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.
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.
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.
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.
Seckel syndrome is an ultrarare autosomal recessive genetically heterogenous condition characterized by intrauterine and postnatal growth restriction, proportionate severe short stature, severe ...microcephaly, intellectual disability, and distinctive facial features including a prominent nose. Up to now, 40 patients with molecularly confirmed Seckel syndrome have been reported with biallelic variants in nine genes: ATR, CENPJ, CEP63, CEP152, DNA2, NIN, NSMCE2, RBBP8, and TRAIP. Homozygosity for nonsense variant (c.129G>A, p.43*) in CEP63 was described in three cousins with microcephaly, short stature, mild to moderate intellectual disability and diagnoses of Seckel syndrome. Here, we report a second family with three siblings who are compound heterozygous for loss‐of‐function variants in CEP63, c.1125T>G, p.(Tyr375*) and c.595del, p.(Glu199Asnfs*11). All siblings present with microcephaly, prominent nose, and intellectual disability but only one has severe short stature. Two siblings have aggressive behavior, a feature previously not reported in Seckel syndrome. This report adds two novel truncating variants in CEP63 and extends the clinical knowledge on CEP63‐related conditions.
Prader–Willi syndrome (PWS; MIM# 176270) is a neurodevelopmental disorder caused by the loss of expression of paternally imprinted genes within the PWS region located on 15q11.2. It is usually caused ...by either maternal uniparental disomy of chromosome 15 (UPD15) or 15q11.2 recurrent deletion(s). Here, we report a healthy carrier of a balanced X;15 translocation and her two daughters, both with the karyotype 45,X,der(X)t(X;15)(p22;q11.2),−15. Both daughters display symptoms consistent with haploinsufficiency of the SHOX gene and PWS. We explored the architecture of the derivative chromosomes and investigated effects on gene expression in patient‐derived neural cells. First, a multiplex ligation‐dependent probe amplification methylation assay was used to determine the methylation status of the PWS‐region revealing maternal UPD15 in daughter 2, explaining her clinical symptoms. Next, short read whole genome sequencing and 10X genomics linked read sequencing was used to pinpoint the exact breakpoints of the translocation. Finally, we performed transcriptome sequencing on neuroepithelial stem cells from the mother and from daughter 1 and observed biallelic expression of genes in the PWS region (including SNRPN) in daughter 1. In summary, our multi‐omics analysis highlights two different PWS mechanisms in one family and provide an example of how structural variation can affect imprinting through long‐range interactions.
Recently, the Swedish government adopted a national planning goal of a yearly wind power generation of 10 TWh by 2015, implying a substantial increase from the current 0.6 TWh level. In this paper, ...we provide an economic assessment of the potential for future wind power investments in Sweden in close conjunction with an analysis of the legal, attitudinal and policy-related uncertainties that face a wind mill investor. It is shown that the economics of Swedish wind power is negatively affected by: (a) the lack of policy stability; (b) public criticism at the local level; and, in particular, (c) the legal provisions governing the assessment of the environmental impacts of wind mills and the planning procedures for mill location. While national and global energy policies as well as the general public point out wind power as particularly environmentally friendly, most of the objections to its expansion at the local level tend to have environmental origins. The interests of those who object to wind mill installations gain strong legal protection, and the municipal territorial planning monopoly in Sweden implies that it is hard to make national energy policy goals heard at the local implementation stage. Compared to its competitors, wind power is the technology that tends to have the most to loose from the risk and uncertainties created by this investment environment. The paper identifies and discusses a number of ways in which the national policy interests could be strengthened at the local level. We discuss the role of citizen participation, as well as solutions within the realms of the legal system. Moreover, since the diffusion of wind power encounters the most strident legal and attitudinal obstacles where it interferes with competing land uses, a move offshore appears to be an efficient strategy from the perspective of a wind mill investor. A stronger political commitment to wind power expansion in legal provisions as well as in the form of long-run stability in policy instrument implementation will probably be necessary to attain the 2015 policy goal.
The paper analyzes the prerequisites for a regulatory-driven transition toward radically lower air and water pollution in industry. This is achieved in the empirical context of the Swedish mining and ...metals industry, and by investigating the environmental licensing processes during two regulatory systems. The paper derives an analytical framework that explores under what circumstances such licensing processes can result in radical emissions reductions without seriously jeopardizing the competitiveness of the industry. Archived material covering six environmental licensing processes, three during each system, is used to illustrate the various design and implementation issues. The results suggest that regulatory-driven green transitions benefit from trust-based bargaining procedures in which companies are involved in repeated interactions with regulatory authorities, and which extended probation periods permit tests of novel abatement technologies (including innovation). The findings also illustrate the importance of abstaining from simplified normative notions about policy instrument choice (e.g. taxes versus standards).
Abstract
Context
Only a few genetic causes for childhood obesity have been identified to date. Copy number variants (CNVs) are known to contribute to obesity, both syndromic (15q11.2 deletions, ...Prader-Willi syndrome) and nonsyndromic (16p11.2 deletions) obesity.
Objective
To study the contribution of CNVs to early-onset obesity and evaluate the expression of candidate genes in subcutaneous adipose tissue.
Design and Setting
A case-control study in a tertiary academic center.
Participants
CNV analysis was performed on 90 subjects with early-onset obesity and 67 normal-weight controls. Subcutaneous adipose tissue from body mass index-discordant siblings was used for the gene expression analyses.
Main Outcome Measures
We used custom high-density array comparative genomic hybridization with exon resolution in 1989 genes, including all known obesity loci. The expression of candidate genes was assessed using microarray analysis of messenger RNA from subcutaneous adipose tissue.
Results
We identified rare CNVs in 17 subjects (19%) with obesity and 2 controls (3%). In three cases (3%), the identified variant involved a known syndromic lesion (22q11.21 duplication, 1q21.1 deletion, and 16p11.2 deletion, respectively), although the others were not known. Seven CNVs in 10 families were inherited and segregated with obesity. Expression analysis of 37 candidate genes showed discordant expression for 10 genes (PCM1, EFEMP1, MAMLD1, ACP6, BAZ2B, SORBS1, KLF15, MACROD2, ATR, and MBD5).
Conclusions
Rare CNVs contribute possibly pathogenic alleles to a substantial fraction of children with early-onset obesity. The involved genes might provide insights into pathogenic mechanisms and involved cellular pathways. These findings highlight the importance of CNV screening in children with early-onset obesity.
We studied genetic copy number variants in subjects with childhood-onset obesity and normal-weight controls. Rare variants were significantly more common in affected individuals than in controls.
Whereas there is evidence that mixed-species approaches to production forestry in general can provide positive outcomes relative to monocultures, it is less clear to what extent multiple benefits can ...be derived from specific mixed-species alternatives. To provide such insights requires evaluations of an encompassing suite of ecosystem services, biodiversity, and forest management considerations provided by specific mixtures and monocultures within a region. Here, we conduct such an assessment in Sweden by contrasting even-aged Norway spruce (Picea abies)-dominated stands, with mixed-species stands of spruce and birch (Betula pendula or B. pubescens), or spruce and Scots pine (Pinus sylvestris). By synthesizing the available evidence, we identify positive outcomes from mixtures including increased biodiversity, water quality, esthetic and recreational values, as well as reduced stand vulnerability to pest and pathogen damage. However, some uncertainties and risks were projected to increase, highlighting the importance of conducting comprehensive interdisciplinary evaluations when assessing the pros and cons of mixtures.
The Water Framework Directive (WFD) is an ambitious piece of legislation designed to protect and improve water quality throughout Europe. However, forests are only mentioned once in the WFD, and ...forestry is not mentioned at all, despite its potential implications for streams, rivers and lakes. Here we present a transdisciplinary commentary on the WFD and its implications for forests and forestry in Sweden. This commentary has been prepared by forestry stakeholders, biophysical and social scientists. While we were cognizant of a large body of discipline-specific research, there are very few inter- or trans-disciplinary commentaries which link academic and stakeholder perspectives on the WFD. We had originally felt that there would be little commonality in our concerns. However, we found significant areas of agreement. Our key areas of concern about the implications of the WFD for forestry in Sweden included: (i) concerns about what is meant by good ecological status and how it is assessed; (ii) a perceived lack of clarity in the legal framework; (iii) an inadequate environmental impact assessment process; and (iv) uncertainties about appropriate programs of measures for improving water quality. We were also concerned that ecosystem services provided by forests and the positive effects of forestry on water quality are inadequately recognized in the WFD.
Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics.
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).
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.
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.
Display omitted
Bladder exstrophy is a rare congenital malformation leaving the urinary bladder open in the midline of the abdomen at birth. There is a clear genetic background with chromosome aberrations, but so ...far, no consistent findings apart from 22q11‐duplications detected in about 2%–3% of all patients. Some genes are implicated like the LZTR1, ISL1, CELSR3, and the WNT3 genes, but most are not explained molecularly. We have performed chromosomal microarray analysis on a cohort of 140 persons born with bladder exstrophy to look for submicroscopic chromosomal deletions and duplications. Pathogenic or possibly pathogenic microdeletions or duplications were found in 16 patients (11.4%) and further 9 with unknown significance. Two findings were in regions linked to known syndromes, two findings involved the same gene (MCC), and all other findings were unique. A closer analysis suggests a few gene networks that are involved in the pathogenesis of bladder exstrophy; the WNT‐signaling pathway, the chromosome 22q11 region, the RIT2 and POU families, and involvement of the Golgi apparatus. Bladder exstrophy is a rare malformation and is reported to be associated with several chromosome aberrations. Our data suggest involvement of some specific molecular pathways.
PDF
