Publications by authors named "Pawel Sztromwasser"

19 Publications

  • Page 1 of 1

Remus: A Web Application for Prioritization of Regulatory Regions and Variants in Monogenic Diseases.

Authors:
Paweł Sztromwasser Damian Skrzypczak Arkadiusz Michalak Wojciech Fendler

Front Genet 2021 5;12:638960. Epub 2021 Mar 5.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, Łódź, Poland.

Background: Analysis of variants in distant regulatory elements could improve the current 25-50% yield of genetic testing for monogenic diseases. However, the vast size of the regulome, great number of variants, and the difficulty in predicting their phenotypic impact make searching for pathogenic variants in the regulatory genome challenging. New tools for the identification of regulatory variants based on their relevance to the phenotype are needed.

Methods: We used tissue-specific regulatory mapped by ENCODE and FANTOM, together with miRNA-gene interactions from miRTarBase and miRWalk, to develop Remus, a web application for the identification of tissue-specific regulatory regions. Remus searches for regulatory features linked to the known disease-associated genes and filters them using activity status in the target tissues relevant for the studied disorder. For user convenience, Remus provides a web interface and facilitates in-browser filtering of variant files suitable for sensitive patient data.

Results: To evaluate our approach, we used a set of 146 regulatory mutations reported causative for 68 distinct monogenic disorders and a manually curated a list of tissues affected by these disorders. In 89.7% of cases, Remus identified the regulator containing the pathogenic mutation. The tissue-specific search limited the number of considered variants by 82.5% as compared to a tissue-agnostic search.

Conclusion: Remus facilitates the identification of regulatory regions potentially associated with a monogenic disease and can supplement classical analysis of coding variations with the aim of improving the diagnostic yield in whole-genome sequencing experiments.
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http://dx.doi.org/10.3389/fgene.2021.638960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978111PMC
March 2021

The First Report of Biallelic Missense Mutations in the Gene Causing Pyle Disease in Two Siblings.

Authors:
Anna Sowińska-Seidler Paweł Sztromwasser Katarzyna Zawadzka Dawid Sielski Ewelina Bukowska-Olech Paweł Zawadzki Kazimierz Kozłowski Aleksander Jamsheer

Front Genet 2020 23;11:593407. Epub 2020 Oct 23.

Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.

Background: Pyle disease is a rare autosomal recessive bone dysplasia characterized by the broadening of metaphyses with generalized cortical thinning. Homozygous truncating mutations in secreted frizzled-related protein 4 () were, to date, the only known variants causative for this type of skeletal disorder. SFRP4 controls cortical and trabecular bone remodeling by differential regulation of the canonical and non-canonical WNT signaling in both bone compartments. Loss-of-function mutations in the gene lead to the protein deficiency causing skeletal phenotype typical for Pyle disease.

Results: Herein, we report on the first missense mutations that occurred in compound heterozygosity in two siblings affected by Pyle disease, and which we have identified using a whole-genome sequencing approach followed by a comprehensive pathogenicity assessment. The variants we have found were extremely rare and evaluated to be disease-causing by several online available tools and software.

Conclusion: With this paper, we have shown that Pyle disease may be related not only to truncating mutations but also to other loss-of-function alterations that possibly impair the protein capacity to bind WNT ligands. As we have expanded here, the range of deleterious variants underlying Pyle disease, we contribute to the knowledge on the pathogenesis of this rare skeletal disorder.
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http://dx.doi.org/10.3389/fgene.2020.593407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646522PMC
October 2020

Meta-analysis of whole-exome sequencing data from two independent cohorts finds no evidence for rare variant enrichment in Parkinson disease associated loci.

Authors:
Johannes Jernqvist Gaare Gonzalo Nido Christian Dölle Paweł Sztromwasser Guido Alves Ole-Bjørn Tysnes Kristoffer Haugarvoll Charalampos Tzoulis

PLoS One 2020 1;15(10):e0239824. Epub 2020 Oct 1.

Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Parkinson disease (PD) is a complex neurodegenerative disorder influenced by both environmental and genetic factors. While genome wide association studies have identified several susceptibility loci, many causal variants and genes underlying these associations remain undetermined. Identifying these is essential in order to gain mechanistic insight and identify biological pathways that may be targeted therapeutically. We hypothesized that gene-based enrichment of rare mutations is likely to be found within susceptibility loci for PD and may help identify causal genes. Whole-exome sequencing data from two independent cohorts were analyzed in tandem and by meta-analysis and a third cohort genotyped using the NeuroX-array was used for replication analysis. We employed collapsing methods (burden and the sequence kernel association test) to detect gene-based enrichment of rare, protein-altering variation within established PD susceptibility loci. Our analyses showed trends for three genes (GALC, PARP9 and SEC23IP), but none of these survived multiple testing correction. Our findings provide no evidence of rare mutation enrichment in genes within PD-associated loci, in our datasets. While not excluding that rare mutations in these genes may influence the risk of idiopathic PD, our results suggest that, if such effects exist, much larger sequencing datasets will be required for their detection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239824PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529297PMC
November 2020

Compound heterozygous GLI3 variants in siblings with thyroid hemiagenesis.

Authors:
Ewelina Szczepanek-Parulska Bartłomiej Budny Martyna Borowczyk Katarzyna Zawadzka Paweł Sztromwasser Marek Ruchała

Endocrine 2021 Feb 21;71(2):514-519. Epub 2020 Jul 21.

Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 49 Przybyszewskiego Street, 60-355, Poznan, Poland.

Purpose: Thyroid hemiagenesis (THA) is an inborn absence of one thyroid lobe of largely unknown etiopathogenesis, affecting 0.05-0.5% population. The aim of the study was an identification of genetic factors responsible for thyroid maldevelopment in two siblings with THA.

Methods: We evaluated a three-generation THA family with two sisters presenting the disorder. Proband (Patient II:3) was diagnosed at the age of 45 due to neck asymmetry. Left lobe agenesis and nontoxic multinodular goiter were depicted. Proband's sister (Patient II:6) was euthyroid, showed up at the age of 39 due to neck discomfort and left-sided THA was demonstrated. Affected individuals were subjected to whole-exome sequencing (WES) (Illumina, TruSeq Exome Kit) and all identified variants were evaluated for pathogenicity. Sanger sequencing was used to confirm WES data and check segregation among first-degree relatives.

Results: In both siblings, a compound heterozygous mutations NM_000168.6: c.[2179G>A];[4039C>A] (NP_000159.3: p.[Gly727Arg];[Gln1347Lys]) were identified in the GLI3 gene, affecting exon 14 and 15, respectively. According to the American College of Medical Genetics, variants are classified as of uncertain significance, and were found to be very rare (GnomAD MAF 0.007131 and 0.00003187). The segregation mapping and analysis of relatives indicated causativeness of compound heterozygosity.

Conclusions: We demonstrated for the first time a unique association of THA phenotype and the presence of compound heterozygous mutations p.[Gly727Arg];[Gln1347Lys] of GLI3 gene in two siblings.
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http://dx.doi.org/10.1007/s12020-020-02422-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881956PMC
February 2021

Impact of processing method on donated human breast milk microRNA content.

Authors:
Urszula Smyczynska Marcin A Bartlomiejczyk Marcin M Stanczak Pawel Sztromwasser Aleksandra Wesolowska Olga Barbarska Emilia Pawlikowska Wojciech Fendler

PLoS One 2020 15;15(7):e0236126. Epub 2020 Jul 15.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.

Pasteurization of donated human milk preserves it for storage and makes it safe for feeding, but at the expense of its composition, nutritional values and functions. Here, we aimed to investigate the impact of Holder Pasteurization (HoP) and High Pressure Processing (HPP) methods on miRNA in human milk and to evaluate impact of these changes on miRNA functions. Milk samples obtained from women in 50th day of lactation (n = 3) were subjected either to HoP, HPP or remained unpasteurized as a control. Subsequently, miRNA was isolated from whole material and exosomal fraction and sequenced with Illumina NextSeq 500. Sequencing data were processed, read counts were mapped to miRNA and analyzed both quantitatively with DESeq2 and functionally with DIANA mirPath v.3. While HPP caused statistically insignificant decrease in number of miRNA reads compared to unprocessed material, HoP led to 82-fold decrease in whole material (p = 0.0288) and 302-fold decrease in exosomes (p = 0.0021) not leaving enough reads for further analysis. Changes in composition of miRNA fraction before and after HPP indicated uneven stability of individual miRNAs under high pressure conditions, with miR-30d-5p identified as relatively stable and miR-29 family as sensitive to HPP. Interestingly, about 2/3 of unprocessed milk miRNA content consists of only 10 distinct miRNAs with miR-148a-3p at the top. Functional analysis of most abundant human milk miRNAs showed their involvement in signaling pathways, cell communication, proliferation and metabolism that are obviously important in rapidly growing infants. Functions of miRNAs which suffered the greatest depletion during HPP were similar to roles of the majority of unprocessed human milk's miRNA, which indicates that those functions may be weakened although not completely lost. Our findings indicate that HPP is less detrimental to human milk miRNAs than HoP and should be considered in further research on recommended processing procedures for human milk banks.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236126PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363072PMC
September 2020

Spread of equine arteritis virus among Hucul horses with different EqCXCL16 genotypes and analysis of viral quasispecies from semen of selected stallions.

Authors:
Wojciech Socha Pawel Sztromwasser Magdalena Dunowska Barbara Jaklinska Jerzy Rola

Sci Rep 2020 02 19;10(1):2909. Epub 2020 Feb 19.

National Veterinary Research Institute, Al. Partyzantow 57, 24-100, Pulawy, Poland.

Equine arteritis virus (EAV) is maintained in the horse populations through persistently infected stallions. The aims of the study were to monitor the spread of EAV among Polish Hucul horses, to analyse the variability of circulating EAVs both between- and within-horses, and to identify allelic variants of the serving stallions EqCXCL16 gene that had been previously shown to strongly correlate with long-term EAV persistence in stallions. Serum samples (n = 221) from 62 horses including 46 mares and 16 stallions were collected on routine basis between December 2010 and May 2013 and tested for EAV antibodies. In addition, semen from 11 stallions was tested for EAV RNA. A full genomic sequence of EAV from selected breeding stallions was determined using next generation sequencing. The proportion of seropositive mares among the tested population increased from 7% to 92% during the study period, while the proportion of seropositive stallions remained similar (64 to 71%). The EAV genomes from different stallions were 94.7% to 99.6% identical to each other. A number (41 to 310) of single nucleotide variants were identified within EAV sequences from infected stallions. Four stallions possessed EqCXCL16S genotype correlated with development of long-term carrier status, three of which were persistent shedders and the shedder status of the remaining one was undetermined. None of the remaining 12 stallions with EqCXCL16R genotype was identified as a persistent shedder.
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http://dx.doi.org/10.1038/s41598-020-59870-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031528PMC
February 2020

Corrigendum: Occurrence and Characterization of -Positive Isolated From Food-Producing Animals in Poland, 2011-2016.

Authors:
Magdalena Zając Paweł Sztromwasser Valeria Bortolaia Pimlapas Leekitcharoenphon Lina M Cavaco Anna Ziȩtek-Barszcz Rene S Hendriksen Dariusz Wasyl

Front Microbiol 2019;10:2816. Epub 2019 Dec 4.

Department of Microbiology, National Veterinary Research Institute, Puławy, Poland.

[This corrects the article DOI: 10.3389/fmicb.2019.01753.].
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http://dx.doi.org/10.3389/fmicb.2019.02816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904549PMC
December 2019

A cross-sectional study of patients referred for HNF1B-MODY genetic testing due to cystic kidneys and diabetes.

Authors:
Paweł Sztromwasser Arkadiusz Michalak Beata Małachowska Paulina Młudzik Karolina Antosik Anna Hogendorf Agnieszka Zmysłowska Maciej Borowiec Wojciech Młynarski Wojciech Fendler

Pediatr Diabetes 2020 05 29;21(3):422-430. Epub 2020 Jan 29.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.

Background/objectives: Patients referred for HNF1B testing present very heterogeneous phenotypes. Despite suggestive characteristics, many do not harbor mutations in HNF1B. Our objective was to evaluate the clinical characteristics of probands referred for HNF1B genetic testing through a nationwide monogenic diabetes screening program.

Methods: Probands tested for HNF1B mutations in the 2005-2018 period (N = 50) were identified in the Polish Monogenic Diabetes Registry, which prospectively recruits primarily pediatric patients and their families on a nationwide scale. Variants that had been reported pathogenic were reassessed using criteria of the American College of Medical Genetics and Genomics (ACMG). A structured medical interview was performed with all available individuals, their parents, and/or their physicians. For each patient, HNF1B score was calculated based on available clinical information.

Results: The study group numbered 36 unrelated probands (28% lost to follow-up): 14 with pathogenic or likely-pathogenic variants in HNF1B, one with a variant of uncertain significance, and 21 negative for HNF1B mutations. Presence of cystic kidneys (OR = 9.17, 95% CI:1.87-44.92), pancreatic abnormalities (OR = 15, 95% CI:1.55-145.23), elevated liver enzymes (OR = 15, 95% CI:1.55-145.23) best discriminated HNF1B-positive cases from the negative ones. Presence of impaired glucose tolerance coupled with kidney disease in the proband and one parent was also highly predictive for HNF1B mutations (OR = 11.11, 95% CI:1.13-109.36). HNF1B-score with recommended cutoff distinguished patients with and without HNF1B findings with 100% sensitivity and 47.6% specificity. Addition of four clinical variables to select patients based on HNF1B score improved specificity to 71.4% (95% CI:47.8%-88.7%) while retaining 100% sensitivity.

Conclusions: Detailed medical interview may enable more accurate patient selection for targeted genetic testing.
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http://dx.doi.org/10.1111/pedi.12959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217165PMC
May 2020

Occurrence and Characterization of -Positive Isolated From Food-Producing Animals in Poland, 2011-2016.

Authors:
Magdalena Zając Paweł Sztromwasser Valeria Bortolaia Pimlapas Leekitcharoenphon Lina M Cavaco Anna Ziȩtek-Barszcz Rene S Hendriksen Dariusz Wasyl

Front Microbiol 2019 8;10:1753. Epub 2019 Aug 8.

Department of Microbiology, National Veterinary Research Institute, Puławy, Poland.

The emergence of plasmid-mediated colistin resistance ( genes) threatens the effectiveness of polymyxins, which are last-resort drugs to treat infections by multidrug- and carbapenem-resistant Gram-negative bacteria. Based on the occurrence of colistin resistance the aims of the study were to determine possible resistance mechanisms and then characterize the -positive . The research used material from the Polish national and EU harmonized antimicrobial resistance (AMR) monitoring programs. A total of 5,878 commensal from fecal samples of turkeys, chickens, pigs, and cattle collected in 2011-2016 were screened by minimum inhibitory concentration (MIC) determination for the presence of resistance to colistin (R) defined as > 2 mg/L. Strains with MIC = 2 mg/L isolated in 2014-2016 were also included. A total of 128 isolates were obtained, and most (66.3%) had colistin MIC of 2 mg/L. PCR revealed in 80 (62.5%) isolates recovered from 61 turkeys, 11 broilers, 2 laying hens, 1 pig, and 1 bovine. No other -type genes (including to -) were detected. Whole-genome sequencing (WGS) of the -positive isolates showed high diversity in the multi-locus sequence types (MLST) of , plasmid replicons, and AMR and virulence genes. Generally was detected on the same contig as the IncX4 (76.3%) and IncHI2 (6.3%) replicons. One isolate harbored . on the chromosome. Various extended-spectrum beta-lactamase (, , , , , and ) and quinolone resistance genes (, , and chromosomal , and mutations) were present in the .-positive . A total of 49 sequence types (ST) were identified, ST354, ST359, ST48, and ST617 predominating. One isolate, identified as ST189, belonged to atypical enteropathogenic Our findings show that . has spread widely among production animals in Poland, particularly in turkeys and appears to be transferable mainly by IncX4 and IncHI2 plasmids spread across diverse lineages. Interestingly, most of these -positive would remain undetected using phenotypic methods with the current epidemiological cut-off value (ECOFF). The appearance and spread of among various animals, but notably in turkeys, might be considered a food chain, and public health hazard.
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http://dx.doi.org/10.3389/fmicb.2019.01753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694793PMC
August 2019

Rare genetic variation in mitochondrial pathways influences the risk for Parkinson's disease.

Authors:
Johannes J Gaare Gonzalo S Nido Paweł Sztromwasser Per M Knappskog Olav Dahl Morten Lund-Johansen Jodi Maple-Grødem Guido Alves Ole-Bjørn Tysnes Stefan Johansson Kristoffer Haugarvoll Charalampos Tzoulis

Mov Disord 2018 10 5;33(10):1591-1600. Epub 2018 Sep 5.

Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: Mitochondrial dysfunction plays a key role in PD, but the underlying molecular mechanisms remain unresolved. We hypothesized that the disruption of mitochondrial function in PD is primed by rare, protein-altering variation in nuclear genes controlling mitochondrial structure and function.

Objective: The objective of this study was to assess whether genetic variation in genes associated with mitochondrial function influences the risk of idiopathic PD.

Methods: We employed whole-exome sequencing data from 2 independent cohorts of clinically validated idiopathic PD and controls, the Norwegian ParkWest cohort (n = 411) and the North American Parkinson's Progression Markers Initiative (n = 640). We applied burden-based and variance-based collapsing methods to assess the enrichment of rare, nonsynonymous, and damaging genetic variants on genes, exome-wide, and on a comprehensive set of mitochondrial pathways, defined as groups of genes controlling specific mitochondrial functions.

Results: Using the sequence kernel association test, we detected a significant polygenic enrichment of rare, nonsynonymous variants in the gene-set encoding the pathway of mitochondrial DNA maintenance. Notably, this was the strongest association in both cohorts and survived multiple testing correction (ParkWest P = 6.3 × 10 , Parkinson's Progression Markers Initiative P = 6.9 × 10 , metaanalysis P = 3.2 × 10 ).

Conclusions: Our results show that the enrichment of rare inherited variation in the pathway controlling mitochondrial DNA replication and repair influences the risk of PD. We propose that this polygenic enrichment contributes to the impairment of mitochondrial DNA homeostasis, thought to be a key mechanism in the pathogenesis of PD, and explains part of the disorder's "missing heritability." © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282592PMC
October 2018

No evidence for rare TRAP1 mutations influencing the risk of idiopathic Parkinson's disease.

Authors:
Johannes J Gaare Gonzalo S Nido Pawel Sztromwasser Per M Knappskog Olav Dahl Morten Lund-Johansen Guido Alves Ole-Bjørn Tysnes Stefan Johansson Kristoffer Haugarvoll Charalampos Tzoulis

Brain 2018 03;141(3):e16

Department of Neurology, Haukeland University Hospital, 5021, Bergen, Norway.

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http://dx.doi.org/10.1093/brain/awx378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837630PMC
March 2018

Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry.

Authors:
Bente B Johansson Henrik U Irgens Janne Molnes Paweł Sztromwasser Ingvild Aukrust Petur B Juliusson Oddmund Søvik Shawn Levy Torild Skrivarhaug Geir Joner Anders Molven Stefan Johansson Pål R Njølstad

Diabetologia 2017 04 2;60(4):625-635. Epub 2016 Dec 2.

K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway.

Aims/hypothesis: MODY can be wrongly diagnosed as type 1 diabetes in children. We aimed to find the prevalence of MODY in a nationwide population-based registry of childhood diabetes.

Methods: Using next-generation sequencing, we screened the HNF1A, HNF4A, HNF1B, GCK and INS genes in all 469 children (12.1%) negative for both GAD and IA-2 autoantibodies and 469 antibody-positive matched controls selected from the Norwegian Childhood Diabetes Registry (3882 children). Variants were classified using clinical diagnostic criteria for pathogenicity ranging from class 1 (neutral) to class 5 (pathogenic).

Results: We identified 58 rare exonic and splice variants in cases and controls. Among antibody-negative patients, 6.5% had genetic variants of classes 3-5 (vs 2.4% in controls; p = 0.002). For the stricter classification (classes 4 and 5), the corresponding number was 4.1% (vs 0.2% in controls; p = 1.6 × 10). HNF1A showed the strongest enrichment of class 3-5 variants, with 3.9% among antibody-negative patients (vs 0.4% in controls; p = 0.0002). Antibody-negative carriers of variants in class 3 had a similar phenotype to those carrying variants in classes 4 and 5.

Conclusions/interpretation: This is the first study screening for MODY in all antibody-negative children in a nationwide population-based registry. Our results suggest that the prevalence of MODY in antibody-negative childhood diabetes may reach 6.5%. One-third of these MODY cases had not been recognised by clinicians. Since a precise diagnosis is important for treatment and genetic counselling, molecular screening of all antibody-negative children should be considered in routine diagnostics.
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http://dx.doi.org/10.1007/s00125-016-4167-1DOI Listing
April 2017

RareVariantVis: new tool for visualization of causative variants in rare monogenic disorders using whole genome sequencing data.

Authors:
Tomasz Stokowy Mateusz Garbulowski Torunn Fiskerstrand Rita Holdhus Kornel Labun Pawel Sztromwasser Christian Gilissen Alexander Hoischen Gunnar Houge Kjell Petersen Inge Jonassen Vidar M Steen

Bioinformatics 2016 10 10;32(19):3018-20. Epub 2016 Jun 10.

Department of Clinical Science, University of Bergen, Bergen 5020, Norway Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 5021, Norway.

Motivation: The search for causative genetic variants in rare diseases of presumed monogenic inheritance has been boosted by the implementation of whole exome (WES) and whole genome (WGS) sequencing. In many cases, WGS seems to be superior to WES, but the analysis and visualization of the vast amounts of data is demanding.

Results: To aid this challenge, we have developed a new tool-RareVariantVis-for analysis of genome sequence data (including non-coding regions) for both germ line and somatic variants. It visualizes variants along their respective chromosomes, providing information about exact chromosomal position, zygosity and frequency, with point-and-click information regarding dbSNP IDs, gene association and variant inheritance. Rare variants as well as de novo variants can be flagged in different colors. We show the performance of the RareVariantVis tool in the Genome in a Bottle WGS data set.

Availability And Implementation: https://www.bioconductor.org/packages/3.3/bioc/html/RareVariantVis.html

Contact: tomasz.stokowy@k2.uib.no

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btw359DOI Listing
October 2016

PNKP Mutations Identified by Whole-Exome Sequencing in a Norwegian Patient with Sporadic Ataxia and Edema.

Authors:
C Tzoulis Paweł Sztromwasser Stefan Johansson Ivar Otto Gjerde Per Knappskog L A Bindoff

Cerebellum 2017 02;16(1):272-275

Department of Neurology, Haukeland University Hospital, 5021, Bergen, Norway.

We identified PNKP mutations in a Norwegian woman with AOA. This patient had the typical findings with cognitive dysfunction, peripheral neuropathy, cerebellar dysarthria, horizontal nystagmus, oculomotor apraxia, and severe truncal and appendicular ataxia. In addition, she had hypoalbuminemia and massive lower limb edema which showed some improvement with treatment. Exome sequencing identified two heterozygous mutations, one in exon 14 (c.1196T>C, p.Leu399Pro) and one in exon 16 (c.1393_1396del, p.Glu465*). This is the first non-Portuguese patient with AOA due to PNKP mutations and provides independent verification that PNKP mutations cause AOA.
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http://dx.doi.org/10.1007/s12311-016-0784-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5243888PMC
February 2017

Novel SLC19A3 Promoter Deletion and Allelic Silencing in Biotin-Thiamine-Responsive Basal Ganglia Encephalopathy.

Authors:
Irene Flønes Paweł Sztromwasser Kristoffer Haugarvoll Christian Dölle Maria Lykouri Thomas Schwarzlmüller Inge Jonassen Hrvoje Miletic Stefan Johansson Per M Knappskog Laurence A Bindoff Charalampos Tzoulis

PLoS One 2016 10;11(2):e0149055. Epub 2016 Feb 10.

Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: Biotin-thiamine responsive basal ganglia disease is a severe, but potentially treatable disorder caused by mutations in the SLC19A3 gene. Although the disease is inherited in an autosomal recessive manner, patients with typical phenotypes carrying single heterozygous mutations have been reported. This makes the diagnosis uncertain and may delay treatment.

Methods And Results: In two siblings with early-onset encephalopathy dystonia and epilepsy, whole-exome sequencing revealed a novel single heterozygous SLC19A3 mutation (c.337T>C). Although Sanger-sequencing and copy-number analysis revealed no other aberrations, RNA-sequencing in brain tissue suggested the second allele was silenced. Whole-genome sequencing resolved the genetic defect by revealing a novel 45,049 bp deletion in the 5'-UTR region of the gene abolishing the promoter. High dose thiamine and biotin therapy was started in the surviving sibling who remains stable. In another patient two novel compound heterozygous SLC19A3 mutations were found. He improved substantially on thiamine and biotin therapy.

Conclusions: We show that large genomic deletions occur in the regulatory region of SLC19A3 and should be considered in genetic testing. Moreover, our study highlights the power of whole-genome sequencing as a diagnostic tool for rare genetic disorders across a wide spectrum of mutations including non-coding large genomic rearrangements.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149055PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749299PMC
July 2016

Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration.

Authors:
Dario Brunetti Janniche Torsvik Cristina Dallabona Pedro Teixeira Pawel Sztromwasser Erika Fernandez-Vizarra Raffaele Cerutti Aurelio Reyes Carmela Preziuso Giulia D'Amati Enrico Baruffini Paola Goffrini Carlo Viscomi Ileana Ferrero Helge Boman Wenche Telstad Stefan Johansson Elzbieta Glaser Per M Knappskog Massimo Zeviani Laurence A Bindoff

EMBO Mol Med 2016 Mar;8(3):176-90

Department of Neurology, Haukeland University Hospital, Bergen, Norway Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway

Mitochondrial dysfunction and altered proteostasis are central features of neurodegenerative diseases. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests oligopeptides, including the mitochondrial targeting sequences that are cleaved from proteins imported across the inner mitochondrial membrane and the mitochondrial fraction of amyloid beta (Aβ). We identified two siblings carrying a homozygous PITRM1 missense mutation (c.548G>A, p.Arg183Gln) associated with an autosomal recessive, slowly progressive syndrome characterised by mental retardation, spinocerebellar ataxia, cognitive decline and psychosis. The pathogenicity of the mutation was tested in vitro, in mutant fibroblasts and skeletal muscle, and in a yeast model. A Pitrm1(+/-) heterozygous mouse showed progressive ataxia associated with brain degenerative lesions, including accumulation of Aβ-positive amyloid deposits. Our results show that PITRM1 is responsible for significant Aβ degradation and that impairment of its activity results in Aβ accumulation, thus providing a mechanistic demonstration of the mitochondrial involvement in amyloidotic neurodegeneration.
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http://dx.doi.org/10.15252/emmm.201505894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772954PMC
March 2016

A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.

Authors:
Karianne Fjeld Frank Ulrich Weiss Denise Lasher Jonas Rosendahl Jian-Min Chen Bente B Johansson Holger Kirsten Claudia Ruffert Emmanuelle Masson Solrun J Steine Peter Bugert Miriam Cnop Robert Grützmann Julia Mayerle Joachim Mössner Monika Ringdal Hans-Ulrich Schulz Matthias Sendler Peter Simon Paweł Sztromwasser Janniche Torsvik Markus Scholz Erling Tjora Claude Férec Heiko Witt Markus M Lerch Pål R Njølstad Stefan Johansson Anders Molven

Nat Genet 2015 May 16;47(5):518-522. Epub 2015 Mar 16.

KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.

Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 × 10(-6) by two-tailed Fisher's exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2-8.5; P = 1.2 × 10(-11); formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.
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http://dx.doi.org/10.1038/ng.3249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321495PMC
May 2015

High myopia-excavated optic disc anomaly associated with a frameshift mutation in the MYC-binding protein 2 gene (MYCBP2).

Authors:
Cecilie Bredrup Stefan Johansson Laurence A Bindoff Pawel Sztromwasser Jostein Kråkenes Anne E C Mellgren Kari R Brurås Ola Lind Helge Boman Per M Knappskog Eyvind Rødahl

Am J Ophthalmol 2015 May 26;159(5):973-9.e2. Epub 2015 Jan 26.

Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway. Electronic address:

Purpose: To investigate the ocular and neurologic manifestations, and to identify the causative mutation in a family with an excavated optic disc anomaly, high myopia, enlarged axial lengths, and abnormal visual evoked response (VER).

Design: Prospective observational case series with whole exome sequencing.

Methods: Institutional study of 8 family members from 3 generations. Clinical examination included visual field examination, optical coherence tomography, axial length measurement, audiometry, visual evoked response (VER), orbital and cerebral magnetic resonance imaging (MRI), and renal ultrasound. DNA was analyzed by whole exome sequencing and Sanger sequencing. Main outcome measures were clinical and radiological findings, and DNA sequence data.

Results: Three affected family members, a father and his 2 daughters, were examined. The parents and siblings of the father were healthy. Affected individuals presented with excavated optic discs, high myopia (-1.00 to -16.00 diopters), and increased axial lengths. Reduced visual acuity (0.05-0.8) and decreased sensitivity on visual field examination were observed. VER revealed prolonged latency times. Affected eyes appeared ovoid on MRI and the father had thin optic nerves. Exome sequencing revealed that the father was heterozygous for a de novo 5 bp deletion in MYCBP2, c.5906_5910del; p.Glu1969Valfs*26. The same mutation was found in his 2 affected daughters, but not in his parents or siblings, or in public databases.

Conclusion: We describe a distinct excavated optic disc anomaly associated with high myopia and increased axial length. The condition appears to follow an autosomal dominant pattern and segregate with a deletion in MYCBP2. We suggest naming this entity high myopia-excavated optic disc anomaly.
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http://dx.doi.org/10.1016/j.ajo.2015.01.021DOI Listing
May 2015

Data partitioning enables the use of standard SOAP Web Services in genome-scale workflows.

Authors:
Pawel Sztromwasser Pål Puntervoll Kjell Petersen

J Integr Bioinform 2011 Jul 26;8(2):163. Epub 2011 Jul 26.

Department of Informatics, University of Bergen, Norway.

Biological databases and computational biology tools are provided by research groups around the world, and made accessible on the Web. Combining these resources is a common practice in bioinformatics, but integration of heterogeneous and often distributed tools and datasets can be challenging. To date, this challenge has been commonly addressed in a pragmatic way, by tedious and error-prone scripting. Recently however a more reliable technique has been identified and proposed as the platform that would tie together bioinformatics resources, namely Web Services. In the last decade the Web Services have spread wide in bioinformatics, and earned the title of recommended technology. However, in the era of high-throughput experimentation, a major concern regarding Web Services is their ability to handle large-scale data traffic. We propose a stream-like communication pattern for standard SOAP Web Services, that enables efficient flow of large data traffic between a workflow orchestrator and Web Services. We evaluated the data-partitioning strategy by comparing it with typical communication patterns on an example pipeline for genomic sequence annotation. The results show that data-partitioning lowers resource demands of services and increases their throughput, which in consequence allows to execute in-silico experiments on genome-scale, using standard SOAP Web Services and workflows. As a proof-of-principle we annotated an RNA-seq dataset using a plain BPEL workflow engine.
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http://dx.doi.org/10.2390/biecoll-jib-2011-163DOI Listing
July 2011