mutation with suitable cardiovascular prevention. Methods: We performed mutation analysis on blood samples from first-degree relatives of 25 cases with normal autopsy findings identified in the national Swedish study of sudden cardiac death in 15- to 35-year-olds from 1992 to 1999. Results: We found three families with long QT syndrome through mutation screening, and the mutations were verified in two of the deceased. Eight family members were found to be mutation carriers and have been provided with suitable cardiovascular prevention. Mutation screening also identified a number of common polymorphisms in the individuals screened. Clinical history revealed one family each with short QT syndrome and hypertrophic cardiomyopathy, respectively, but no mutations were found in the family members or in the deceased. Two SCDs each had occurred in two of the affected families. Conclusion: Cardiac/genetic evaluation of relatives long after SUDY can reveal a diagnosis in 5/25 (20%) of cases. Since DNA extraction of formalin fixed paraffin embedded samples is unreliable, it is important that blood or tissue samples be stored at autopsy of such cases. This can facilitate establishing a diagnosis and thereby save lives in the future. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

  • 35.
    Wisten, Aase
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Krantz, Peter
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Sudden cardiac death among the young in Sweden from 2000 to 2010: an autopsy-based study2017In: Europace, ISSN 1099-5129, E-ISSN 1532-2092, Vol. 19, no 8, p. 1327-1334Article in journal (Refereed)
    Abstract [en]

    Aims: To study the incidence and aetiology of sudden cardiac death (SCD) in 1-to 35-year-olds in Sweden from 2000 to 2010. Methods and results: We used the database of the Swedish National Board of Forensic Medicine and the Swedish Cause of Death Registry and identified SCD cases by review of forensic files and death certificates. We identified 552 individuals with SCD in 1-to 35-year-olds; 156 (28%) were women. In 393 (71%), a forensic autopsy had been performed; in 131 (24%), a clinical autopsy had been performed; in 28 (5%) with no autopsy, a cardiac disease was diagnosed before death. The incidence of SCD per 100 000 person-years was 1.3 in 1- to 35-year-olds and 1.8 in 15- to 35-year-olds. In women, the incidence rates yearly decreased during the study period by 11% (95% confidence interval 6.6-14.2). The most common aetiology in 1- to 35-year-olds was sudden arrhythmic death syndrome (31%) and coronary artery disease (15%). In cases with forensic autopsy, death occurred during daily activity (48%), sleep (38%), and physical activity (14%); death was unwitnessed in 60%. Co-morbidity in 15- to 35-year-olds, e.g. psychiatric disorder, obesity, or diabetes, was present in 93/340 (27%) (73 men). Conclusion: The incidence of SCD among 1- to 35-year-olds in Sweden during 2000-10 was 1.3 per 100 000 person-years (28% women); incidence was decreasing in women. Sudden arrhythmic death syndrome was the most common diagnosis. Co-morbidity such as psychiatric disorders and obesity was common among men.

  • 36. Wisten, Aase
    et al.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    [Sudden cardiac death among young people: important to find individuals at risk. A number of underlying diagnoses have been identified, several of them hereditary]2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 8, p. 516-520Article in journal (Refereed)
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