Unraveling mucolipidosis type III gamma through whole genome sequencing in late-onset retinitis pigmentosa: a case report.

BACKGROUND: We describe the case of a 47-year-old man referred to a retinal clinic and diagnosed with late-onset retinitis pigmentosa. Surprisingly, genetic testing revealed compound heterozygous pathogenic variants in GNPTG, leading to the diagnosis of the autosomal recessive lysosomal storage disorder mucolipidosis type III gamma. Mucolipidosis type III gamma is typically diagnosed during childhood due to symptoms relating to skeletal dysplasia. Retinal dystrophy is not a common phenotypic feature. CASE PRESENTATION: Ophthalmologic examination was consistent with a mild form of retinitis pigmentosa and included fundus photography, measurement of best-corrected visual acuity, optical coherence tomography, electroretinogram and visual field testing. Extraocular findings included joint restriction and pains from an early age leading to bilateral hip replacement by age 30, aortic insufficiency, and hypertension. Genetic analysis was performed by whole genome sequencing filtered for a gene panel of 325 genes associated with retinal disease. Two compound heterozygous pathogenic variants were identified in GNPTG, c.347_349del and c.607dup. The diagnosis of mucolipidosis type III gamma was confirmed biochemically by measurement of increased activities of specific lysosomal enzymes in plasma. CONCLUSION: To our knowledge this is the first description of retinitis pigmentosa caused by compound heterozygous variants in GNPTG, providing further indications that late-onset retinal dystrophy is part of the phenotypic spectrum of mucolipidosis type III gamma.

Faculty development participants' experiences of working with change in clinical settings.

OBJECTIVES: Many universities offer faculty development to support teachers in developing and improving clinical education in the health professions. Although research shows outcomes on individual levels after faculty development, little is known about its contribution to change within the organisation. To advance current faculty development and ensure that it can support wider educational change in healthcare organisations, a better understanding of educational change practices in these settings is needed. This study therefore explores the experiences of working with educational change in clinical workplaces from the perspective of clinical educators that have undergone faculty development training. The study adopts perspectives on change as influenced by context to include the impact from clinical workplaces on individuals' change work. METHODS: A collective case study design with a multi-institutional approach was applied and individual interviews with 14 clinical educators from two universities, one in Sweden and one in South Africa, were conducted. Data were analysed separately before a cross-case analysis was performed, synthesising the findings from both sites. FINDINGS: Participants shared experiences of having limited opportunities to work with educational change beyond their own individual teaching practices within their clinical workplaces. Also, participants appeared to refrain from leading change and rather pursued change on their own or relied on indirect approaches to change. They described several workplace aspects influencing their work, including the organisation and management of teaching, the resources and incentives for teaching and the attitudes and beliefs about teaching within the clinical community. CONCLUSIONS: The study shows that clinical educators are part of communities and contexts that shape their approaches to educational change and influence which changes are feasible and which ones are not. It thus adds to the understanding of change as contextual and dynamic and contributes with implications for how to advance faculty development to better support change in practice.

HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN.

Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic. They may result from genetic defects. Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFß pathway and (c) smooth muscle contractile mechanism. Timely diagnosis allows for prompt aortic surveillance and prophylactic surgery, hence improving life expectancy and reducing maternal complications as well as providing reassurance to family members when a diagnosis is ruled out. This document is an expert opinion reflecting strategies put forward by medical experts and patient representatives involved in the HTAD Rare Disease Working Group of VASCERN. It aims to provide a patient pathway that improves patient care by diminishing time to diagnosis, facilitating the establishment of a correct diagnosis using molecular genetics when possible, excluding the diagnosis in unaffected persons through appropriate family screening and avoiding overuse of resources. It is being recommended that patients are referred to an expert centre for further evaluation if they meet at least one of the following criteria: (1) thoracic aortic dissection (<70 years if hypertensive; all ages if non-hypertensive), (2) thoracic aortic aneurysm (all adults with Z score >3.5 or 2.5-3.5 if non-hypertensive or hypertensive and <60 years; all children with Z score >3), (3) family history of HTAD with/without a pathogenic variant in a gene linked to HTAD, (4) ectopia lentis without other obvious explanation and (5) a systemic score of >5 in adults and >3 in children. Aortic imaging primarily relies on transthoracic echocardiography with magnetic resonance imaging or computed tomography as needed. Genetic testing should be considered in those with a high suspicion of underlying genetic aortopathy. Though panels vary among centers, for patients with thoracic aortic aneurysm or dissection or systemic features these should include genes with a definitive or strong association to HTAD. Genetic cascade screening and serial aortic imaging should be considered for family screening and follow-up. In conclusion, the implementation of these strategies should help standardise the diagnostic work-up and follow-up of patients with suspected HTAD and the screening of their relatives.

How workplace learning is put into practice: contrasting the medical and nursing contexts from the perspective of teaching and learning regimes.

Health professions education places significant emphasis on learning in the clinical environment. While experiences of workplace learning have been extensively investigated, practices of workplace learning explored through field work have been less utilized. The theoretical framework of teaching and learning regimes acknowledges aspects of power and conflict in its consideration of what guides teachers and learners in their practice of workplace learning. This study aimed to explore practices of workplace learning in the two adjacent healthcare professions; medicine and nursing. We adopted an ethnographic qualitative design. Field observations and follow-up interviews were performed in three clinical departments and the data set comprised 12 full days of observations and 16 formal follow-up interviews. Thematic analysis was performed deductively according to the theoretical framework. Four teaching and learning regimes were found in the data. In the medical context, workplace learning was either practiced as reproduction of current practice or through stimulation of professional development. In the nursing context, workplace learning was either based on development of partnership between student and supervisor or on conditional membership in a professional community. The medical and nursing contexts demonstrated varying underpinnings and assumptions relating to teaching and learning. The respective practices of workplace learning in the medical and nursing context appear to hold substantial differences which might have implications for how we understand practices of workplace learning. We further conclude that the theoretical framework of teaching and learning regimes in this study proved useful in exploring workplace learning.

Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability.

PURPOSE: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. METHODS: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). RESULTS: The diagnostic yield was 35% (GS-first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. CONCLUSION: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time- and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients.

Navigating Affordances for Learning in Clinical Workplaces: A Qualitative Study of General Practitioners' Continued Professional Development.

Medical specialists' lifelong learning is essential for improving patients' health. This study identifies affordances for learning general practitioners (GPs) engage in, and explores what influences engagement in those affordances. Eleven GPs were interviewed and the interview transcripts were analysed thematically. Stephen Billett's theoretical framework of workplace participatory practices was used as an analytical lens to explore the topic. Challenging patient cases were identified as the main trigger for engagement in learning. Local, national and international colleagues from the same and other specialties, were found to be an important affordance for learning, as was written material such as websites, journals and recommendations. Other inputs for learning were conferences and courses. Workplace aspects that were essential for GPs to engage in learning related to: place and time to talk, relevance to work, opportunity for different roles, organisation of work and workload, and working climate. Importantly, the study identifies a need for a holistic approach to lifelong learning, including spontaneous and structured opportunities for interaction over time with colleagues, establishment of incentives and arenas for exchange linked to peer learning, and acknowledgement of the workplace as an important place for learning and sufficient time with patients. This study contributes with a deepened understanding of how GPs navigate existing affordances for learning both within and outside their workplaces.

Merged testing for colorectal cancer syndromes and re-evaluation of genetic variants improve diagnostic yield: Results from a nationwide prospective cohort.

Approximately 5% of patients with colorectal cancer (CRC) have a Mendelian predisposition for the disease. Identification of the disease-causing genetic variant enables carrier testing and tailored cancer prevention within affected families. To determine the panorama and genetic variation of Mendelian CRC syndromes among referrals at the cancer genetics clinics in Sweden, 850 patients clinically selected for CRC genetic investigation were included in a prospective study that tested for all major hereditary polyposis and nonpolyposis CRC conditions. Genetically defined syndromes were diagnosed in 11% of the patients. Lynch syndrome was predominant (n = 73) followed by familial adenomatous polyposis (n = 12) and MUTYH-associated polyposis (n = 8); the latter of which two patients presented with CRC before polyposis was evident. One patient with a history of adolescent-onset CRC and polyposis had biallelic disease-causing variants diagnostic for constitutional mismatch repair deficiency syndrome. Post-study review of detected variants of unknown clinical significance (n = 129) resulted in the reclassification of variants as likely benign (n = 59) or as diagnostic for Lynch syndrome (n = 2). Our results reveal the panorama of Mendelian CRC syndromes at the cancer genetics clinics in Sweden and show that unified testing for polyposis and nonpolyposis CRC conditions as well as regular reexamination of sequence data improve the diagnostic yield.

A retrospective two centre study of Birt-Hogg-Dubé syndrome reveals a pathogenic founder mutation in FLCN in the Swedish population.

Birt-Hogg-Dube syndrome (BHDS) (MIM: 135150) is a rare autosomal dominant disorder with variable penetrance, caused by pathogenic variants in the FLCN gene. Only a few hundreds of families have so far been described in the literature. Patients with BHDS present with three distinct symptoms: fibrofolliculomas, pneumothorax due to lung cyst formation, and increased lifetime risk of kidney tumours. The aim of the current study was to estimate the incidence of BHDS in the Swedish population and further describe the clinical manifestations and their frequency. Splice variant c.779+1G>T was the most common pathogenic variant, found in 57% of the families, suggesting this may be a founder mutation in the Swedish population. This was further investigated using haplotype analysis in 50 families that shared a common haplotype. Moreover, according to gnomAD the carrier frequency of the c.779+1G>T variant has been estimated to be 1/3265 in the Swedish population, however our data suggest that the carrier frequency in the Swedish population may be significantly higher. These findings should raise awareness among physicians of different specialties to patients presenting with fibrofolliculomas, pneumothorax and/or kidney tumours. We also stress the importance of consensus recommendations regarding diagnosis and clinical management of this, not that uncommon, syndrome.

[Medical doctor specialists - an overview of the research on formal and informal continued professional development]. / Specialistläkares fortbildning ­ effekt, förutsättningar, drivkrafter.

An overview of the research literature about physicians' continuing development was conducted and shows that formal learning activities often target individuals and their development, and focus on increasing knowledge and influencing attitudes. Research studies showing changes in practice are less common. Regulated continuous medical education may lead to instrumental approaches to learning. Informal learning occurs continuously during work, is often spontaneous and focussed on problem solving. Patients and colleagues as well as the physical and social environment provide opportunities for learning. Organizations can offer time and space to facilitate physicians' continuing development, enabling possibilities for formal and informal sharing of knowledge to take place, for example, by enabling collegial discussions.

Discordant structural chromosomal aberrations in chorionic villi and amniotic fluid leading to a formation of an isochromosome 21: a case report.

BACKGROUND: Fetoplacental discrepancies occur in approximately 1-2% of analyzed prenatal cases. They are typically due to confined placental mosaicism, where an aberration is observed in the placental cells but not found in the fetal cells. Confined placental mosaicism usually involves aneuploidies and more sparsely structural chromosomal aberrations. To the best of our knowledge, this is the first reported case of a discrepancy in the analyses of chorionic villus sampling and amniocentesis involving two different structural chromosomal aberrations of chromosome 21. CASE PRESENTATION: We report a 33-year-old woman who was referred for a non-invasive prenatal testing due to an increased risk of trisomy 21 gleaned from a combined ultrasound and blood test. The non-invasive prenatal testing showed an increased risk of trisomy 21 with a normalized coverage signal that did not match the fetal cell-free DNA fraction. Rapid aneuploidy detection performed on uncultured chorionic villi indicated mosaicism for trisomy 21. The follow-up analyses revealed discordant chromosomal aberrations: 46,XY,der(21)t(10;21)(p11.21;q10) in the analysis of the chorionic villus sampling and 46,XY, + 21,der(21;21)(q10;q10) in the analysis of the amniocentesis. Thus, the analyses indicated mosaicism for a cell line containing trisomy 21 and a cell line containing a partially duplicated short arm of chromosome 10 in the chorionic villi and complete trisomy 21 resulting from an isochromosome 21 in the amniotic fluid. The analyses of the lymphocytes and the fibroblasts of the woman were normal. CONCLUSIONS: We propose a multiple-step mechanism as a possible theoretical explanation for the formation of these discordant structural chromosomal aberrations in the chorionic villi and amniotic fluid. With this case report, we want to highlight the importance of understanding the possible underlying embryological mechanisms when interpreting results from different prenatal analyses.

Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients.

BACKGROUND: We report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at the Genomic Medicine Center Karolinska-Rare Diseases (GMCK-RD) since mid-2015. GMCK-RD represents a long-term collaborative initiative between Karolinska University Hospital and Science for Life Laboratory to establish advanced, genomics-based diagnostics in the Stockholm healthcare setting. METHODS: Our analysis covers detection and interpretation of SNVs, INDELs, uniparental disomy, CNVs, balanced structural variants, and short tandem repeat expansions. Visualization of results for clinical interpretation is carried out in Scout-a custom-developed decision support system. Results from both singleton (84%) and trio/family (16%) analyses are reported. Variant interpretation is done by 15 expert teams at the hospital involving staff from three clinics. For patients with complex phenotypes, data is shared between the teams. RESULTS: Overall, 40% of the patients received a molecular diagnosis ranging from 19 to 54% for specific disease groups. There was heterogeneity regarding causative genes (n = 754) with some of the most common ones being COL2A1 (n = 12; skeletal dysplasia), SCN1A (n = 8; epilepsy), and TNFRSF13B (n = 4; inborn errors of immunity). Some causative variants were recurrent, including previously known founder mutations, some novel mutations, and recurrent de novo mutations. Overall, GMCK-RD has resulted in a large number of patients receiving specific molecular diagnoses. Furthermore, negative cases have been included in research studies that have resulted in the discovery of 17 published, novel disease-causing genes. To facilitate the discovery of new disease genes, GMCK-RD has joined international data sharing initiatives, including ClinVar, UDNI, Beacon, and MatchMaker Exchange. CONCLUSIONS: Clinical WGS at GMCK-RD has provided molecular diagnoses to over 1200 individuals with a broad range of rare diseases. Consolidation and spread of this clinical-academic partnership will enable large-scale national collaboration.

Room for improvement: One third of Lynch syndrome patients presenting for genetic testing in a highly specialised centre in Stockholm already have cancer.

BACKGROUND: Lynch syndrome is caused by germline mutations in the mismatch repair genes and is characterised by a familial accumulation of colorectal and other cancers. Earlier identification of Lynch syndrome patients enables surveillance and might reduce the risk of cancer. It is important to explore whether today's clinical care discovers patients with Lynch syndrome suitable for surveillance in time. This study aimed to describe what led to a diagnosis of Lynch syndrome in the cohort referred to the Hereditary Gastrointestinal Cancer Unit, Karolinska University Hospital, Solna, Sweden for gastrointestinal surveillance. METHODS: This was a descriptive study. Data from 1975 to 2018 were collected and compiled as a database. Age at diagnosis was calculated from the date when a pathogenic MMR gene mutation was confirmed, from the period June 1994-September 2018. Data were collected from patient protocols prospectively during patient consultations and medical records retrospectively. Criteria for inclusion were registration at the outpatient clinic and a confirmed mismatch repair gene mutation. RESULTS: A total of 305 patients were eligible for inclusion. Three major reasons for diagnosis were identified: 1. Predictive testing of a previously known mutation in the family (62%, mean age 37), 2. A family history of Lynch associated tumours (9%, mean age 37), 3. A diagnosis of cancer (29%, mean age 51). The proportion diagnosed due to cancer has not changed over time. CONCLUSION: A high proportion of patients (29%) were identified with Lynch syndrome after they had been diagnosed with an associated cancer, which suggests that there is significant room for improvement in the diagnosis of patients with Lynch syndrome before cancer develops.

Collaborative knotworking - transforming clinical teaching practice through faculty development.

BACKGROUND: Faculty development is important for advancing teaching practice in health professions education. However, little is known regarding how faculty development outcomes are achieved and how change in practice may happen through these activities. In this study, we explored how clinical educators integrated educational innovations, developed within a faculty development programme, into their clinical workplaces. Thus, the study seeks to widen the understanding of how change following faculty development unfolds in clinical systems. METHODS: The study was inspired by case study design and used a longitudinal faculty development programme as a case offering an opportunity to study how participants in faculty development work with change in practice. The study applied activity theory and its concept of activity systems in a thematic analysis of focus group interviews with 14 programme attendees. Participants represented two teaching hospitals, five clinical departments and five different health professions. RESULTS: We present the activity systems involved in the integration process and the contradiction that arose between them as the innovations were introduced in the workplace. The findings depict how the faculty development participants and the clinicians teaching in the workplace interacted to overcome this contradiction through iterative processes of negotiating a mandate for change, reconceptualising the innovation in response to workplace reactions, and reconciliation as temporary equilibria between the systems. CONCLUSION: The study depicts the complexities of how educational change is brought about in the workplace after faculty development. Based on our findings and the activity theoretical concept of knotworking, we suggest that these complex processes may be understood as collaborative knotworking between faculty development participants and workplace staff through which both the output from faculty development and the workplace practices are transformed. Increasing our awareness of these intricate processes is important for enhancing our ability to make faculty development reach its full potential in bringing educational change in practice.

Corrigendum: C1R Mutations Trigger Constitutive Complement 1 Activation in Periodontal Ehlers-Danlos Syndrome.

[This corrects the article DOI: 10.3389/fimmu.2019.02537.].

European reference network for rare vascular diseases (VASCERN) consensus statement for the screening and management of patients with pathogenic ACTA2 variants.

The ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic aneurysm and/or dissection is the main clinical manifestation, a variety of occlusive vascular disease and extravascular manifestations occur in ACTA2-related vasculopathy. Current data suggest possible mutation-specific manifestations of vascular and extra-aortic traits.Despite its relatively high prevalence, comprehensive recommendations on the care of patients and families with pathogenic variants in ACTA2 have not yet been established. We aimed to develop a consensus document to provide medical guidance for health care professionals involved in the diagnosis and treatment of patients and relatives with pathogenic variants in ACTA2.The HTAD Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) convened to review current literature and discuss expert opinions on clinical management of ACTA2 related vasculopathy. This consensus statement summarizes our recommendations on diagnosis, monitoring, treatment, pregnancy, genetic counselling and testing in patients with ACTA2-related vasculopathy. However, there is a clear need for additional prospective multicenter studies to further define proper guidelines.

C1R Mutations Trigger Constitutive Complement 1 Activation in Periodontal Ehlers-Danlos Syndrome.

Heterozygous missense or in-frame insertion/deletion mutations in complement 1 subunits C1r and C1s cause periodontal Ehlers-Danlos Syndrome (pEDS), a specific EDS subtype characterized by early severe periodontal destruction and connective tissue abnormalities like easy bruising, pretibial haemosiderotic plaques, and joint hypermobility. We report extensive functional studies of 16 C1R variants associated with pEDS by in-vitro overexpression studies in HEK293T cells followed by western blot, size exclusion chromatography and surface plasmon resonance analyses. Patient-derived skin fibroblasts were analyzed by western blot and Enzyme-linked Immunosorbent Assay (ELISA). Overexpression of C1R variants in HEK293T cells revealed that none of the pEDS variants was integrated into the C1 complex but cause extracellular presence of catalytic C1r/C1s activities. Variants showed domain-specific abnormalities of intracellular processing and secretion with preservation of serine protease function in the supernatant. In contrast to C1r wild type, and with the exception of a C1R missense variant disabling a C1q binding site, pEDS variants had different impact on the cell: retention of C1r fragments inside the cell, secretion of aggregates, or a new C1r cleavage site. Overexpression of C1R variants in HEK293T as well as western blot analyses of patient fibroblasts showed decreased levels of secreted C1r. Importantly, all available patient fibroblasts exhibited activated C1s and activation of externally added C4 in the supernatant while control cell lines secreted proenzyme C1s and showed no increase in C4 activation. The central elements in the pathogenesis of pEDS seem to be the intracellular activation of C1r and/or C1s, and extracellular presence of activated C1s that independently of microbial triggers can activate the classical complement cascade.

Contradictions in clinical teachers' engagement in educational development: an activity theory analysis.

Many medical universities offer educational development activities to support clinical teachers in their teaching role. Research has focused on the scope and effectiveness of such activities and on why individual teachers attend. However, systemic perspectives that go beyond a focus on individual participants are scarce in the existing literature. Employing activity theory, we explored how clinical teachers' engagement in educational development was affected by the systems they act within. Three focus groups were held with clinical teachers from different professions. A thematic analysis was used to map the contradictions between the systems that the participants were part of and the manifestations of these contradictions in the system of education. In our model, clinical teachers were part of three activity systems directed by the objects of patient care, research and education respectively. Contradictions arose between these systems as their objects were not aligned. This manifested through the enacted values of the academic hospital, difficulties establishing educational discussions in the clinical workplace, the transient nature of educational employments, and impediments to developing a teacher identity. These findings offer insights into the complexities of engaging in educational development as clinical teachers' priorities interact with the practices and values of the academic hospital, suggesting that attention needs to shift from individual teachers to developing the systems in which they work.

A retrospective study of extracolonic, non-endometrial cancer in Swedish Lynch syndrome families.

BACKGROUND: Lynch Syndrome is an autosomal dominant cancer syndrome caused by pathogenic germ-line variants in one of the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. Carriers are predisposed to colorectal and endometrial cancer, but also other cancer types. The purpose of this retrospective study was to characterize the tumour spectrum of the Swedish Lynch syndrome families. METHODS: Data were obtained from genetically verified 235 Lynch families from five of the six health care regions in Sweden. The material was stratified for gender, primary cancer, age and mutated gene and the relative proportions of specific cancer types were compared to those in the general population. RESULTS: A total of 1053 family members had 1493 cancer diagnoses of which 1011 were colorectal or endometrial cancer. Individuals with pathogenic variants in MLH1 and MSH2 comprised 78% of the cohort. Among the 482 non-colorectal/non-endometrial cancer diagnoses, MSH2 carriers demonstrated a significantly increased proportion of urinary tract, gastric, small bowel, ovarian and non-melanoma skin cancer compared to the normal population. MLH1 carriers had an elevated proportion of gastrointestinal cancers (gastric, small bowel, pancreas), while MSH6 carriers had more ovarian cancer than expected. Gastric cancer was predominantly noted in older generations. CONCLUSION: Lynch syndrome confers an increased risk for multiple cancers other than colorectal and endometrial cancer. The proportions of other cancers vary between different MMR genes, with highest frequency in MSH2-carriers. Gender and age also affect the tumour spectrum, demonstrating the importance of additional environmental and constitutional parameters in determining the predisposition for different cancer types.