| 1. |
- Baturova, Maria A., et al.
(author)
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Evolution of P-wave indices during long-term follow-up as markers of atrial substrate progression in arrhythmogenic right ventricular cardiomyopathy
- 2021
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In: Europace. - : Oxford University Press. - 1099-5129 .- 1532-2092. ; 23:Supplement_1, s. i29-i37
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Journal article (peer-reviewed)abstract
- AIMS: Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) have increased prevalence of atrial arrhythmias indicating atrial involvement in the disease. We aimed to assess the long-term evolution of P-wave indices as electrocardiographic (ECG) markers of atrial substrate during ARVC progression.METHODS AND RESULTS: We included 100 patients with a definite ARVC diagnosis according to 2010 Task Force criteria [34% females, median age 41 (inter-quartile range 30-55) years]. All available sinus rhythm ECGs (n = 1504) were extracted from the regional electronic ECG databases and automatically processed using Glasgow algorithm. P-wave duration, P-wave area, P-wave frontal axis, and prevalence of abnormal P terminal force in lead V1 (aPTF-V1) were assessed and compared at ARVC diagnosis, 10 years before and up to 15 years after diagnosis.Prior to ARVC diagnosis, none of the P-wave indices differed significantly from the data at ARVC diagnosis. After ascertainment of ARVC diagnosis, P-wave area in lead V1 decreased from -1 to -30 µV ms at 5 years (P = 0.002). P-wave area in lead V2 decreased from 82 µV ms at ARVC diagnosis to 42 µV ms 10 years after ARVC diagnosis (P = 0.006). The prevalence of aPTF-V1 increased from 5% at ARVC diagnosis to 18% by the 15th year of follow-up (P = 0.004). P-wave duration and frontal axis did not change during disease progression.CONCLUSION: Initial ARVC progression was associated with P-wave flattening in right precordial leads and in later disease stages an increased prevalence of aPTF-V1 was seen.
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| 2. |
- Bergviken Rensfeldt, Annika, 1969, et al.
(author)
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Critically Examining Education Digitalisation – Nordic Empirical, Conceptual and Methodological Contributions
- 2023
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In: Symposium for the Nordic Education Research Association Conference, "Digitalization and Technologies in Education Opportunities and Challenges", 15-17 March 2023, Oslo Norway.
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Conference paper (other academic/artistic)abstract
- Symposium participants: Discussant(s): Neil Selwyn - Monash University, Australia 1 ‘We just have to trust them’ - Professional Responsibility in Digital Practices - Ida Martinez Lunde, University of Oslo 2 Lost in Digital Transformations? - Cathrine Tømte, University of Agder 3 Tracing Global Platformisation Locally: Differences and Inequalities in Teachers’ Digital Work in Publicly and Privately Owned Schools - Annika Bergviken Rensfeldt, Catarina Player-Koro, Thomas Hillman & Mona Lundin, University of Gothenburg 4 The Desires of Privatization in Ed-Tech Assemblages - Antti Paakkari, Anna Siippainen 5 Speculative Fiction of Digital Futures in Higher Education, Hanna Teräs, Marko Teräs & Juho Suoranta, Tampere University This symposium aims to draw together researchers engaged in research on education digitalisation in the Nordic countries who share an interest in critically examining how digital technologies are integrated into education systems, policies, institutions and practices. The overall question raised is: What are the critical issues on education digitalisation raised from the Nordic countries, and how can they be examined empirically, conceptually and methodologically? There are two important starting points for this symposium. Firstly, that the politico-economic push for education digitalisation is a decades-long process both on a global scale and within the Nordic countries. The ongoing push has had wide-ranging consequences for the power relations between public education, educational practices and actors as new alignments with private ed-tech businesses and digital platforms have been established. Secondly, that research on the topic is fruitfully based on the premise that many education practices nowadays are deeply interwoven with digital technologies and that new forms of inequalities and power imbalances appear. As the boundaries between digital and non-digital practices are blurring, this suggests that we re-think concepts and methods in line with the transformations referred to as the “postdigital turn” (Jandrić & Knox, 2022). The critical approaches often used in Nordic research on education digitalisation share interests in seeing digital technologies as mutually shaped with social practices, and education digitalisation as a dynamic and complex matter, played out socially, politically, economically and culturally. The research to be presented in this symposium includes, but is not limited to, explorations of concepts like relationality, processuality, network, assemblage, socio-materialism, and performativity (c.f. Castaneda & Williamson, 2021). As a part of this, a commonly shared interest is how different forms of education policy processes, regulations and discourses on digitalisation are enacted, translated and re-shaping education and educational practices. The research presented draws on ongoing discussions within critical and digital research in education, and on discussion of what the relevant contributions from the Nordic contexts are whether they be empirical, conceptual or methodological. The research to be discussed will include themes such as: –Platformisation, datafication and AI –Digital and non-digital inequalities and new power imbalances –Sustainable (post-)digital education work and futures The aim of the symposium is to address the NERA 2023 theme by: –providing empirical, conceptual and methodological contributions from scholars critically investigating opportunities and challenges related to the digitalisation of education. –identifying and discussing the critical questions and issues on the digitalisation of education that must be raised in the Nordic countries to create sustainable education systems that can contribute to the common good for both individuals and society.
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| 3. |
- Bergviken Rensfeldt, Annika, et al.
(author)
-
“I log in to several systems then I flip between them” : Teachers’ work in digital platform infrastructures.
- 2021
-
Conference paper (other academic/artistic)abstract
- School teachers’ work in the Nordics and elsewhere has become deeply affected by the ongoing school digitalization, through digital platform investments, digitalization reforms, and the pandemic situation. By focusing on how teachers’ work currently is shaped by emerging digital platform infrastructures, and how teachers’ themselves shape their digital work, this study aims to critically explore the implications of new platform ecologies. By drawing on a Swedish case project funded by Forte, we exemplify of how global commercial platform infrastructures have been integrated into and added to a highly marketized school system. While earlier studies critically approached school platform infrastructures mainly as managerial modes of governance, recent research has revealed its wider democratic implications for the public sector, e.g. the creating of technical lock-ins (Kerssens & van Dijck 2021). Based on a sociotechnical understanding of teachers’ digital work, digital platforms are not seen as simply ‘enablers’, but as agentic and carrying certain values alongside prescribed institutional uses that together regulate teacher work. Methodologically, trace and policy ethnography were used. First, we traced the digital work of four upper secondary school teachers (two men, two women) from two schools (one public municipal school, and one private consortia-owned school) via self-reported work activity time logs, followed up by focus group interviews, as well as a “go-along method”, for observing teachers’ online work. Lastly, we ‘moved out’ to trace the school and wider platform infrastructure from a national and international policy infrastructural perspective. Our preliminary results show how teachers operate within an institutional logic of bureaucratic, market and professional concerns (Friedson 2001) in their digital work, resulting in problems like work intensification and work-life imbalances. One related finding is also that different platform ecologies emerge across different private and public school forms. The dependence of global platform infrastructures in schools is currently increasing. This study hopefully can add a needed Nordic and critical dimension to how this affects teachers’ digital work.
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| 4. |
- Bergviken Rensfeldt, Annika, 1969, et al.
(author)
-
“I log in to several systems then I flip between them”: Teachers’ work in digital platform infrastructures.
- 2021
-
In: Paper for Nordic Educational Research Association (NERA), Odense, Denmark, 3-5 Nov 2021..
-
Conference paper (other academic/artistic)abstract
- School teachers’ work in the Nordics and elsewhere has become deeply affected by the ongoing school digitalization, through digital platform investments, digitalization reforms, and the pandemic situation. By focusing on how teachers’ work currently is shaped by emerging digital platform infrastructures, and how teachers’ themselves shape their digital work, this study aims to critically explore the implications of new platform ecologies. By drawing on a Swedish case project funded by Forte, we exemplify of how global commercial platform infrastructures have been integrated into and added to a highly marketized school system. While earlier studies critically approached school platform infrastructures mainly as managerial modes of governance, recent research has revealed its wider democratic implications for the public sector, e.g. the creating of technical lock-ins (Kerssens & van Dijck 2021). Based on a sociotechnical understanding of teachers’ digital work, digital platforms are not seen as simply ‘enablers’, but as agentic and carrying certain values alongside prescribed institutional uses that together regulate teacher work. Methodologically, trace and policy ethnography were used. First, we traced the digital work of four upper secondary school teachers (two men, two women) from two schools (one public municipal school, and one private consortia-owned school) via self-reported work activity time logs, followed up by focus group interviews, as well as a “go-along method”, for observing teachers’ online work. Lastly, we ‘moved out’ to trace the school and wider platform infrastructure from a national and international policy infrastructural perspective. Our preliminary results show how teachers operate within an institutional logic of bureaucratic, market and professional concerns (Friedson 2001) in their digital work, resulting in problems like work intensification and work-life imbalances. One related finding is also that different platform ecologies emerge across different private and public school forms. The dependence of global platform infrastructures in schools is currently increasing. This study hopefully can add a needed Nordic and critical dimension to how this affects teachers’ digital work. References Freidson, E. (2001). Professionalism, the third logic: On the practice of knowledge. Uni of Chicago Press. Kerssens, N., & van Dijck, J. (2021). The platformization of primary education in The Netherlands. Learning, Media and Technology 46(3), 250-263. DOI: 10.1080/17439884.2021.1876725
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| 5. |
- Bergviken Rensfeldt, Annika, 1969, et al.
(author)
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Pressed for Time? : How Platform Infrastructures and Professional Demands condition Teachers’ Digital Work
- 2021
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In: European Conference on Educational Research.
-
Conference paper (peer-reviewed)abstract
- What had often been praised by techno-enthusiasts as “disruption” and “innovation” became more of a harsh reality during 2020 with the fast reorganization to online learning due to the pandemic. With a short timeframe, schools were forced to prepare for distance education and teachers had to adapt, creating online teaching activities while at the same time making sure students were well-cared for educationally, socially, emotionally, and technologically. With the fast reorganization to online learning during the pandemic, the global platform market received more influence and further reached into the core of schools’ everyday work (Williamson & Hogan, 2020). In this sense, fast digitalization has not only made the political economy of school digitalization more apparent, but also highlights how digital work is conditioned by time and the socio-technical coordination of people and technologies (Wajcman, 2015). This paper focus on how teachers regulate and are regulated by digital platform work and in particular, how digital work is regulated by time in different ways. Our interest is both the kind of work done by teachers on digital platforms and how platform infrastructures condition and challenge teachers’ work and work time. The purpose is to explore and problematize the temporal governance of digital work, inscribed in the uses and logics of digital platforms, and forms of governing powers where productivity is considered core value. Analytically, instances where there are pronounced tensions in terms of temporal issues, between the demands of digital infrastructures or professional performance, and school teachers’ everyday work priorities and regulated work hours is of particular interest. The study builds on analyses of already identified tensions in relation to school reforms more generally as existing between the regulating principles of market efficiency governance and the teaching profession’s work conditions (Anderson & Cohen, 2015; Ball, 2003; Lundström & Parding, 2011). The political economy that pushes for school digitization was already strong in Europe and many other parts of the world before the pandemic began. Platform infrastructures, commonly provided by global platform businesses like Google and Microsoft and through Learning Management Systems are not exotic anymore, but are instead everyday technologies in workplaces like schools. Even so, platform technology provided by for example Google increasingly has taken the role of an infrastructure, sociotechnically connecting clouds, software, people, data (Plantin et al., 2018). This “platformization” comes with the business logic of platform capitalism (Srnicek, 2017), profiting on the individuals’ data production with the arguments of making public sector workplaces more efficient and streamlined, and of facilitating teachers’ pedagogical and administrative work. Questions around workload and the intensification of teachers’ work have once again risen up the political agenda (c.f. Fitzgerald et al., 2019). However, research on how school teachers’ work and work situations are changing in relation to digitalization still is relatively scarce (Bergviken Rensfeldt, Hillman, Selwyn, 2018; Selwyn, 2020; Selwyn, Nemorin & Johnson, 2017; Shulte, 2019). We draw on a Swedish project case, in collaboration with and extending an Australian project (e.g. Selwyn, Nemorin & Johnson, 2017). Empirical material was collected in and connected to the digital work of teachers in two upper secondary school forms, two school forms that characterize the Swedish marketized education system, namely, one public school and one independent for-profit school. Methodologically, the ethnographical approach used is policy and infrastructure ethnography, combined with trace ethnography of teachers’ online and offline work. Methodology, Methods, Research Instruments or Sources Used For conducting the policy ethnography, we firstly examined the policies and infrastructures implicated in teachers’ work, combining analyses of policies and platform technologies (Kitchen & Laurialt, 2014). Policy material from the regional municipality or school consortia organizations of the two schools, including extensions to national and European or international levels, e.g. strategies, guidelines, agreements on work time, digital work and platform infrastructure implementation, maintenance and support, was combined with analyses of the digital platforms and applications used in the school organizations of the participating teachers in the study. Further information from stakeholders like IT management or external platform provider companies on decisions, regulations and functionality on these different levels of platform use or data platform infrastructures, e.g. classifications of work activities in data platform standards was also collected via policy documents and interviews. Starting from the schools in the selection of policies and moving out from them, have resulted in a variety of policies that can be considered influencing digital work. In line with this, rather than regarding policies as archival documents, we aimed at selecting policies that were in use, “at work” and perhaps contested in the school workplaces in different ways. The trace ethnography started with four teachers (one man and one woman from each school) self-reporting their own activity logs on digital work based on three selected work days, followed up by a form of online focus group interview which was based on the logs and questions raised from the researchers and focus of the study. The teachers were then also involved in identifying and documenting their own data production and the traces they leave on different digital platforms via a digital self-tracking application capturing time-based screen activity. Conducting digital trace ethnography raise ethical concerns around private integrity which we have tried to counteract by involving the teacher participants themselves in self-tracking of their digital activities of work and by providing tools (self-reported activity logs included) allowing self-reflection of when and where their digital work takes place. The integrative trace ethnography approach (Geiger & Ribes, 2011) used, hence include both ethnographic and computational social science methods. These methods are themselves characterized by temporal categories, timelines, etc. but invites for making visible different temporalities in the ethnographic material. Conclusions, Expected Outcomes or Findings Digital work was analyzed based on tensions between temporalities that could be both static and dynamic but nonetheless were shaping teachers’ work (c.f. Thompson & Cook, 2017). The temporalities were understood as constructs and intertwined with spatialities of school teachers’ digital work. A preliminary finding is that digital work of online learning follows the assigned task and rhythms of schooling, but also extends more widely with the global time of digital platforms and the different temporalities produced in such environments, expanding, fragmentarizing and interrupting work in different ways. In line with Alirezabeigi, Masschelein & Decuypere (2020, p. 203), the digital work activities “not only follow the school time-table and the script of the teacher, but it equally follows the global time”. For example, the analyses included the teacher’s officially-regulated working hours in terms of classroom and workplace time, their self-regulated work time (“förtroendearbetstid”) as well as non-regularized time, all governed by certain ideals of performativity (c.f. Ball, 2003). Similarly, such entities were also translated into platforms datafication classifications of standard school activities (mainly teaching, examining and “other activities”). Hence, digital work temporalities were co-created with the operating tasks prompted by commercial platforms and activities inscribed in the systems, and the overall life cycles of platform infrastructures (updates, procurements, etc). Furthermore, the pandemic situation from March 2020 made certain temporalities around digital work visible, describing a “before-during-after Corona”, with transformed digital work experiences around attending to students and fulfilling new work tasks, implicating work intensification, strategies for work-life balance and coping with presence bleed. In sum, different temporalities and concerns in teachers’ digital work are at work, co-shaped by professional concerns, and the political economy and governance of platform infrastructures, which further add to the aforementioned research which identified tensions of market governance and teachers’ work conditions and professional concerns. References Alhadeff-Jones, M. (2018). Time and the Rhythms of Emancipatory Education Rethinking the temporal complexity of self and society. Routledge. Alirezabeigi, S., Masschelein, J., & Decuypere, M. (2020). Investigating digital doings through breakdowns: a sociomaterial ethnography of a Bring Your Own Device school, Learning, Media and Technology, 45(2), 193-207. Anderson, G., & Cohen, M I. (2015). Redesigning for identities of teachers and leader: A framework for studying new professionalism and educator resistance. Education Policy Archives, 23(85), 1-25. Ball, S. J. (2003) “The Teacher’s Soul and the Terrors of Performativity.” Journal of Education Policy 18(2), 215-228. Bergviken Rensfeldt, A., Hillman, T., & Selwyn, N. (2018). Teachers ‘liking’ their work? Exploring the realities of teacher Facebook groups. British Journal of Education Research, 44(2), 230-250. Decuypere, M. & Vanden Broeck, P. (2020). Time and educational (re-)forms: Inquiring the temporal dimension of education, Educational Philosophy and Theory, 52(6), 602-612. Fitzgerald, S., McGrath-Champ, S., Stacey, M., Wilson, R. & Gavin, M. (2019). Intensification of teachers’ work under devolution:
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| 6. |
- Bergviken Rensfeldt, Annika, 1969, et al.
(author)
-
Teachers’ (future) digital work within platform infrastructures
- 2021
-
In: Paper for "The Future of Work" - examining discourses and social practices. International and interdisciplinary conference, Sorbonne University, Paris, France November 25-26, 2021..
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Conference paper (other academic/artistic)abstract
- This paper focuses on the inscribed uses and imaginaries of teachers’ digital work, currently formed through school platform infrastructures. Based on Swedish and Australian project cases, where the public education sector has experienced a substantial marketization and deep penetration of commercial platform infrastructures, we explore current imaginaries and driving forces of digital work. Our ethnographical material is teacher and management interviews, platform studies, activity logs and infrastructural policies. Theoretically, we approach digital work as constituted by socio-technical assemblages, made from social practices and technology inscriptions within cross-platform infrastructures (Plantin et al 2018), that prescribe particular forms of digital work, which make the existing and future work of teachers visible, thinkable and actionable in particular ways. From our two cases superficial differences appear but ultimately the same logics are evident; a highly visible discourse of the teacher professional, in charge of the platform work and simply supported or augmented in their professional judgements. One example is how platform providers and policies promote interoperability and automation across platforms (cf. Perotta et al 2021). In reality and in combination with the business logic of educational platforms (Kerssens & van Dijck 2021), the discourse is highly questionable. It positions teachers as rentieers (Komljenovic 2021), expected to manage digital work seamlessly regardless of platform provider or accompanied by a (robot) colleague or application (Selwyn 2021). Concurrently, teachers are expected to act as creators of school data production for providing school results (Foucault 1975) on platforms where data exploitation however is rule and data ownership unregulated. At least three powerful forces elevate the digital work; 1) disruptive situations, such as the COVID-19 pandemic where teachers are to solve the situation, 2) public sector reform, exposing teachers to increased public accountability, and 3) teacher care for students to provide social support and compensating for structural inequalities. References: Foucault, M. (1975). Surveiller et punir. Gallimard. Kerssens, N., & van Dijck, J. (2021). The platformization of primary education in The Netherlands. Learning, Media and Technology. DOI: 10.1080/17439884.2021.1876725 Komljenovic, J. (2021). The rise of education rentiers: digital platforms, digital data and rents, Learning, Media and Technology, DOI: 10.1080/17439884.2021.1891422 Perotta, C., Gulson K.N., Wiliamson, B., and Witzenberger K. (2021). Automation, APIs and the distributed labour of platform pedagogies in Google Classroom. Critical Studies in Education, 62(1): 97- 113. https://doi.org/10.1080/17508487.2020.1855597 Plantin, J.-C., Lagoze, C., Edwards, P. N., & Sandvig, C. (2018). Infrastructure studies meet platform studies in the age of Google and Facebook. New Media & Society, 20(1), 293-310. Selwyn, N. (2021). Digital labor meets the classroom. Research Intelligence, 145. http://der.monash.edu/wp-content/uploads/2021/01/Research-Intelligence-DEC-2020.pdf
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| 7. |
- Bergviken Rensfeldt, Annika, 1969, et al.
(author)
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Tracing Global Platformisation Locally: Differences and Inequalities in Teachers’ Digital Work in Publicly and Privately Owned Schools
- 2023
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In: Paper for The Nordic Education Research Association Conference "Digitalization and Technologies in Education Opportunities and Challenges" 15-17 March 2023, Oslo Norway.
-
Conference paper (other academic/artistic)abstract
- The research critically examining the platformisation and integration of global Big Tech - Google (Alphabet), Apple, Facebook (Meta), Amazon, and Microsoft - into education has grown considerably, as shown in recent special-issued and thematic journals (Decuypere et al., 2021; Nichols & Garcia, 2022). One critical question raised in the research is how the integration of platforms have created infrastructural lock-in effects as part of its business model (Kerssens & van Dijck, 2021). Therefore, as education institutions procure platform-compatible hardware, systems and apps, they not only buy into specific platform infrastructural ecosystems, they also need to accept their data extraction, automated synchronisations and algorithmic orderings of content. Based on a working life-funded research project study, we aim to show how the global platformisation is co-shaped by local edtech market governance and public procurement regulations within a domestic setting. This, we argue, creates different digital ecosystems and work conditions for schools and teachers. For investigating platformisation’s local establishments and consequences, we have ethnographically traced teachers’ work relating to platforms in the Swedish setting based on its two school ownership forms, public and private schools. This has been done from within, by shadowing teacher work and engaging them in reflective interviews, and out to policy ethnographies on platformisation regulations.The latter included that we infrastructurally traced the digital ecosystems of public and private schools by scraping techniques that mapped service providers that form their platform infrastructures respectively. We were able to match the service providers active in the Swedish edtech-market (visible in ‘the Edtech-map’, edtechkartan.se) with their school-clients. Even if there are many similarities in how education institutions and teacher work are conditioned by platformisation, significant differences appear. In contrast to private education who can set up their platform infrastructures more freely, public institutions are regularly required to perform labour-intensive public procurements of platforms and devices. These processes cause interruptions that require extra work and repairs. The study follows up on the forced acceleration of platformisation due to the pandemic in the Nordic and European countries (Cone et al., 2021). In particular, it should contribute methodologically and empirically to show the powers of platformisation are played out in local settings and affect the work and labour of teachers differently and unequally. The paper raises questions on how more sustainable work situations for teachers are possible as schools are platformised. References Decuypere, M., Grimaldi, E., & Landri, P. (2021). Introduction: Critical studies of digital education platforms. Critical Studies in Education, 62(1), 1-16. Nichols, T.P., & Garcia, A. (2022). Platform Studies in Education. Harvard Educational Review 92(2), 209-230. https://doi.org/10.17763/1943-5045-92.2.209 Cone, L., Brøgger, K., Berghmans, M., Decuypere, M., Förschler, A., Grimaldi, E., Hartong, S., Hillman, T., Ideland, M., Landri, P., van de Oudeweetering, K., Player-Koro, C., Bergviken Rensfeldt, A., Ronnberg, L., Taglietti, D., Vanermen, L. (2021). Pandemic acceleration: COVID-19 and the emergency digitalization of European education. European Educational Research Journal 21(5), 845–868.
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| 8. |
- Fernlund, Eva, et al.
(author)
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Novel Mutation in the KCNJ2 Gene Is Associated with a Malignant Arrhythmic Phenotype of Andersen-Tawil Syndrome.
- 2013
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In: Annals of Noninvasive Electrocardiology. - : Wiley. - 1082-720X. ; 18:5, s. 471-478
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Journal article (peer-reviewed)abstract
- Andersen-Tawil syndrome (ATS) is a rare inherited multisystem disorder associated with mutations in KCNJ2 and low prevalence of life-threatening ventricular arrhythmias. Our aim was to describe the clinical course of ATS in a family, in which the proband survived aborted cardiac arrest (ACA) and genetic screening revealed a previously unknown mutation (c.271_282del12[p.Ala91_Leu94del]) in the KCNJ2 gene.
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| 9. |
- Guenat, David, et al.
(author)
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Constitutional and somatic deletions of the Williams-Beuren syndrome critical region in Non-Hodgkin Lymphoma
- 2014
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In: Journal of Hematology & Oncology. - : Springer Science and Business Media LLC. - 1756-8722. ; 7
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Journal article (other academic/artistic)abstract
- Here, we report and investigate the genomic alterations of two novel cases of Non-Hodgkin Lymphoma (NHL) in children with Williams-Beuren syndrome (WBS), a multisystem disorder caused by 7q11.23 hemizygous deletion. Additionally, we report the case of a child with NHL and a somatic 7q11.23 deletion. Although the WBS critical region has not yet been identified as a susceptibility locus in NHL, it harbors a number of genes involved in DNA repair. The high proportion of pediatric NHL reported in WBS is intriguing. Therefore, the role of haploinsufficiency of genes located at 7q11.23 in lymphomagenesis deserves to be investigated.
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| 10. |
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| 11. |
- Ljunger, Elisabeth, et al.
(author)
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Ultrasonographic findings in spontaneous miscarriage : relation to euploidy and aneuploidy
- 2011
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In: Fertility and Sterility. - : Elsevier BV. - 0015-0282 .- 1556-5653. ; 95:1, s. 221-224
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To evaluate a possible correlation between transvaginal ultrasound findings in miscarriages and cytogenetic analyses from chorionic villi obtained by dilatation and curettage. DESIGN: Prospective, population-based study. SETTING: University-based hospital. PATIENT(S): Five hundred seventy-six women with spontaneous miscarriage diagnosed between 6 and 12 completed pregnancy weeks. INTERVENTION(S): Transvaginal ultrasonography and dilatation and curettage. MAIN OUTCOME MEASURE(S): Cytogenetic analyses and ultrasound measurement of embryonic pole. RESULT(S): The mean gestational age was 9.5 weeks. Chromosomal analyses were successful in 259 cases, 159 with cytogenetic abnormalities and 100 euploidy. Empty gestational sacs were equally often found in euploidy and aneuploidy, whereas small embryonic or fetal poles were significantly more often associated with aneuploidy. CONCLUSION(S): A smaller than expected fetal size when a miscarriage is diagnosed during the first trimester is significantly associated with a chromosomal aberration.
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| 12. |
- Lundin, Catarina, et al.
(author)
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B-cell precursor t(8;14)(q11;q32)-positive acute lymphoblastic leukemia in children is strongly associated with Down syndrome or with a concomitant Philadelphia chromosome.
- 2009
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In: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 82:1, s. 46-53
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Journal article (peer-reviewed)abstract
- We review the clinical and cytogenetic features of 44 acute lymphoblastic leukemias (ALLs) with t(8;14)(q11;q32), including three from our department and 41 ascertained in the literature, focusing on age and gender distribution, peripheral blood values, immunophenotypic data, survival and additional chromosomal changes. Most patients are children or young adults, with a median age of 10 yr for children and 28 for adults. There is a male preponderance, particularly in patients with Down syndrome (DS) or in children with concomitant t(9;22)(q34;q11). The median blood values are hemoglobin 72 g/L, platelets 17 x 10(9)/L and white blood cell count 9 x 10(9)/L, with hyperleukocytosis >50 x 10(9)/L having been reported in only approximately 10%. All reported cases have had a B-cell precursor immunophenotype, typically characterized by CD10+, CD19+, CD20+/-, CD22+, CD24+, CD34+, CD45dim/-, CD66c+/- and CD123+. At the time of reporting, 75% of the patients have been alive. The t(8;14) is the sole acquired change in 30%. The most common additional aberrations are t(9;22)(q34;q11), der(14)t(8;14), +21, +X and +14, the presence of which does not seem to confer a prognostic impact. A substantial proportion of the patients have DS (27%) or t(9;22) (16%). All patients with both t(8;14) and t(9;22) have been children without DS; the frequency of t(9;22) in that cohort is 30%. As t(9;22), or its molecular genetic correlate, may escape detection by conventional banding analysis we would strongly suggest that this aberration is actively looked for in pediatric ALL with t(8;14).
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| 13. |
- Lundin, Catarina, et al.
(author)
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Clinical and genetic features of pediatric acute lymphoblastic leukemia in Down syndrome in the Nordic countries
- 2014
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In: Journal of Hematology & Oncology. - : Springer Science and Business Media LLC. - 1756-8722. ; 7, s. 32-
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Journal article (peer-reviewed)abstract
- Background: Children with Down syndrome (DS) have an increased risk for acute lymphoblastic leukemia (ALL). Although previous studies have shown that DS-ALL differs clinically and genetically from non-DS-ALL, much remains to be elucidated as regards genetic and prognostic factors in DS-ALL. Methods: To address clinical and genetic differences between DS-ALL and non-DS-ALL and to identify prognostic factors in DS-ALL, we ascertained and reviewed all 128 pediatric DS-ALL diagnosed in the Nordic countries between 1981 and 2010. Their clinical and genetic features were compared with those of the 4,647 B-cell precursor (BCP) ALL cases diagnosed during the same time period. Results: All 128 DS-ALL were BCP ALL, comprising 2.7% of all such cases. The 5-year event-free survival (EFS) and overall survival (OS) were significantly (P = 0.026 and P = 0.003, respectively) worse for DS-ALL patients with white blood cell counts >= 50 x 10(9)/l. The age distributions varied between the DS and non-DS cases, with age peaks at 2 and 3 years, respectively; none of the DS patients had infant ALL (P = 0.029). The platelet counts were lower in the DS-ALL group (P = 0.005). Abnormal karyotypes were more common in non-DS-ALL (P < 0.0001), and there was a significant difference in the modal number distribution, with only 2% high hyperdiploid DS-ALL cases (P < 0.0001). The 5-year EFS and 5-year OS were significantly worse for DS-ALL (0.574 and 0.691, respectively) compared with non-DS-ALL (0.783 and 0.894, respectively) in the NOPHO ALL-1992/2000 protocols (P < 0.001). Conclusions: The present study adds further support for genetic and clinical differences between DS-ALL and non-DS-ALL.
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| 14. |
- Lundin, Catarina
(author)
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Cytogenetic studies of benign breast lesions
- 1998
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Doctoral thesis (other academic/artistic)abstract
- In the present thesis benign breast lesions of various histologies, i.e., fibrocystic lesions from women with and without a known hereditary predisposition to breast cancer, fibroadenomas, phyllodes tumors, and papillomas were cytogenetically investigated with the aim to characterize the chromosomal patterns, and to relate the findings with those in breast carcinomas. No lesion-specific aberration was detected; on the contrary, changes repeatedly encountered in short-term cultures from breast cancer samples were found in these benign entities as well, e.g., gain of 1q, interstitial deletion of 3p, and trisomies 7, 18, and 20, and some cases even displayed cytogenetic polyclonality. Especially intriguing is the prevalence of rearrangements of the short arm of chromosome 3, with the minimally deleted bands 3p13-14, in proliferative lesions from prophylactic mastectomies in breast cancer families. The potential tumor suppressor gene(s) in this region remains, however, to be identified. In general, the frequency of benign cases with chromosome abnormalities is lower compared to breast cancer, and seems to correlate with the histologic features of the tissue, and the corresponding risk of developing invasive mammary carcinoma. The anomalies are generally less complex than those detected in invasive carcinoma, and more often involve balanced rearrangements. Furthermore, the degree of cytogenetic complexity seems to correlate with the description of a phyllodes tumor as benign or malignant: malignant phyllodes tumors have a more complex karyotype.
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| 15. |
- Lundin, Catarina, et al.
(author)
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High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome
- 2012
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In: Genes, Chromosomes and Cancer. - Malden : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 51:2, s. 196-206
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Journal article (peer-reviewed)abstract
- Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as less than10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrentdup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent.
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| 16. |
- Lundin, Catarina, et al.
(author)
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Submicroscopic genomic imbalances in burkitt lymphomas/leukemias : Association with age and further evidence that 8q24/MYC translocations are not sufficient for leukemogenesis
- 2013
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In: Genes, Chromosomes and Cancer. - : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 52:4, s. 370-377
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Journal article (peer-reviewed)abstract
- Chromosome banding analyses reveal secondary chromosome abnormalities in addition to the MYC translocations t(8;14)(q24;q32), t(8;22)(q24;q11), and t(2;8)(p11;q24) in 60%80% of Burkitt lymphomas/leukemias (BL). The high incidence of such aberrations indicates that additional changes are important, perhaps necessary, for malignant transformation, i.e., the 8q24/MYC rearrangements may not be sufficient. To investigate this possibility, we performed single nucleotide polymorphism (SNP) array analysis on 20 cases of 8q24/MYC-positive BL. Nineteen (95%) harbored genomic imbalances; the only case without such aberrations displayed secondary changes by chromosome banding analysis. Thus, all BL cases had abnormalities in addition to the 8q24 translocation. The adult cases harbored more changes (median 3; range 121) than did the childhood cases (median 1.5; range 05) (P = 0.034). Several recurrent aberrations were detected by SNP array analysis, in particular losses of 6q14.1-q22.33, 9p21.3, and 13q14.2-q14.3, gains of 1q23.3-q31.3, chromosome 7, 13q31.3, and partial uniparental isodisomies for 6p12.2-pter, 9p23-pter, and 17p11.2-pter. The molecular genetic consequences of these changes include deletions of the CDKN2A and TP53 genes, and gains/losses of several genes, such as MIR17HG and E2F2K, involved in the MYC pathway. Thus, deregulation of the MYC pathway, both directly through the 8q24/MYC translocation and indirectly through secondary genomic imbalances, may be essential not only for the initiation but also for the progression of BL.
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| 17. |
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| 18. |
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| 19. |
- Lundin, Catarina, et al.
(author)
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Tiling resolution array CGH of dic(7;9)(p11 approximately 13;p11 approximately 13) in B-cell precursor acute lymphoblastic leukemia reveals clustered breakpoints at 7p11.2 approximately 12.1 and 9p13.1.
- 2007
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In: Cytogenetic and Genome Research. - : S. Karger AG. - 1424-859X .- 1424-8581. ; 118:1, s. 13-18
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Journal article (peer-reviewed)abstract
- The dic( 7; 9)( p11 similar to 13; p11 similar to 13) is a recurrent chromosomal abnormality in acute lymphoblastic leukemia (ALL), mainly of B-lineage. Although more than 20 dic(7; 9)-positive ALLs have been reported to date, the molecular genetic consequences of this aberration are unknown. We performed tiling resolution (32K) genome-wide array-based comparative genomic hybridization ( array CGH) analysis of three cases with dic(7; 9) in order to characterize the breakpoints on 7p and 9p. The analysis showed a clustering of breakpoints within 9p13.1 in all three cases and within 7p11.2 in two cases; the array CGH revealed two different breakpoints - 7p12.1 and 7p14.1 - in the remaining case. Based on these findings the abnormality should hence be designated dic(7; 9)(p11.2 similar to 12.1; p13.1). Locus-specific fluorescence in situ hybridization analysis of one of the cases narrowed down the 7p11.2 breakpoint to a < 500-kb segment in this sub-band, a region containing three known genes. Unfortunately, lack of material precluded further molecular genetic studies, and it thus remains unknown whether the pathogenetically important outcome of the dic(7; 9) is formation of a chimeric gene or loss of 7p and/or 9p material. Copyright (c) 2007 S. Karger AG, Basel.
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| 20. |
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| 21. |
- Meinert, Monika, et al.
(author)
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Danon disease presenting with early onset of hypertrophic cardiomyopathy and peripheral pigmentary retinal dystrophy in a female with a de novo novel mosaic mutation in the LAMP2 gene
- 2019
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In: Ophthalmic Genetics. - : Informa UK Limited. - 1381-6810 .- 1744-5094. ; 40:3, s. 227-236
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Journal article (peer-reviewed)abstract
- Purpose: To describe the phenotype and genotype in a young woman with Danon disease. Methods: The patient underwent an ophthalmic examination including best corrected visual acuity (BCVA), fundus photography and fundus autofluorescence (FAF), full-field electroretinography (full-field ERG), multifocal ERG, optical coherence tomography (OCT) and SAP-Humphrey 30-2 at the ages of 20 and 25. Electrooculography, fluorescein angiography (FA), indocyanine angiography and OCT angiography were performed only once. Genetic testing using a Next-Generation Sequencing panel and immunohistochemical analysis of LAMP2 protein expression were performed in the patient's explanted heart, and the patient's cardiologic and ophthalmologic records were retrospectively reviewed. Results: A de novo, novel, mosaic mutation, c.135dupA; p.(Trp46Metfs*10) was identified in exon 2 of the LAMP2 gene. Immunohistochemical investigation of the myocardium in the explanted heart revealed pronounced deficiency of LAMP2 protein in cardiomyocytes. The color photographs, FAF images and FA revealed more extensive peripheral pigmentary retinal dystrophy (PPRD) at the 5-year follow-up examination. No changes were observed in BCVA, OCT, SAP-Humphrey 30-2 or multifocal ERG findings at follow-up. Full-field ERG showed an asymmetric interocular reduction in ERG response at follow-up: the b-wave amplitude of the rod response had decreased by 29% in the right eye, but by only 6 % in the left eye. The a-wave amplitude of single-flash response had decreased by 9 % in the left eye, while it had increased by 3% in the right eye. Conclusions: Although PPRD progressed slowly, it was an important clue in the diagnosis of the life-threatening condition of Danon disease.
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| 22. |
- Mukama, Trasias, et al.
(author)
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Prospective evaluation of 92 serum protein biomarkers for early detection of ovarian cancer
- 2022
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In: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 126, s. 1301-1309
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Journal article (peer-reviewed)abstract
- Background: CA125 is the best available yet insufficiently sensitive biomarker for early detection of ovarian cancer. There is a need to identify novel biomarkers, which individually or in combination with CA125 can achieve adequate sensitivity and specificity for the detection of earlier-stage ovarian cancer.Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we measured serum levels of 92 preselected proteins for 91 women who had blood sampled ≤18 months prior to ovarian cancer diagnosis, and 182 matched controls. We evaluated the discriminatory performance of the proteins as potential early diagnostic biomarkers of ovarian cancer.Results: Nine of the 92 markers; CA125, HE4, FOLR1, KLK11, WISP1, MDK, CXCL13, MSLN and ADAM8 showed an area under the ROC curve (AUC) of ≥0.70 for discriminating between women diagnosed with ovarian cancer and women who remained cancer-free. All, except ADAM8, had shown at least equal discrimination in previous case-control comparisons. The discrimination of the biomarkers, however, was low for the lag-time of >9–18 months and paired combinations of CA125 with any of the 8 markers did not improve discrimination compared to CA125 alone.Conclusion: Using pre-diagnostic serum samples, this study identified markers with good discrimination for the lag-time of 0–9 months. However, the discrimination was low in blood samples collected more than 9 months prior to diagnosis, and none of the markers showed major improvement in discrimination when added to CA125.
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| 23. |
- Myrin Westesson, Linda, et al.
(author)
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A tortuous route to a capable fatherhood: the experience of being a father to a child with severe haemophilia
- 2015
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In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 21:6, s. 799-805
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Journal article (peer-reviewed)abstract
- Introduction: Haemophilia is a chronic illness that affects the whole family as the child’s reactions to the illness occur in interaction with the parents. Limited research has been conducted on how fathers of children with haemophilia experience their life situation. Aim: The aim of this study was to describe the lived experience of being a father to a child with severe haemophilia. Method: Individual, qualitative interviews were conducted with 14 fathers of 17 children with severe Haemophilia A. Data were analysed by means of a phenomenological hermeneutic method, including na€ıve reading, structural analysis and comprehensive interpretation. Results: The results revealed that the fathers gradually grew into fatherhood through a process that can be explained in the metaphor, ‘A tortuous road to a capable fatherhood’. The fathers experienced sorrow, powerlessness, concern and loss of a regular fatherhood after the child’s diagnosis. The loss of an envisaged fatherhood emerged as the greatest sorrow of being a father to a child with haemophilia. When home treatment with factor concentrates functioned without the involvement of Health Care Personal (HCP), the fathers’ sense of insufficiency decreased. Conclusion: A sense of being a capable father was associated with a sense of independence and control of one’s life situation. Support from the Haemophilia Treatment Centre (HTC) in the learning process is essential for both parents of a child with severe haemophilia. Awareness of the fathers’ struggle to feel capable is also vital while supporting the family in the first years after diagnosis.
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| 24. |
- Myrin Westesson, Linda, et al.
(author)
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Burden on parents of children with haemophilia: The impact of sociodemographic and child's medical condition
- 2019
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In: Journal of Clinical Nursing. - : Wiley. - 0962-1067 .- 1365-2702. ; 28:21-22, s. 4077-4086
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Journal article (peer-reviewed)abstract
- Aims and objectivesTo describe the perceived burden on parents of children with severe or moderate haemophilia and the impact of sociodemographic aspects and the child's medical condition on this.BackgroundParents of children with haemophilia face a multitude of demands. The child needs frequent intravenous injections, hospital visits, extra supervision and care. The child's illness and related management might have psychosocial effects on the parents.DesignA multicentre, cross-sectional study.MethodsCaregiver burden was evaluated in 102 parents of children with haemophilia, using the HEMOCAB questionnaire which consists of 54 items divided into 13 domains which are to be answered on a 5-point Likert scale. To assess the impact of sociodemographic aspects and clinical data on parental burden, linear regression analyses were undertaken. The study followed the STROBE checklist throughout the research process.ResultsGreater burden was seen in parents of children with past or present inhibitors, in parents of younger children, if a family member administered the clotting factor and in parents of children with overweight/obesity. No significant differences in burden were observed for type of haemophilia, if the child had bleeding in the past 12 months, if the child self-infused, had another family member with haemophilia or if the parent had more children.ConclusionsParental perceived burden can be negatively affected by the child's medical condition; our results underline that healthcare professionals need to be aware of increased parental burden if the child is young, has or had inhibitors and has overweight/obesity.Relevance to clinical practiceMore psychosocial support from the healthcare professionals needs to be directed towards parents of younger children and particularly the parents of young children with inhibitors, thus decreasing the parental burden. Parental burden may be reduced if healthcare professionals more actively treat overweight and refer children to appropriate specialists.
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| 25. |
- Myrin Westesson, Lind, et al.
(author)
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Reaching Independence Through Forced Learning: Learning Processes and Illness Management in Parents of Children Affected by Hemophilia
- 2018
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In: Qualitative Health Research. - : SAGE Publications. - 1049-7323 .- 1552-7557. ; 28:14
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Journal article (peer-reviewed)abstract
- Hemophilia is a complex condition to manage, especially for parents to newly diagnosed children. This grounded theory study explores parents' learning processes and illness management in daily life during the first year after the start of their child's treatment. Using a longitudinal qualitative design, eight parents of four children were interviewed repeatedly during 12 to 14 months. The core category, reaching independence through forced learning, reflected the parents' learning process and their experiences of the challenges during the first year after start of treatment. Incentives for learning were characterized by a longing to reach independence and regain control of one's life situation. The emerging key incentive for learning was a desire to become independent of health care professionals. Early home treatment reduced the impact of the illness, and by supporting parents in different ways during the learning process, health care professionals can promote the parents' trajectory toward independency.
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| 26. |
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| 27. |
- Paulussen, Aimee D C, et al.
(author)
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Rare novel variants in the ZIC3 gene cause X-linked heterotaxy
- 2016
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In: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 24:12, s. 1783-1791
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Journal article (peer-reviewed)abstract
- Variants in the ZIC3 gene are rare, but have demonstrated their profound clinical significance in X-linked heterotaxy, affecting in particular male patients with abnormal arrangement of thoracic and visceral organs. Several reports have shown relevance of ZIC3 gene variants in both familial and sporadic cases and with a predominance of mutations detected in zinc-finger domains. No studies so far have assessed the functional consequences of ZIC3 variants in an in vivo model organism. A study population of 348 patients collected over more than 10 years with a large variety of congenital heart disease including heterotaxy was screened for variants in the ZIC3 gene. Functional effects of three variants were assessed both in vitro and in vivo in the zebrafish. We identified six novel pathogenic variants (1,7%), all in either male patients with heterotaxy (n=5) or a female patient with multiple male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression of wild-type and mutated ZIC protein in zebrafish showed full non-functionality of the two frame-shift variants and partial activity of the missense variant compared with wild-type, further underscoring the pathogenic character of these variants. Concluding, we greatly expanded the number of causative variants in ZIC3 and delineated the functional effects of three variants using in vitro and in vivo model systems.
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| 28. |
- Selwyn, Neil, et al.
(author)
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Med digital arbetskraft i klassrummet : Digital Labour Meets The Classroom
- 2020
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In: Bloggpost Medium.
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Other publication (other academic/artistic)abstract
- Digital teknologi associeras ofta med olika samhällstrender, som förändringar i arbets- och anställningsformer. Även i vissa traditionella högstatusyrken (som revisor-, advokat- och läkaryrket) tränger sig såväl digitalisering som automatisering in i det vardagliga arbetet. Nya former av digitalt arbete har uppstått som för tio år sedan skulle ha varit otänkbara. De flesta känner nog till den typ av tjänster och arbetsformer som Uber, Foodora, Yepstr, Tiptap och TaskRunner erbjuder i Sverige idag. Det är kanske inte lika känt att liknande former av digital arbetskraft nu börjat komma in i skolans värld och undervisningen. Dessa inslag i skolan menar vi kräver särskild och noggrann uppmärksamhet från såväl lärarprofessionen själv och lärarfackliga organisationer som andra skolaktörer och forskarsamhället kring skola och utbildning.
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| 29. |
- Selwyn, Neil, et al.
(author)
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Med digital arbetskraft i klassrummet
- 2020
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In: Bloggpost Medium.
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Journal article (peer-reviewed)abstract
- Digital teknologi associeras ofta med olika samhällstrender, som förändringar i arbets- och anställningsformer. Även i vissa traditionella högstatusyrken (som revisor-, advokat- och läkaryrket) tränger sig såväl digitalisering som automatisering in i det vardagliga arbetet. Nya former av digitalt arbete har uppstått som för tio år sedan skulle ha varit otänkbara. De flesta känner nog till den typ av tjänster och arbetsformer som Uber, Foodora, Yepstr, Tiptap och TaskRunner erbjuder i Sverige idag. Det är kanske inte lika känt att liknande former av digital arbetskraft nu börjat komma in i skolans värld och undervisningen. Dessa inslag i skolan menar vi kräver särskild och noggrann uppmärksamhet från såväl lärarprofessionen själv och lärarfackliga organisationer som andra skolaktörer och forskarsamhället kring skola och utbildning.
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| 30. |
- Walsh, Roddy, et al.
(author)
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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
- 2021
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In: Genetics in Medicine. - : Nature Publishing Group. - 1098-3600 .- 1530-0366. ; 23:1, s. 47-58
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Journal article (peer-reviewed)abstract
- Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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