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101. Familial osteochondritis dissecans associated with early osteoarthritis and disproportionate short stature

Author

Stattin, Eva-Lena, Tegner, Y., Domellöf, M., Dahl, Niklas, Stattin, Eva-Lena, Tegner, Y., Domellöf, M., and Dahl, Niklas

Abstract

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.

Published
2008
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102. Early onset autosomal dominant spinocerebellar ataxia with miosis : Four cases

Author

Timby, Niklas, Stattin, Eva-Lena, Kristiansen, Ingela, Eriksson, Urban, Erikson, Anders, Timby, Niklas, Stattin, Eva-Lena, Kristiansen, Ingela, Eriksson, Urban, and Erikson, Anders

Abstract

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.

Published
2008
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105. Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination.

Author

Hilton, Emma N, Manson, Forbes D C, Urquhart, Jill E, Johnston, Jennifer J, Slavotinek, Anne M, Hedera, Peter, Stattin, Eva-Lena, Nordgren, Ann, Biesecker, Leslie G, Black, Graeme C M, Hilton, Emma N, Manson, Forbes D C, Urquhart, Jill E, Johnston, Jennifer J, Slavotinek, Anne M, Hedera, Peter, Stattin, Eva-Lena, Nordgren, Ann, Biesecker, Leslie G, and Black, Graeme C M

Abstract

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.

Published
2007
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109. Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11

Author

Wentzel, Christian, primary, Rajcan-Separovic, Evica, additional, Ruivenkamp, Claudia A L, additional, Chantot-Bastaraud, Sandra, additional, Metay, Corinne, additional, Andrieux, Joris, additional, Annerén, Göran, additional, Gijsbers, Antoinet C J, additional, Druart, Luc, additional, Hyon, Capucine, additional, Portnoi, Marie-France, additional, Stattin, Eva-Lena, additional, Vincent-Delorme, Catherine, additional, Kant, Sarina G, additional, Steinraths, Michelle, additional, Marlin, Sandrine, additional, Giurgea, Irina, additional, and Thuresson, Ann-Charlotte, additional

Published
2011
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112. Longer QTc in Y111C Carriers

Author

Diamant, Ulla-Britt, primary, Winbo, Annika, additional, Rydberg, Annika, additional, Stattin, Eva-Lena, additional, Kesek, Milos, additional, and Jensen, Steen M., additional

Published
2011
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117. Familial and perinatal risk factors for micro- and macroalbuminuria in young IDDM patients.

Author

Rudberg, S, Stattin, Eva-Lena, Dahlquist, G, Rudberg, S, Stattin, Eva-Lena, and Dahlquist, G

Abstract

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

Published
1998

120. The Swedish long QT syndrome R518X/KCNQ1 founder population- origin and clinical phenotype : phenotypic variability partly explained by gender-specific effects of sequence variants in the NOS1AP gene

Author

Winbo, Annika, Stattin, Eva-Lena, Norberg, Anna, Nordin, Charlotte, Diamant, Ulla-Britt, Persson, Johan, Jensen, Steen M, Rydberg, Annika, Winbo, Annika, Stattin, Eva-Lena, Norberg, Anna, Nordin, Charlotte, Diamant, Ulla-Britt, Persson, Johan, Jensen, Steen M, and Rydberg, Annika

Abstract

Background: Genetic modifiers have been proposed to explain phenotypic variability in the long QT syndrome (LQTS). We investigate the origin and phenotype of the worldwide common R518X/KCNQ1 mutation in Sweden, as well as possible associations between p.R518X-LQTS phenotype and previously reported modifying sequence variants in the NOS1AP, KCNH2, KCNE1, SCN5A and KCNQ1(3’UTR) genes. Methods and Results: We identified 19 p.R518X families (101 mutation-carriers, whereof 15 Jervell and Lange-Nielsen (JLNS) cases and 86 LQTS cases). Analyses of microsatellite markers, genealogy and mutation age (ESTIAGE) identified a common northern origin ~700 years ago for 17/19 families and a high prevalence of Swedish p.R518X heterozygotes was suggested (DMLE). Clinical phenotype ranged from severe in JLNS to relatively 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%). In p.R518X-LQTS males, two NOS1AP variants rs12143842 and rs16847548 were associated with a 29 ms QT prolongation (p=0.004), explaining 27% of QTc variability. Three derived 3’UTR-KCNQ1 variants, previously shown to suppress gene expression in an allele-specific manner, were found to segregate with the founder mutation. Conclusion: The R518X/KCNQ1 mutation is a Swedish founder mutation presenting with an expectedly severe phenotype in JLNS and an unusually mild phenotype in LQTS, although intra-familial variability remained. Gender-specific effects of NOS1AP sequence variants explained over a fourth of QTc variance in p.R518X-LQTS males, warranting further studies. Repressive 3’UTR-KCNQ1 sequence variants segregating within the founder haplotype could possibly contribute to its relative benignancy., Manuskriptets titel i avhandlingen: Phenotype and origin of the Swedish long QT syndrome R518X/KCNQ1 founder population - phenotypic variability partly explained by gender-specific effects of genetic modifiers.

122. A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans with short stature and early osteoarthritis

Author

Stattin, Eva-Lena, Wiklund, Fredrik, Lindblom, Karin, Önnerfjord, Patrik, Jonsson, Björn-Anders, Tegner, Yelverton, Sasaki, Takako, Struglics, André, Lohmander, Stefan, Dahl, Niklas, Heinegård, Dick, Aspberg, Anders, Stattin, Eva-Lena, Wiklund, Fredrik, Lindblom, Karin, Önnerfjord, Patrik, Jonsson, Björn-Anders, Tegner, Yelverton, Sasaki, Takako, Struglics, André, Lohmander, Stefan, Dahl, Niklas, Heinegård, Dick, and Aspberg, Anders

123. Long-read sequencing and optical mapping generates near T2T assemblies that resolves a centromeric translocation.

Author

ten Berk de Boer, Esmee, Ameur, Adam, Bunikis, Ignas, Ek, Marlene, Stattin, Eva-Lena, Feuk, Lars, Eisfeldt, Jesper, and Lindstrand, Anna

Subjects
*DIGITAL technology, *GENETIC testing, *HAPLOTYPES, *TELOMERES, *CHROMOSOMAL translocation, *CENTROMERE, *SINOATRIAL node, *NUCLEOTIDE sequencing
Abstract

Long-read genome sequencing (lrGS) is a promising method in genetic diagnostics. Here we investigate the potential of lrGS to detect a disease-associated chromosomal translocation between 17p13 and the 19 centromere. We constructed two sets of phased and non-phased de novo assemblies; (i) based on lrGS only and (ii) hybrid assemblies combining lrGS with optical mapping using lrGS reads with a median coverage of 34X. Variant calling detected both structural variants (SVs) and small variants and the accuracy of the small variant calling was compared with those called with short-read genome sequencing (srGS). The de novo and hybrid assemblies had high quality and contiguity with N50 of 62.85 Mb, enabling a near telomere to telomere assembly with less than a 100 contigs per haplotype. Notably, we successfully identified the centromeric breakpoint of the translocation. A concordance of 92% was observed when comparing small variant calling between srGS and lrGS. In summary, our findings underscore the remarkable potential of lrGS as a comprehensive and accurate solution for the analysis of SVs and small variants. Thus, lrGS could replace a large battery of genetic tests that were used for the diagnosis of a single symptomatic translocation carrier, highlighting the potential of lrGS in the realm of digital karyotyping. [ABSTRACT FROM AUTHOR]

Published
2024
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124. Symptoms and ECG changes precede sudden cardiac death in hypertrophic cardiomyopathy—A nationwide study among the young in Sweden.

Author

Börjesson, Erik, Svennblad, Bodil, Wisten, Aase, Börjesson, Mats, and Stattin, Eva-Lena

Subjects
*MEDICAL examinations of athletes, *CARDIAC arrest, *HYPERTROPHIC cardiomyopathy, *SYMPTOMS, *MEDICAL care, *ELECTROCARDIOGRAPHY
Abstract

Background: Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death (SCD) in the young. We aimed to characterize detailed family history, symptoms, hospital utilization and ECG changes before SCD. Methods: We extracted all cases suffering SCD with HCM from the SUDDY cohort, which includes all cases of SCD between 2000–2010 in Sweden among individuals aged 0–35 years along with their controls. We gathered data from mandatory national registries, autopsy reports, medical records, ECGs (including military conscripts), and detailed family history from an interview-based questionnaire (with relatives, post-mortem). Results: Thirty-eight cases (7 female), mean age 22 years, with HCM were identified. Among these, 71% presented with possible cardiac symptoms (chest pain [26%], syncope [22%], palpitations [37%]), before death; 69% received medical care (vs 21% in controls) within 180 days before death. The majority (68%) died during recreational activity (n = 14) or exercise/competitive sports (n = 12). Fifteen (39%) had a known cardiac disorder prior to death, with HCM being diagnosed pre-mortem in nine cases. 58% presented with abnormal ECG recordings pre-mortem, and 50% had a positive family history (1st-3rd generation) for heart disease. Conclusion: In this comprehensive, nationwide study of SCD due to HCM, 87% (33/38) of cases had one or more abnormality prior to death, including cardiac symptoms, a positive family history, known cardiac disease or ECG abnormalities. They sought medical care prior death, to a larger extent than controls. These findings suggest that cardiac screening should be expanded beyond competitive athletes to aid SCD prevention in the young population with HCM. [ABSTRACT FROM AUTHOR]

Published
2022
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125. High frequency of intermediary alleles in the HTT gene in Northern Sweden - The Swedish Huntingtin Alleles and Phenotype (SHAPE) study.

Author

Sundblom, Jimmy, Niemelä, Valter, Ghazarian, Maria, Strand, Ann-Sofi, Bergdahl, Ingvar A., Jansson, Jan-Håkan, Söderberg, Stefan, and Stattin, Eva-Lena

Subjects
*ALLELES, *PHENOTYPES, *TRINUCLEOTIDE repeats, *GENES, *HUNTINGTIN protein
Abstract

Trinucleotide (CAG) repeat expansions longer than 39 in the huntingtin (HTT) gene cause Huntington's disease (HD). The frequency of intermediate alleles (IA) with a length of 27–35 in the general population is not fully known, but studied in specific materials connected to the incidence of HD. The Swedish Huntingtin Alleles and Phenotype (SHAPE) study aims to assess the frequency of trinucleotide repeat expansions in the HTT gene in north Sweden. 8260 individuals unselected for HD from the counties of Norr- and Västerbotten in the north of Sweden were included. DNA samples were obtained and analysis of the HTT gene was performed, yielding data on HTT gene expansion length in 7379 individuals. A high frequency of intermediate alleles, 6.8%, was seen. Also, individuals with repeat numbers lower than ever previously reported (<5) were found. These results suggest a high frequency of HD in the norther parts of Sweden. Subsequent analyses may elucidate the influence of IA:s on traits other than HD. [ABSTRACT FROM AUTHOR]

Published
2020
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126. A progressive and complex clinical course in two family members with ERF-related craniosynostosis: a case report.

Author

Körberg, Izabella, Nowinski, Daniel, Bondeson, Marie-Louise, Melin, Malin, Kölby, Lars, and Stattin, Eva-Lena

Subjects
*CRANIOSYNOSTOSES, *HETEROZYGOSITY, *INTRACRANIAL hypertension, *INTRACRANIAL pressure, *ETIOLOGY of diseases, *FAMILIES
Abstract

Background: ERF-related craniosynostosis are a rare, complex, premature trisutural fusion associated with a broad spectrum of clinical features and heterogeneous aetiology. Here we describe two cases with the same pathogenic variant and a detailed description of their clinical course. Case presentation: Two subjects; a boy with a BLSS requiring repeated skull expansions and his mother who had been operated once for sagittal synostosis. Both developed intracranial hypertension at some point during the course, which was for both verified by formal invasive intracranial pressure monitoring. Exome sequencing revealed a pathogenic truncating frame shift variant in the ERF gene. Conclusions: Here we describe a boy and his mother with different craniosynostosis patterns, but both with verified intracranial hypertension and heterozygosity for a truncating variant of ERF c.1201_1202delAA (p.Lys401Glufs*10). Our work provides supplementary evidence in support of previous phenotypic descriptions of ERF-related craniosynostosis, particularly late presentation, an evolving synostotic pattern and variable expressivity even among affected family members. [ABSTRACT FROM AUTHOR]

Published
2020
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127. Exercise related sudden cardiac death (SCD) in the young - Pre-mortal characterization of a Swedish nationwide cohort, showing a decline in SCD among athletes.

Author

Wisten, Aase, Börjesson, Mats, Krantz, Peter, and Stattin, Eva-Lena

Subjects
*CARDIAC arrest, *AUTOPSY, *ARRHYTHMOGENIC right ventricular dysplasia, *HYPERTROPHIC cardiomyopathy, *SUDDEN death, *PROOF & certification of death
Abstract

Aims: To study the frequency, etiology, and premortal abnormalities in exercise-related sudden cardiac death (SCD) in the young in Sweden.Methods: All subjects with SCD in 10-35-year olds in Sweden during 2000-10, were included (n = 514). Information about each case was retrieved from death certifications, autopsy- and medical records. The number of SCD in athletes was compared to national figures from 1992-99.Results: Exercise-related SCD occurred in 12% (62/514) of the SCD-population, a majority being men (56/62; 90%). Cardiopulmonary resuscitation (CPR) was started in 87% (54/62). In total, 48% (30/62), had a cardiac diagnosis, symptoms, family history and/or ECG-changes, before the fatal event. The most prevalent autopsy diagnosis was sudden arrhythmic death syndrome (15/62; 24%). The frequency of hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) was significantly higher in exercise-related SCD compared to non-exertional SCD. Exercise-related SCD was more common in athletes (21/29) than in non-athletes (41/485) (P < 0.0001). The total number of SCDs/year in athletes 15-35 years old, are approximately halved in 2000-10 compared to the years 1992-99.Conclusion: The increased risk of exercise-related SCD in HCM and ARVC underlines the importance of early detection and eligibility recommendations. There is a major reduction in deaths among athletes in the 2000s, compared to the previous decade. These results may partly be explained by improved acute preparedness for sudden cardiac arrest (CPR, defibrillation), but as a substantial percentage have preceding risk factors, such as symptoms and ECG-abnormalities, increased cardiac screening and increased general awareness, may also play a role. [ABSTRACT FROM AUTHOR]

Published
2019
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128. Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFβ signaling in FTAAD

Author

Renard, Marjolijn, Callewaert, Bert, Baetens, Machteld, Campens, Laurence, MacDermot, Kay, Fryns, Jean-Pierre, Bonduelle, Maryse, Dietz, Harry C., Gaspar, Isabel Mendes, Cavaco, Diogo, Stattin, Eva-Lena, Schrander-Stumpel, Constance, Coucke, Paul, Loeys, Bart, De Paepe, Anne, and De Backer, Julie

Subjects
*MYOSIN, *PROTEIN genetics, *ACTIN, *GENETIC mutation, *CELLULAR signal transduction, *TRANSFORMING growth factors-beta, *THORACIC aneurysms, *PHENOTYPES
Abstract

Abstract: 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 (TGFβ) signaling (TGFβ 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 TGFβ 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 TGFβ signaling. [Copyright &y& Elsevier]

Published
2013
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129. Identification of genetic variants associated with Huntington's disease progression

Author

Davina J Hensman Moss, Antonio F Pardiñas, Douglas Langbehn, Kitty Lo, Blair R Leavitt, Raymund Roos, Alexandra Durr, Simon Mead, Peter Holmans, Lesley Jones, Sarah J Tabrizi, A Coleman, R Dar Santos, J Decolongon, A Sturrock, E Bardinet, C Jauff Ret, D Justo, S Lehericy, C Marelli, K Nigaud, R Valabrègue, SJA van den Bogaard, E M Dumas, J van der Grond, EP t'Hart, C Jurgens, M-N Witjes-Ane, N Arran, J Callaghan, C Stopford, C Frost, R Jones, N Hobbs, N Lahiri, R Ordidge, G Owen, T Pepple, J Read, M Say, E Wild, A Patel, N C Fox, C Gibbard, I Malone, H Crawford, D Whitehead, S Keenan, D M Cash, C Berna, N Bechtel, S Bohlen, A Hoff Man, P Kraus, E Axelson, C Wang, T Acharya, S Lee, W Monaco, C Campbell, S Queller, K Whitlock, M Campbell, E Frajman, C Milchman, A O'Regan, I Labuschagne, J Stout, B Landwehrmeyer, D Craufurd, R Scahill, S Hicks, C Kennard, H Johnson, A Tobin, HD Rosas, R Reilmann, B Borowsky, C Pourchot, S C Andrews, Anne-Catherine Bachoud-Lévi, Anna Rita Bentivoglio, Ida Biunno, Raphael Bonelli, Jean-Marc Burgunder, Stephen Dunnett, Joaquim Ferreira, Olivia Handley, Arvid Heiberg, Torsten Illmann, G. Bernhard Landwehrmeyer, Jamie Levey, Maria A. Ramos-Arroyo, Jørgen Nielsen, Susana Pro Koivisto, Markku Päivärinta, Raymund A.C. Roos, A Rojo Sebastián, Sarah Tabrizi, Wim Vandenberghe, Christine Verellen-Dumoulin, Tereza Uhrova, Jan Wahlström, Jacek Zaremba, Verena Baake, Katrin Barth, Monica Bascuñana Garde, Sabrina Betz, Reineke Bos, Jenny Callaghan, Adrien Come, Leonor Correia Guedes, Daniel Ecker, Ana Maria Finisterra, Ruth Fullam, Mette Gilling, Lena Gustafsson, Olivia J Handley, Carina Hvalstedt, Christine Held, Kerstin Koppers, Claudia Lamanna, Matilde Laurà, Asunción Martínez Descals, Saül Martinez-Horta, Tiago Mestre, Sara Minster, Daniela Monza, Lisanne Mütze, Martin Oehmen, Michael Orth, Hélène Padieu, Laurent Paterski, Nadia Peppa, Martina Di Renzo, Amandine Rialland, Niini Røren, Pavla Šašinková, Erika Timewell, Jenny Townhill, Patricia Trigo Cubillo, Wildson Vieira da Silva, Marleen R van Walsem, Carina Whalstedt, Marie-Noelle Witjes-Ané, Grzegorz Witkowski, Abigail Wright, Daniel Zielonka, Eugeniusz Zielonka, Paola Zinzi, Raphael M. Bonelli, Sabine Lilek, Karen Hecht, Brigitte Herranhof, Anna Holl, Hans-Peter Kapfhammer, Michael Koppitz, Markus Magnet, Nicole Müller, Daniela Otti, Annamaria Painold, Karin Reisinger, Monika Scheibl, Helmut Schöggl, Jasmin Ullah, Eva-Maria Braunwarth, Florian Brugger, Lisa Buratti, Eva-Maria Hametner, Caroline Hepperger, Christiane Holas, Anna Hotter, Anna Hussl, Christoph Müller, Werner Poewe, Klaus Seppi, Fabienne Sprenger, Gregor Wenning, Andrea Boogaerts, Godelinde Calmeyn, Isabelle Delvaux, Dirk Liessens, Nele Somers, Michel Dupuit, Cécile Minet, Dominique van Paemel, Pascale Ribaï, Dimphna van Reijen, Jirí Klempír, Veronika Majerová, Jan Roth, Irena Stárková, Lena E. Hjermind, Oda Jacobsen, Jørgen E. Nielsen, Ida Unmack Larsen, Tua Vinther-Jensen, Heli Hiivola, Hannele Hyppönen, Kirsti Martikainen, Katri Tuuha, Philippe Allain, Dominique Bonneau, Marie Bost, Bénédicte Gohier, Marie-Anne Guérid, Audrey Olivier, Adriana Prundean, Clarisse Scherer-Gagou, Christophe Verny, Blandine Babiloni, Sabrina Debruxelles, Charlotte Duché, Cyril Goizet, Laetitia Jameau, Danielle Lafoucrière, Umberto Spampinato, Rekha Barthélémy, Christelle De Bruycker, Maryline Cabaret Anne-Sophie Carette, Eric Decorte Luc Defebvre, Marie Delliaux, Arnaud Delval, Alain Destee, Kathy Dujardin, Marie-Hélène Lemaire, Sylvie Manouvrier, Mireille Peter, Lucie Plomhouse, Bernard Sablonnière, Clémence Simonin, Stéphanie Thibault-Tanchou, Isabelle Vuillaume, Marcellin Bellonet, Hassan Berrissoul, Stéphanie Blin, Françoise Courtin, Cécile Duru, Véronique Fasquel, Olivier Godefroy, Pierre Krystkowiak, Béatrice Mantaux, Martine Roussel, Sandrine Wannepain, Jean-Philippe Azulay, Marie Delfini, Alexandre Eusebio, Frédérique Fluchere, Laura Mundler, Mathieu Anheim, Celine Julié, Ouhaid Lagha Boukbiza, Nadine Longato, Gabrielle Rudolf, Christine Tranchant, Marie-Agathe Zimmermann, Christoph Michael Kosinski, Eva Milkereit, Daniela Probst, Kathrin Reetz, Christian Sass, Johannes Schiefer, Christiane Schlangen, Cornelius J. Werner, Harald Gelderblom, Josef Priller, Harald Prüß, Eike Jakob Spruth, Gisa Ellrichmann, Lennard Herrmann, Rainer Hoffmann, Barbara Kaminski, Peter Kotz, Christian Prehn, Carsten Saft, Herwig Lange, Robert Maiwald, Matthias Löhle, Antonia Maass, Simone Schmidt, Cecile Bosredon, Alexander Storch, Annett Wolz, Martin Wolz, Philipp Capetian, Johann Lambeck, Birgit Zucker, Kai Boelmans, Christos Ganos, Walburgis Heinicke, Ute Hidding, Jan Lewerenz, Alexander Münchau, Jenny Schmalfeld, Lars Stubbe, Simone Zittel, Gabriele Diercks, Dirk Dressler, Heike Gorzolla, Christoph Schrader, Pawel Tacik, Michael Ribbat, Bernhard Longinus, Katrin Bürk, Jens Carsten Möller, Ida Rissling, Mark Mühlau, Alexander Peinemann, Michael Städtler, Adolf Weindl, Juliane Winkelmann, Cornelia Ziegler, Natalie Bechtel, Heike Beckmann, Stefan Bohlen, Eva Hölzner, Ralf Reilmann, Stefanie Rohm, Silke Rumpf, Sigrun Schepers, Natalia Weber, Matthias Dose, Gabriele Leythäuser, Ralf Marquard, Tina Raab, Alexandra Wiedemann, Andrea Buck, Julia Connemann, Carolin Geitner, Andrea Kesse, Bernhard Landwehrmeyer, Christina Lang, Franziska Lezius, Solveig Nepper, Anke Niess, Ariane Schneider, Daniela Schwenk, Sigurd Süßmuth, Sonja Trautmann, Patrick Weydt, Claudia Cormio, Vittorio Sciruicchio, Claudia Serpino, Marina de Tommaso, Sabina Capellari, Pietro Cortelli, Roberto Galassi, Giovanni Rizzo, Roberto Poda, Cesa Scaglione, Elisabetta Bertini, Elena Ghelli, Andrea Ginestroni, Francesca Massaro, Claudia Mechi, Marco Paganini, Silvia Piacentini, Silvia Pradella, Anna Maria Romoli, Sandro Sorbi, Giovanni Abbruzzese, Monica Bandettini di Poggio, Giovanna Ferrandes, Paola Mandich, Roberta Marchese, Alberto Albanese, Daniela Di Bella, Anna Castaldo, Stefano Di Donato, Cinzia Gellera, Silvia Genitrini, Caterina Mariotti, Lorenzo Nanetti, Dominga Paridi, Paola Soliveri, Chiara Tomasello, Giuseppe De Michele, Luigi Di Maio, Marco Massarelli, Silvio Peluso, Alessandro Roca, Cinzia Valeria Russo, Elena Salvatore, Pierpaolo Sorrentino, Enrico Amico, Mariagrazia Favellato, Annamaria Griguoli, Irene Mazzante, Martina Petrollini, Ferdinando Squitieri, Barbara D'Alessio, Chiara Esposito, Rita Bentivoglio, Marina Frontali, Arianna Guidubaldi, Tamara Ialongo, Gioia Jacopini, Carla Piano, Silvia Romano, Francesco Soleti, Maria Spadaro, Monique S.E. van Hout, Marloes E. Verhoeven, Jeroen P.P. van Vugt, A. Marit de Weert, J.J.W. Bolwijn, M. Dekker, B. Kremer, K.L. Leenders, J.C.H. van Oostrom, Simon J.A. van den Bogaard, Eve M. Dumas, Ellen P. 't Hart, Berry Kremer, C.C.P. Verstappen, Olaf Aaserud, Jan Frich C, Ragnhild Wehus, Kathrine Bjørgo, Madeleine Fannemel, Per F. 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P., Aaserud, Olaf, Jan Frich, C., Wehus, Ragnhild, Bjã¸rgo, Kathrine, Fannemel, Madeleine, Gã¸rvell, Per F., Lorentzen, Eirin, Retterstã¸l, Lar, Stokke, Bodil, Bjã¸rnevoll, Inga, Sando, Sigrid Botne, Dziadkiewicz, Artur, Nowak, Malgorzata, Robowski, Piotr, Sitek, Emilia, Slawek, Jaroslaw, Soltan, Witold, Szinwelski, Michal, Blaszcyk, Magdalena, Boczarska-Jedynak, Magdalena, Ciach-Wysocka, Ewelina, Gorzkowska, Agnieszka, Jasinska-Myga, Barbara, Klodowska-Duda, Gabriela, Opala, Gregorz, Stompel, Daniel, Banaszkiewicz, Krzysztof, Bocwinska, Dorota, Bojakowska-Jaremek, Kamila, Dec, Malgorzata, Krawczyk, Malgorzata, Rudzinska, Monika, Szczygiel, Elzbieta, Szczudlik, Andrzej, Wasielewska, Anna, Wã³jcik, Magdalena, Bryl, Anna, Ciesielska, Anna, Klimberg, Aneta, Marcinkowski, Jerzy, Samara, Husam, Sempolowicz, Justyna, Gogol, Anna, Janik, Piotr, Kwiecinski, Hubert, Jamrozik, Zygmunt, Antczak, Jakub, Jachinska, Katarzyna, Krysa, Wioletta, Rakowicz, Maryla, Richter, Przemyslaw, Rola, Rafal, Ryglewicz, Danuta, Sienkiewicz-Jarosz, Halina, Stepniak, Iwona, Sulek, Anna, Zdzienicka, Elzbieta, Zieora-Jakutowicz, Karolina, Ferreira, Joaquim J, Coelho, Miguel, Mendes, Tiago, Valadas, Anabela, Andrade, Carlo, Gago, Miguel, Garrett, Carolina, Guerra, Maria Rosália, Herrera, Carmen Durán, Garcia, Patrocinio Moreno, Barbera, Miquel Aguilar, Guia, Dolors Badene, Hernanz, Laura Casa, Catena, Judit López, Ferrer, Pilar Quiléz, Sebastiã¡n, Ana Rojo, Carruesco, Gemma Tome, Bas, Jordi, Busquets, Nãºria, Calopa, Matilde, Robert, Misericordia Floriach, Viladrich, Celia Mareca, Idiago, Jesús Miguel Ruiz, Riballo, Antonio Villa, Cubo, Esther, Polo, Cecilia Gil, Mariscal, Natividad, Rivadeneyra, Perez Jessica, Barrero, Francisco, Morales, Bla, Fenollar, Marã­a, Garcã­a, Rocío García-Ramo, Ortega, Paloma, Villanueva, Clara, Alegre, Javier, Bascuã±ana, Mã³nica, Caldentey, Juan Garcia, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Frech, Fernando Alonso, Ruã­z, Pedro J. García, Martínez-Descals, Asunciã³n, Guerrero, Rosa, Artiga, María José Saiz, Sã¡nchez, Vicenta, Perea, María Fuensanta Noguera, Fortuna, Lorenza, Manzanares, Salvadora, Reinante, Gema, Torres, María Martirio Antequera, Moreau, Laura Vivanco, González González, Sonia, Guisasola, Luis Menéndez, Salvador, Carlo, Martã­n, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazãº, Lopera, Mónica Rodriguez, Arques, Penelope Nava, Rodrã­guez, María José Torre, Pastor, Barbara Vive, Gaston, Itziar, Martinez-Jaurrieta, Maria Dolore, Moreno, Jose Manuel Garcia, Lucena, Carolina Mendez, Damas, Fatima, Cortegana, Hermoso Eva Pacheco, Peã±a, José Chacón, Redondo, Lui, Carrillo, Fã¡tima, Teresa Cáceres, Marã­a, Mir, Pablo, Suarez, María José Lama, Vargas-González, Laura, Bosca, Maria E., Brugada, Francisco Castera, Burguera, Juan Andre, Campos, Anabel, Vilaplana, Garcia Carmen Peiró, Berglund, Peter, Constantinescu, Radu, Fredlund, Gunnel, Høsterey-Ugander, Ulrika, Linnsand, Petra, Neleborn-Lingefjärd, Liselotte, Wentzel, Magnu, Loutfi, Ghada, Olofsson, Carina, Stattin, Eva-Lena, Westman, Laila, Wikstrã¶m, Birgitta, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schã¼pbach, Michael, Weber Zaugg, Sabine, Hauer, Maria, Gonzenbach, Roman, Jung, Hans H., Mihaylova, Violeta, Petersen, Jen, Jack, Roisin, Matheson, Kirsty, Miedzybrodzka, Zosia, Rae, Daniela, Simpson, Sheila A, Summers, Fiona, Ure, Alexandra, Vaughan, Vivien, Akhtar, Shahbana, Crooks, Jenny, Curtis, Adrienne, de Souza, Jenny, Piedad, John, Rickards, Hugh, Wright, Jan, Coulthard, Elizabeth, Gethin, Louise, Hayward, Beverley, Sieradzan, Kasia, Armstrong, Matthew, Barker, Roger A., O'Keefe, Deidre, Di Pietro, Anna, Fisher, Kate, Goodman, Anna, Hill, Susan, Kershaw, Ann, Mason, Sarah, Paterson, Nicole, Raymond, Lucy, Swain, Rachel, Guzman, Natalie Valle, Busse, Monica, Butcher, Cynthia, Clenaghan, Catherine, Hunt, Sarah, Jones, Una, Khalil, Hanan, Owen, Michael, Price, Kathleen, Rosser, Anne, Edwards, Maureen, Carrie, Ho, Hughes, Teresa, Mcgill, Marie, Pearson, Pauline, Porteous, Mary, Smith, Paul, Brockie, Peter, Foster, Jillian, Johns, Nicola, Mckenzie, Sue, Rothery, Jean, Thomas, Gareth, Yates, Shona, Burrows, Liz, Chu, Carol, Fletcher, Amy, Gallantrae, Deena, Hamer, Stephanie, Harding, Alison, Klã¶ppel, Stefan, Kraus, Alison, Laver, Fiona, Lewis, Monica, Longthorpe, Mandy, Markova, Ivana, Raman, Ashok, Robertson, Nicola, Silva, Mark, Thomson, Aileen, Wild, Sue, Yardumian, Pam, Evans, Carole, Gallentrae, Deena, Hobson, Emma, Jamieson, Stuart, Musgrave, Hannah, Rowett, Liz, Toscano, Jean, Bourne, Colin, Clapton, Jackie, Clayton, Carole, Dipple, Heather, Freire-Patino, Dawn, Grant, Janet, Gross, Diana, Hallam, Caroline, Middleton, Julia, Murch, Ann, Thompson, Catherine, Alusi, Sundu, Davies, Rhy, Foy, Kevin, Gerrans, Emily, Pate, Louise, Andrews, Thomasin, Dougherty, Andrew, Golding, Charlotte, Kavalier, Fred, Laing, Hana, Lashwood, Alison, Robertson, Dene, Ruddy, Deborah, Santhouse, Alastair, Whaite, Anna, Bruno, Stefania, Doherty, Karen, Haider, Salman, Hensman, Davina, Lahiri, Nayana, Novak, Marianne, Patel, Aakta, Rosser, Elisabeth, Taylor, Rachel, Warner, Thoma, Wild, Edward, Arran, Natalie, Bek, Judith, Craufurd, David, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary, Murphy, Helen, Oughton, Emma, Partington-Jones, Lucy, Rogers, Dawn, Sollom, Andrea, Snowden, Julie, Stopford, Cheryl, Thompson, Jennifer, Trender-Gerhard, Iri, Verstraelen, Nichola, Westmoreland, Leann, Armstrong, Richard, Dixon, Kathryn, Nemeth, Andrea H, Siuda, Gill, Valentine, Ruth, David, Harrison, Hughes, Max, Parkinson, Andrew, Soltysiak, Beverley, Bandmann, Oliver, Bradbury, Alyson, Gill, Paul, Fairtlough, Helen, Fillingham, Kay, Foustanos, Isabella, Kazoka, Mbombe, O'Donovan, Kirsty, Taylor, Cat, Tidswell, Katherine, Quarrell, Oliver, Lau, Puay Ngoh, Pica, Emmanul, Tan, Louis, Amsterdam Neuroscience - Neurodegeneration, Neurology, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Moss, Davina J Hensman, Lo, Kitty, Pardiñas, Antonio F, Santos, R Dar, Ret, C Jauff, Valabrègue, R., Witjes-Ane, M. -N., Man, A Hoff, Bachoud-Lévi, Anne-Catherine, Nielsen, Jørgen, Päivärinta, Markku, Sebastián, A Rojo, Wahlström, Jan, Garde, Monica Bascuñana, Laurà, Matilde, Descals, Asunción Martínez, Martinez-Horta, Saül, Mütze, Lisanne, Padieu, Hélène, Røren, Niini, Šašinková, Pavla, Witjes-Ané, Marie-Noelle, Müller, Nicole, Schöggl, Helmut, Müller, Christoph, Minet, Cécile, Ribaï, Pascale, Klempír, Jirí, Majerová, Veronika, Stárková, Irena, Nielsen, Jørgen E., Hyppönen, Hannele, Gohier, Bénédicte, Guérid, Marie-Anne, Duché, Charlotte, Lafoucrière, Danielle, Barthélémy, Rekha, Lemaire, Marie-Hélène, Sablonnière, Bernard, Simonin, Clémence, Thibault-Tanchou, Stéphanie, Blin, Stéphanie, Courtin, Françoise, Duru, Cécile, Fasquel, Véronique, Mantaux, Béatrice, Fluchere, Frédérique, Julié, Celine, Prüß, Harald, Löhle, Matthia, Münchau, Alexander, Bürk, Katrin, Möller, Jens Carsten, Mühlau, Mark, Städtler, Michael, Hölzner, Eva, Leythäuser, Gabriele, Süßmuth, Sigurd, Marchese, Roberta, DI MAIO, Luigi, ’t Hart, Ellen P., Bjørgo, Kathrine, Gørvell, Per F., Retterstøl, Lar, Bjørnevoll, Inga, Wójcik, Magdalena, Guerra, Maria Rosália, Herrera, Carmen Durán, Catena, Judit López, Ferrer, Pilar Quiléz, Sebastián, Ana Rojo, Busquets, Núria, Idiago, Jesús Miguel Ruiz, Fenollar, María, García, Rocío García-Ramo, Bascuñana, Mónica, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Ruíz, Pedro J García, Martínez-Descals, Asunción, Artiga, María José Saiz, Sánchez, Vicenta, Perea, María Fuensanta Noguera, Torres, María Martirio Antequera, González González, Sonia, Guisasola, Luis Menéndez, Martín, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazú, Lopera, Mónica Rodriguez, Rodríguez, María José Torre, Peña, José Chacón, Carrillo, Fátima, Teresa Cáceres, María, Suarez, María José Lama, Vargas-González, Laura, Vilaplana, Garcia Carmen Peiró, Høsterey-Ugander, Ulrika, Neleborn-Lingefjärd, Liselotte, Wikström, Birgitta, Schüpbach, Michael, Ho, Carrie, Klöppel, Stefan, Harrison, David, Cardiff University, University of Iowa [Iowa City], University of British Columbia (UBC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UCL, Institute of Neurology [London], National Oceanography Centre [Southampton] (NOC), University of Southampton, Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), IFR de Neuroimagerie Fonctionnelle (IFR 49), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), TRACK-HD investigators, Pardinas, Antonio F, Langbehn, Douglas, Lee, S Hong, TRACK-HD Investigators, and REGISTRY Investigators

Subjects
0301 basic medicine, Oncology, Registrie, Genome-wide association study, Longitudinal Studie, Disease, Bioinformatics, Severity of Illness Index, Principal Component Analysi, Longitudinal Studies, Registries, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Huntington disease, DNA-Binding Proteins, Settore MED/26 - NEUROLOGIA, Adult, Genome-Wide Association Study, Humans, Huntington Disease, MutS Homolog 3 Protein, Principal Component Analysis, Disease Progression, Neurology (clinical), huntingtin gene, age of onest, Huntington’s disease, Human, medicine.medical_specialty, cag repeat, instability, DNA-Binding Protein, Clinical Neurology, Principal component analysis, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, Huntington's disease, Internal medicine, medicine, SNP, genome-wide association study, medicine.disease, R1, meta-analysis, Minor allele frequency, 030104 developmental biology, Age of onset, Trinucleotide repeat expansion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. Funding The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.

Published
2017
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130. A national long-read sequencing study on chromosomal rearrangements uncovers hidden complexities.

Author

Eisfeldt J, Ameur A, Lenner F, Ten Berk de Boer E, Ek M, Wincent J, Vaz R, Ottosson J, Jonson T, Ivarsson S, Thunström S, Topa A, Stenberg S, Rohlin A, Sandestig A, Nordling M, Palmebäck P, Burstedt M, Nordin F, Stattin EL, Sobol M, Baliakas P, Bondeson ML, Höijer I, Saether KB, Lovmar L, Ehrencrona H, Melin M, Feuk L, and Lindstrand A

Subjects
Humans, Sweden, Karyotyping methods, Gene Rearrangement, DNA Copy Number Variations, Translocation, Genetic, High-Throughput Nucleotide Sequencing methods, Male, Female, Genomic Structural Variation, Chromosome Inversion, Sequence Analysis, DNA methods, Chromosome Aberrations
Abstract

Clinical genetic laboratories often require a comprehensive analysis of chromosomal rearrangements/structural variants (SVs), from large events like translocations and inversions to supernumerary ring/marker chromosomes and small deletions or duplications. Understanding the complexity of these events and their clinical consequences requires pinpointing breakpoint junctions and resolving the derivative chromosome structure. This task often surpasses the capabilities of short-read sequencing technologies. In contrast, long-read sequencing techniques present a compelling alternative for clinical diagnostics. Here, Genomic Medicine Sweden-Rare Diseases has explored the utility of HiFi Revio long-read genome sequencing (lrGS) for digital karyotyping of SVs nationwide. The 16 samples from 13 families were collected from all Swedish healthcare regions. Prior investigations had identified 16 SVs, ranging from simple to complex rearrangements, including inversions, translocations, and copy number variants. We have established a national pipeline and a shared variant database for variant calling and filtering. Using lrGS, 14 of the 16 known SVs are detected. Of these, 13 are mapped at nucleotide resolution, and one complex rearrangement is only visible by read depth. Two Chromosome 21 rearrangements, one mosaic, remain undetected. Average read lengths are 8.3-18.8 kb with coverage exceeding 20× for all samples. De novo assembly results in a limited number of phased contigs per individual (N50 6-86 Mb), enabling direct characterization of the chromosomal rearrangements. In a national pilot study, we demonstrate the utility of HiFi Revio lrGS for analyzing chromosomal rearrangements. Based on our results, we propose a 5-year plan to expand lrGS use for rare disease diagnostics in Sweden., (© 2024 Eisfeldt et al.; Published by Cold Spring Harbor Laboratory Press.)

Published
2024
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131. Pushing the boundaries of rare disease diagnostics with the help of the first Undiagnosed Hackathon.

Author

Delgado-Vega AM, Cederroth H, Taylan F, Ekholm K, Ek M, Thonberg H, Jemt A, Nilsson D, Eisfeldt J, Bilgrav Saether K, Höijer I, Akgun-Dogan O, Asano Y, Barakat TS, Batkovskyte D, Baynam G, Bodamer O, Chetruengchai W, Corcoran P, Couse M, Danis D, Demidov G, Dohi E, Erhardsson M, Fernandez-Luna L, Fujiwara T, Garg N, Giugliani R, Gonzaga-Jauregui C, Grigelioniene G, Groza T, Gunnarsson C, Hammarsjö A, Hammond CK, Hatirnaz Ng Ö, Hesketh S, Hettiarachchi D, Johansson Soller M, Kirmani UA, Kjellberg M, Kvarnung M, Kvlividze O, Lagerstedt-Robinson K, Lasko P, Lassmann T, Lau LYS, Laurie S, Lim WK, Liu Z, Lysenkova Wiklander M, Makay P, Maiga AB, Maya-González C, Meyn MS, Neethiraj R, Nigro V, Nordgren F, Nordlund J, Orrsjö S, Ottosson J, Ozbek U, Özdemir Ö, Partin C, Pearce DA, Peck R, Pedersen A, Pettersson M, Pongpanich M, Posada de la Paz M, Ramani A, Romero JA, Romero VI, Rosenquist R, Saw AM, Spencer M, Stattin EL, Srichomthong C, Tapia-Paez I, Taruscio D, Taylor JP, Tkemaladze T, Tully I, Tümer Z, van Zelst-Stams WAG, Verloes A, Västerviga E, Wang S, Yang R, Yamamoto S, Yépez VA, Zhang Q, Shotelersuk V, Wiafe SA, Alanay Y, Botto LD, Kirmani S, Lumaka A, Palmer EE, Puri RD, Wirta V, Lindstrand A, Buske OJ, Cederroth M, and Nordgren A

Published
2024
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132. Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature.

Author

Gazdagh G, Hunt D, Gonzalez AMC, Rodriguez MP, Chaudhry A, Madruga M, Vansenne F, Shears D, Curie A, Stattin EL, Anderlid BM, Trajkova S, Angelovska ES, McWilliam C, Wyatt PR, O'Driscoll M, Atton G, Bergman AK, Zacher P, Mewasingh LD, López AG, Alonso-Luengo O, Wai HA, Rohde O, Boiroux P, Debant A, Schmidt S, and Baralle D

Subjects
Humans, Phenotype, Mutation, Mutation, Missense, Microcephaly genetics, Nervous System Malformations
Abstract

The TRIO gene encodes a rho guanine exchange factor, the function of which is to exchange GDP to GTP, and hence to activate Rho GTPases, and has been described to impact neurodevelopment. Specific genotype-to-phenotype correlations have been established previously describing striking differentiating features seen in variants located in specific domains of the TRIO gene that are associated with opposite effects on RAC1 activity. Currently, 32 cases with a TRIO gene alteration have been published in the medical literature. Here, we report an additional 25, previously unreported individuals who possess heterozygous TRIO variants and we review the literature. In addition, functional studies were performed on the c.4394A > G (N1465S) and c.6244-2A > G TRIO variants to provide evidence for their pathogenicity. Variants reported by the current study include missense variants, truncating nonsense variants, and an intragenic deletion. Clinical features were previously described and included developmental delay, learning difficulties, microcephaly, macrocephaly, seizures, behavioral issues (aggression, stereotypies), skeletal problems including short, tapering fingers and scoliosis, dental problems (overcrowding/delayed eruption), and variable facial features. Here, we report clinical features that have not been described previously, including specific structural brain malformations such as abnormalities of the corpus callosum and ventriculomegaly, additional psychological and dental issues along with a more recognizable facial gestalt linked to the specific domains of the TRIO gene and the effect of the variant upon the function of the encoded protein. This current study further strengthens the genotype-to-phenotype correlation that was previously established and extends the range of phenotypes to include structural brain abnormalities, additional skeletal, dental, and psychiatric issues., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Published
2023
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134. Family History and Warning Symptoms Precede Sudden Cardiac Death in Arrhythmogenic Right Ventricular Cardiomyopathy (from a Nationwide Study in Sweden).

Author

Delgado-Vega AM, Kommata V, Svennblad B, Wisten A, Hagström E, and Stattin EL

Subjects
Death, Sudden, Cardiac epidemiology, Death, Sudden, Cardiac etiology, Humans, Risk Factors, Sweden epidemiology, Syncope epidemiology, Syncope etiology, Arrhythmogenic Right Ventricular Dysplasia complications, Arrhythmogenic Right Ventricular Dysplasia epidemiology, Arrhythmogenic Right Ventricular Dysplasia genetics
Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease explaining about 4% of sudden cardiac death (SCD) cases in the young in Sweden. This study aimed to describe the circumstances preceding SCD in all victims &lt;35 years of age who received an autopsy-confirmed diagnosis of ARVC from January 1, 2000, to December 31, 2010, in Sweden (n = 22). Data on demographics, medical and family history, circumstances of death, and anatomopathological findings were collected from several compulsory national health registries, clinical records, family interviews, and autopsy reports. Registry-based data were compared with age-matched, gender-matched, and geographically-matched population controls. During the 6 months preceding SCD, 15 cases (68%) had experienced symptoms of cardiac origin, mainly syncope or presyncope (54%) and chest discomfort (27%). A total of 8 cases (36%) had sought medical care because of cardiac symptoms. The occurrence of hospital visits was significantly increased in cases compared with controls (odds ratio 4.62 [1.35 to 15.8]). A total of 10 cases (45%) had a family history of SCD. The most common activity at the time of death was exercise (41%). A complete cardiac investigation was seldom performed; only 1 case was diagnosed with ARVC before death. In conclusion, in this nationwide study, we observed a high prevalence of symptoms of cardiac origin, healthcare use, and family history of SCD preceding SCD in the young caused by ARVC. Increased awareness of these warning signals in younger patients is critical to improving risk stratification and early disease detection., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2022
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135. Multi-Omic Investigations of a 17-19 Translocation Links MINK1 Disruption to Autism, Epilepsy and Osteoporosis.

Author

Eisfeldt J, Schuy J, Stattin EL, Kvarnung M, Falk A, Feuk L, and Lindstrand A

Subjects
Chromosome Mapping, Humans, Translocation, Genetic, Autistic Disorder genetics, Epilepsy genetics, Osteoporosis genetics, Protein Serine-Threonine Kinases genetics
Abstract

Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes and, in symptomatic carriers, pinpoint the disease-causing mechanisms. Here, we report an individual with autism, epilepsy and osteoporosis and a de novo balanced reciprocal translocation: t(17;19) (p13;p11). The genomic DNA was analyzed by short-, linked- and long-read genome sequencing, as well as optical mapping. Transcriptional consequences were assessed by transcriptome sequencing of patient-specific neuroepithelial stem cells derived from induced pluripotent stem cells (iPSC). The translocation breakpoints were only detected by long-read sequencing, the first on 17p13, located between exon 1 and exon 2 of MINK1 (Misshapen-like kinase 1), and the second in the chromosome 19 centromere. Functional validation in induced neural cells showed that MINK1 expression was reduced by >50% in the patient’s cells compared to healthy control cells. Furthermore, pathway analysis revealed an enrichment of changed neural pathways in the patient’s cells. Altogether, our multi-omics experiments highlight MINK1 as a candidate monogenic disease gene and show the advantages of long-read genome sequencing in capturing centromeric translocations.

Published
2022
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136. Spontaneous Coronary Artery Dissection and Papillary Muscle Rupture in Patient With Undiagnosed Vascular Ehler-Danlos Syndrome.

Author

Hopfgarten J, Christersson C, Forsblad J, Stattin EL, and Albåge A

Abstract

We present the case of a woman with acute coronary syndrome on the basis of spontaneous coronary artery dissection causing a papillary muscle rupture with severe mitral regurgitation and acute heart failure. The patient subsequently underwent successful emergent surgery of both the mitral and tricuspid valves. Postoperatively, the patient was diagnosed with vascular Ehlers-Danlos syndrome. ( Level of Difficulty: Advanced. )., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Published
2022
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137. Novel missense ACAN gene variants linked to familial osteochondritis dissecans cluster in the C-terminal globular domain of aggrecan.

Author

Stattin EL, Lindblom K, Struglics A, Önnerfjord P, Goldblatt J, Dixit A, Sarkar A, Randell T, Suri M, Raggio C, Davis J, Carter E, and Aspberg A

Subjects
Aggrecans genetics, Aggrecans metabolism, Humans, Mutation, Missense, Dwarfism genetics, Osteochondritis Dissecans congenital, Osteochondritis Dissecans genetics
Abstract

The cartilage aggrecan proteoglycan is crucial for both skeletal growth and articular cartilage function. A number of aggrecan (ACAN) gene variants have been linked to skeletal disorders, ranging from short stature to severe chondrodyplasias. Osteochondritis dissecans is a disorder where articular cartilage and subchondral bone fragments come loose from the articular surface. We previously reported a missense ACAN variant linked to familial osteochondritis dissecans, with short stature and early onset osteoarthritis, and now describe three novel ACAN gene variants from additional families with this disorder. Like the previously described variant, these are autosomal dominant missense variants, resulting in single amino acid residue substitutions in the C-type lectin repeat of the aggrecan G3 domain. Functional studies showed that neither recombinant variant proteins, nor full-length variant aggrecan proteoglycan from heterozygous patient cartilage, were secreted to the same level as wild-type aggrecan. The variant proteins also showed decreased binding to known cartilage extracellular matrix ligands. Mapping these and other ACAN variants linked to hereditary skeletal disorders showed a clustering of osteochondritis dissecans-linked variants to the G3 domain. Taken together, this supports a link between missense ACAN variants affecting the aggrecan G3 domain and hereditary osteochondritis dissecans., (© 2022. The Author(s).)

Published
2022
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138. Genetic and functional insights into CDA-I prevalence and pathogenesis.

Author

Olijnik AA, Roy NBA, Scott C, Marsh JA, Brown J, Lauschke K, Ask K, Roberts N, Downes DJ, Brolih S, Johnson E, Xella B, Proven M, Hipkiss R, Ryan K, Frisk P, Mäkk J, Stattin EM, Sadasivam N, McIlwaine L, Hill QA, Renella R, Hughes JR, Gibbons RJ, Groth A, McHugh PJ, Higgs DR, Buckle VJ, and Babbs C

Subjects
Anemia, Dyserythropoietic, Congenital pathology, Female, Gene Expression Regulation genetics, Genetic Testing, Genetics, Population, Humans, Male, Multiprotein Complexes genetics, Mutation genetics, Anemia, Dyserythropoietic, Congenital genetics, Genetic Predisposition to Disease, Glycoproteins genetics, Nuclear Proteins genetics, Transcription Factors genetics
Abstract

Background: Congenital dyserythropoietic anaemia type I (CDA-I) is a hereditary anaemia caused by biallelic mutations in the widely expressed genes CDAN1 and C15orf41 . Little is understood about either protein and it is unclear in which cellular pathways they participate., Methods: Genetic analysis of a cohort of patients with CDA-I identifies novel pathogenic variants in both known causative genes. We analyse the mutation distribution and the predicted structural positioning of amino acids affected in Codanin-1, the protein encoded by CDAN1 . Using western blotting, immunoprecipitation and immunofluorescence, we determine the effect of particular mutations on both proteins and interrogate protein interaction, stability and subcellular localisation., Results: We identify six novel CDAN1 mutations and one novel mutation in C15orf41 and uncover evidence of further genetic heterogeneity in CDA-I. Additionally, population genetics suggests that CDA-I is more common than currently predicted. Mutations are enriched in six clusters in Codanin-1 and tend to affect buried residues. Many missense and in-frame mutations do not destabilise the entire protein. Rather C15orf41 relies on Codanin-1 for stability and both proteins, which are enriched in the nucleolus, interact to form an obligate complex in cells., Conclusion: Stability and interaction data suggest that C15orf41 may be the key determinant of CDA-I and offer insight into the mechanism underlying this disease. Both proteins share a common pathway likely to be present in a wide variety of cell types; however, nucleolar enrichment may provide a clue as to the erythroid specific nature of CDA-I. The surprisingly high predicted incidence of CDA-I suggests that better ascertainment would lead to improved patient care., Competing Interests: Competing interests: JRH is a founder and shareholder of Nucleome Therapeutics., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2021
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139. Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome.

Author

Baderkhan H, Wanhainen A, Stenborg A, Stattin EL, and Björck M

Subjects
Adolescent, Adult, Aged, Dose-Response Relationship, Drug, Drug Administration Schedule, Ehlers-Danlos Syndrome complications, Feasibility Studies, Female, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Logistic Models, Male, Middle Aged, Retrospective Studies, Treatment Outcome, Young Adult, Adrenergic beta-1 Receptor Antagonists therapeutic use, Celiprolol therapeutic use, Ehlers-Danlos Syndrome drug therapy
Abstract

Objective: Vascular Ehlers-Danlos syndrome (vEDS) is a rare monogenetic disease caused by pathogenic variants in procollagen 3A1. Arterial rupture is the most serious clinical manifestation. A randomised controlled trial, the Beta-Blockers in Ehlers-Danlos Syndrome Treatment (BBEST) trial, reported a significant protective effect of the beta blocker celiprolol. The aim was to study the outcome of celiprolol treatment in a cohort of Swedish patients with vEDS., Methods: Uppsala is a national referral centre for patients with vEDS. They are assessed by vascular surgeons, angiologists, and clinical geneticists. Family history, previous and future clinical events, medication, and side effects are registered. Celiprolol was administered twice daily and titrated up to a maximum dose of 400 mg daily. Logistic regression was used to analyse predictors of vascular events., Results: Forty patients with pathogenic sequence variants in COL3A1 were offered treatment with celiprolol in the period 2011-2019. The median follow up was 22 months (range 1-98 months); total follow up was 106 patient years. In two patients, uptitration of the dose is ongoing. Of the remaining 38, 26 (65%) patients reached the target dose of 400 mg daily. Dose uptitration was unsuccessful in six patients because of side effects; one died before reaching the maximum dose, and five terminated the treatment. Five major vascular events occurred; four were fatal (ruptured ascending aorta; aortic rupture after type B dissection; ruptured cerebral aneurysm; and ruptured pulmonary artery). One bled from a branch of the internal iliac artery, which was successfully coiled endovascularly. The annual risk of a major vascular event was 4.7% (n = 5/106), similar to the treatment arm of the BBEST trial (5%) and lower than in the control arm of the same trial (12%). No significant predictor of vascular events was identified., Conclusion: Treatment with celiprolol is tolerated in most patients with vEDS. Despite fatal vascular events, these observations suggest that celiprolol may have a protective effect in vEDS., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2021
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141. A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders.

Author

Wilbe M, Gudmundsson S, Johansson J, Ameur A, Stattin EL, Annerén G, Malmgren H, Frykholm C, and Bondeson ML

Subjects
Female, Humans, Male, Mosaicism, Pregnancy, Preimplantation Diagnosis, Risk Assessment, DNA Mutational Analysis methods, Mandibulofacial Dysostosis diagnosis, Noonan Syndrome diagnosis, Nuclear Proteins genetics, Phosphoproteins genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics
Abstract

Objective: De novo mutations contribute significantly to severe early-onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred., Methods: We demonstrate the power of using SMRT sequencing and ddPCR to determine parental origin and allele frequencies of de novo mutations in germ cells in two families whom had undergone assisted reproduction., Results: In the first family, a TCOF1 variant c.3156C>T was identified in the proband with Treacher Collins syndrome. The variant affects splicing and was determined to be of paternal origin. It was present in <1% of the paternal germ cells, suggesting a very low recurrence risk. In the second family, the couple had undergone several unsuccessful pregnancies where a de novo mutation PTPN11 c.923A>C causing Noonan syndrome was identified. The variant was present in 40% of the paternal germ cells suggesting a high recurrence risk., Conclusions: Our findings highlight a successful strategy to identify the parental origin of mutations and to investigate the recurrence risk in couples that have undergone assisted reproduction with an unknown donor or in couples with gonadal mosaicism that will undergo preimplantation genetic diagnosis., (© 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Published
2017
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142. Generation of induced pluripotent stem cells (ARO-iPSC1-11) from a patient with autosomal recessive osteopetrosis harboring the c.212+1G>T mutation in SNX10 gene.

Author

Xu M, Stattin EL, Murphy M, and Barry F

Subjects
Adult, Female, Gene Expression, Humans, Mutation, Osteopetrosis metabolism, Osteopetrosis pathology, Sorting Nexins metabolism, Induced Pluripotent Stem Cells metabolism, Osteopetrosis genetics, Sorting Nexins genetics
Abstract

Pathogenic sequence variants in the Sorting Nexin 10 (SNX10) gene have been associated with autosomal recessive osteopetrosis (ARO) in human. In this study, an induced pluripotent stem cell (iPSC) line (ARO-iPSC1-11) was generated from an ARO patient carrying the homozygous c.212+1G>T mutation in SNX10, using a retroviral-based reprogramming protocol. Characterization confirmed that the generated iPSCs expressed pluripotency markers, displayed normal karyotype, showed pluripotent differentiation capacity and retained the targeted mutation. Disease modeling with this ARO patient-specific iPSC line will shed further light on the critical role of the SNX10 mutation in ARO development., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2017
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143. Sudden cardiac death among the young in Sweden from 2000 to 2010: an autopsy-based study.

Author

Wisten A, Krantz P, and Stattin EL

Subjects
Activities of Daily Living, Adolescent, Adult, Age Distribution, Arrhythmias, Cardiac pathology, Autopsy, Cause of Death, Child, Child, Preschool, Comorbidity, Databases, Factual, Death, Sudden, Cardiac pathology, Exercise, Female, Humans, Incidence, Infant, Male, Registries, Risk Factors, Sex Distribution, Sleep, Sweden, Time Factors, Young Adult, Arrhythmias, Cardiac mortality, Death, Sudden, Cardiac epidemiology
Abstract

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Published
2017
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144. Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum.

Author

Moutton S, Fergelot P, Naudion S, Cordier MP, Solé G, Guerineau E, Hubert C, Rooryck C, Vuillaume ML, Houcinat N, Deforges J, Bouron J, Devès S, Le Merrer M, David A, Geneviève D, Giuliano F, Journel H, Megarbane A, Faivre L, Chassaing N, Francannet C, Sarrazin E, Stattin EL, Vigneron J, Leclair D, Abadie C, Sarda P, Baumann C, Delrue MA, Arveiler B, Lacombe D, Goizet C, and Coupry I

Subjects
Alleles, Amino Acid Substitution, Exons, Facies, Female, Filamins genetics, Humans, Male, Pedigree, Sequence Analysis, DNA, Craniofacial Abnormalities diagnosis, Craniofacial Abnormalities genetics, Genetic Association Studies, Hand Deformities, Congenital diagnosis, Hand Deformities, Congenital genetics, Mutation, Osteochondrodysplasias diagnosis, Osteochondrodysplasias genetics, Phenotype
Abstract

Otopalatodigital spectrum disorders (OPDSD) constitute a group of dominant X-linked osteochondrodysplasias including four syndromes: otopalatodigital syndromes type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia, and Melnick-Needles syndrome. These syndromes variably associate specific facial and extremities features, hearing loss, cleft palate, skeletal dysplasia and several malformations, and show important clinical overlap over the different entities. FLNA gain-of-function mutations were identified in these conditions. FLNA encodes filamin A, a scaffolding actin-binding protein. Here, we report phenotypic descriptions and molecular results of FLNA analysis in a large series of 27 probands hypothesized to be affected by OPDSD. We identified 11 different missense mutations in 15 unrelated probands (n=15/27, 56%), of which seven were novel, including one of unknown significance. Segregation analyses within families made possible investigating 20 additional relatives carrying a mutation. This series allows refining the phenotypic and mutational spectrum of FLNA mutations causing OPDSD, and providing suggestions to avoid the overdiagnosis of OPD1.

Published
2016
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145. Genetic screening in sudden cardiac death in the young can save future lives.

Author

Stattin EL, Westin IM, Cederquist K, Jonasson J, Jonsson BA, Mörner S, Norberg A, Krantz P, and Wisten A

Subjects
Adolescent, Adult, Child, Child, Preschool, Death, Sudden, Cardiac etiology, Female, Forensic Genetics, Genetic Variation, Humans, KCNQ1 Potassium Channel genetics, Mutation, Prospective Studies, Sequence Analysis, DNA, Young Adult, Death, Sudden, Cardiac prevention & control, Genetic Carrier Screening, Genetic Testing, Long QT Syndrome genetics, Tachycardia, Ventricular genetics
Abstract

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.

Published
2016
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146. [Familial thoracic aortic aneurysms and dissections can be divided into three different main categories].

Author

Hannuksela M, Stattin EL, Nyberg P, and Carlberg B

Subjects
Humans, Mutation, Pedigree, Syndrome, Aortic Dissection diagnosis, Aortic Dissection etiology, Aortic Dissection genetics, Aortic Dissection prevention & control, Aortic Aneurysm, Thoracic diagnosis, Aortic Aneurysm, Thoracic etiology, Aortic Aneurysm, Thoracic genetics, Aortic Aneurysm, Thoracic prevention & control
Abstract

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.

Published
2014

147. [Sudden cardiac death among young people--important to find individuals at risk. A number of underlying diagnoses have been identified, several of them hereditary].

Author

Wisten A and Stattin EL

Subjects
Adolescent, Cardiovascular Diseases complications, Cardiovascular Diseases diagnosis, Cardiovascular Diseases genetics, Cause of Death, Death, Sudden, Cardiac epidemiology, Death, Sudden, Cardiac prevention & control, Female, Heart Defects, Congenital complications, Heart Defects, Congenital diagnosis, Heart Defects, Congenital genetics, Humans, Incidence, Life Style, Male, Risk Factors, Sports, Sweden epidemiology, Young Adult, Death, Sudden, Cardiac etiology
Published
2010

148. [Long QT syndrome can be effectively treated. Important to identify mutation carriers].

Author

Jensen SM, Stattin EL, and Rydberg A

Subjects
Adrenergic beta-Antagonists therapeutic use, Adult, Child, Child, Preschool, Female, Genetic Carrier Screening, Genetic Techniques, Humans, Infant, Male, Mutation, Missense, Pedigree, Pregnancy, Prenatal Diagnosis, Prognosis, Risk Assessment, Long QT Syndrome diagnosis, Long QT Syndrome drug therapy, Long QT Syndrome genetics
Published
2007

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