Publications by authors named "Peter Bauer"

398 Publications

Co-Morbid Palmoplantar Keratoderma Type 1A and Loeys-Dietz Syndrome Type 3 in a Patient with a Chromosome 15 Microdeletion.

J Eur Acad Dermatol Venereol 2022 Jan 21. Epub 2022 Jan 21.

Department of Pathology, Faculty of Medicine and Surgery, University of Malta.

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http://dx.doi.org/10.1111/jdv.17942DOI Listing
January 2022

Crab-Eating Monkey Acidic Chitinase (CHIA) Efficiently Degrades Chitin and Chitosan under Acidic and High-Temperature Conditions.

Molecules 2022 Jan 9;27(2). Epub 2022 Jan 9.

Department of Chemistry and Life Science, Kogakuin University, Tokyo 192-0015, Japan.

Chitooligosaccharides, the degradation products of chitin and chitosan, possess anti-bacterial, anti-tumor, and anti-inflammatory activities. The enzymatic production of chitooligosaccharides may increase the interest in their potential biomedical or agricultural usability in terms of the safety and simplicity of the manufacturing process. Crab-eating monkey acidic chitinase (CHIA) is an enzyme with robust activity in various environments. Here, we report the efficient degradation of chitin and chitosan by monkey CHIA under acidic and high-temperature conditions. Monkey CHIA hydrolyzed α-chitin at 50 °C, producing -acetyl-d-glucosamine (GlcNAc) dimers more efficiently than at 37 °C. Moreover, the degradation rate increased with a longer incubation time (up to 72 h) without the inactivation of the enzyme. Five substrates (α-chitin, colloidal chitin, P-chitin, block-type, and random-type chitosan substrates) were exposed to monkey CHIS at pH 2.0 or pH 5.0 at 50 °C. P-chitin and random-type chitosan appeared to be the best sources of GlcNAc dimers and broad-scale chitooligosaccharides, respectively. In addition, the pattern of the products from the block-type chitosan was different between pH conditions (pH 2.0 and pH 5.0). Thus, monkey CHIA can degrade chitin and chitosan efficiently without inactivation under high-temperature or low pH conditions. Our results show that certain chitooligosaccharides are enriched by using different substrates under different conditions. Therefore, the reaction conditions can be adjusted to obtain desired oligomers. Crab-eating monkey CHIA can potentially become an efficient tool in producing chitooligosaccharide sets for agricultural and biomedical purposes.
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http://dx.doi.org/10.3390/molecules27020409DOI Listing
January 2022

A disorder clinically resembling cystic fibrosis caused by biallelic variants in the gene.

J Med Genet 2021 Dec 24. Epub 2021 Dec 24.

Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany.

Purpose: We sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause.

Methods: Exome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed.

Results: We identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in , (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant transcripts caused by an intronic variant and complete absence of transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes.

Conclusion: We describe a previously unrecognised autosomal recessive disorder caused by variants. -related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.
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http://dx.doi.org/10.1136/jmedgenet-2021-108150DOI Listing
December 2021

High rate of abnormal findings in Prenatal Exome Trio in low risk pregnancies and apparently normal fetuses.

Prenat Diagn 2021 Dec 17. Epub 2021 Dec 17.

The Genetic Institute of Maccabi Health Services, Rehovot, Israel.

Objective: Data on the value of exome sequencing in fetuses with no structural anomalies are limited, especially in the early stages of pregnancy and in low risk pregnancies. We investigated the yield of targeted clinical prenatal trio exome sequencing (pES) in pregnancies with and without fetal structural anomalies.

Methods: We performed pES in 353 pregnancies: Group 1 included 143 pregnancies with high clinical suspicion for a genetic disease: pregnancies with increased nuchal translucency, ultrasound structural defects, intrauterine growth restriction, polyhydramnios, or effusion/nuchal edema. Group 2 included 210 pregnancies with no notable abnormal fetal ultrasound findings. 2a. Low risk pregnancies with minor ultrasound findings, referred to the geneticist due to mildly increased risk for genetic disease (50); and 2b. Normal pregnancy surveillance (160).

Results: Overall, 26 (7.36%) fetal analyses had pathogenic (P)/likely pathogenic (LP) variants. In group 1, 20/143 (13.99%) cases had P/LP variants. In group 2, 6/210 (2.86%) cases were found to have P/LP variants [5/50 in (2a) and 1/160 in (2b)].

Conclusion: These results show a high rate of abnormal findings on pES even in apparently normal pregnancies.
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http://dx.doi.org/10.1002/pd.6077DOI Listing
December 2021

Noninsect-Based Diet Leads to Structural and Functional Changes of Acidic Chitinase in Carnivora.

Mol Biol Evol 2022 Jan;39(1)

Department of Chemistry and Life Science, Kogakuin University, Tokyo, Japan.

Acidic chitinase (Chia) digests the chitin of insects in the omnivorous stomach and the chitinase activity in carnivorous Chia is significantly lower than that of the omnivorous enzyme. However, mechanistic and evolutionary insights into the functional changes in Chia remain unclear. Here we show that a noninsect-based diet has caused structural and functional changes in Chia during the course of evolution in Carnivora. By creating mouse-dog chimeric Chia proteins and modifying the amino acid sequences, we revealed that F214L and A216G substitutions led to the dog enzyme activation. In 31 Carnivora, Chia was present as a pseudogene with stop codons in the open reading frame (ORF) region. Importantly, the Chia proteins of skunk, meerkat, mongoose, and hyena, which are insect-eating species, showed high chitinolytic activity. The cat Chia pseudogene product was still inactive even after ORF restoration. However, the enzyme was activated by matching the number and position of Cys residues to an active form and by introducing five meerkat Chia residues. Mutations affecting the Chia conformation and activity after pseudogenization have accumulated in the common ancestor of Felidae due to functional constraints. Evolutionary analysis indicates that Chia genes are under relaxed selective constraint in species with noninsect-based diets except for Canidae. These results suggest that there are two types of inactivating processes in Carnivora and that dietary changes affect the structure and activity of Chia.
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http://dx.doi.org/10.1093/molbev/msab331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789059PMC
January 2022

Predicting Hospital Length of Stay at Admission Using Global and Country-Specific Competing Risk Analysis of Structural, Patient, and Nutrition-Related Data from nutritionDay 2007-2015.

Nutrients 2021 Nov 16;13(11). Epub 2021 Nov 16.

Department of Health Economics, Center for Public Health, Medical University of Vienna, 1090 Vienna, Austria.

Hospital length of stay (LOS) is an important clinical and economic outcome and knowing its predictors could lead to better planning of resources needed during hospitalization. This analysis sought to identify structure, patient, and nutrition-related predictors of LOS available at the time of admission in the global nutritionDay dataset and to analyze variations by country for countries with > 750. Data from 2006-2015 ( = 155,524) was utilized for descriptive and multivariable cause-specific Cox proportional hazards competing-risks analyses of total LOS from admission. Time to event analysis on 90,480 complete cases included: discharged ( = 65,509), transferred ( = 11,553), or in-hospital death ( = 3199). The median LOS was 6 days (25th and 75th percentile: 4-12). There is robust evidence that LOS is predicted by patient characteristics such as age, affected organs, and comorbidities in all three outcomes. Having lost weight in the last three months led to a longer time to discharge (Hazard Ratio (HR) 0.89; 99.9% Confidence Interval (CI) 0.85-0.93), shorter time to transfer (HR 1.40; 99.9% CI 1.24-1.57) or death (HR 2.34; 99.9% CI 1.86-2.94). The impact of having a dietician and screening patients at admission varied by country. Despite country variability in outcomes and LOS, the factors that predict LOS at admission are consistent globally.
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http://dx.doi.org/10.3390/nu13114111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624242PMC
November 2021

Glucocerebrosidase (GBA) gene variants in a multi-ethnic Asian cohort with Parkinson's disease: mutational spectrum and clinical features.

J Neural Transm (Vienna) 2022 Jan 15;129(1):37-48. Epub 2021 Nov 15.

The Mah Pooi Soo and Tan Chin Nam Centre for Parkinson's and Related Disorders, University of Malaya, Kuala Lumpur, Malaysia.

GBA variants are associated with increased risk and earlier onset of Parkinson's disease (PD), and more rapid disease progression especially with "severe" variants typified by p.L483P. GBA mutation screening studies from South-East Asia, with > 650 million inhabitants of diverse ancestries, are very limited. We investigated the spectrum of GBA variants, and associated clinico-demographic features, in a multi-ethnic PD cohort in Malaysia. Patients (n = 496) were recruited from seven centres, primarily of Chinese (45%), Malay (37%), and Indian (13%) ethnicities. All GBA coding exons were screened using a next-generation sequencing-based PD gene panel and verified with Sanger sequencing. We identified 14 heterozygous GBA alleles consisting of altogether 17 missense variants (8 classified as pathogenic or likely pathogenic for PD) in 25 (5.0%) patients, with a substantially higher yield among early (< 50 years) vs. late-onset patients across all three ethnicities (9.1-13.2% vs. 1.0-3.2%). The most common variant was p.L483P (including RecNciI, n = 11, 2.2%), detected in all three ethnicities. Three novel variants/recombinant alleles of uncertain significance were found; p.P71L, p.L411P, and p.L15S(;)S16G(;)I20V. The common European risk variants, p.E365K, p.T408M, and p.N409S, were not detected. A severe disease course was noted in the majority of GBA-variant carriers, across a range of detected variants. We report a potentially novel observation of spine posture abnormalities in GBA-variant carriers. This represents the largest study on GBA variation from South-East Asia, and highlights that these populations, especially those with EOPD, would be relevant for studies including clinical trials targeting GBA pathways.
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http://dx.doi.org/10.1007/s00702-021-02421-0DOI Listing
January 2022

Mouse Acidic Chitinase Effectively Degrades Random-Type Chitosan to Chitooligosaccharides of Variable Lengths under Stomach and Lung Tissue pH Conditions.

Molecules 2021 Nov 5;26(21). Epub 2021 Nov 5.

Department of Chemistry and Life Science, Kogakuin University, Tokyo 192-0015, Japan.

Chitooligosaccharides exhibit several biomedical activities, such as inflammation and tumorigenesis reduction in mammals. The mechanism of the chitooligosaccharides' formation in vivo has been, however, poorly understood. Here we report that mouse acidic chitinase (Chia), which is widely expressed in mouse tissues, can produce chitooligosaccharides from deacetylated chitin (chitosan) at pH levels corresponding to stomach and lung tissues. Chia degraded chitin to produce -acetyl-d-glucosamine (GlcNAc) dimers. The block-type chitosan (heterogenous deacetylation) is soluble at pH 2.0 (optimal condition for mouse Chia) and was degraded into chitooligosaccharides with various sizes ranging from di- to nonamers. The random-type chitosan (homogenous deacetylation) is soluble in water that enables us to examine its degradation at pH 2.0, 5.0, and 7.0. Incubation of these substrates with Chia resulted in the more efficient production of chitooligosaccharides with more variable sizes was from random-type chitosan than from the block-type form of the molecule. The data presented here indicate that Chia digests chitosan acquired by homogenous deacetylation of chitin in vitro and in vivo. The degradation products may then influence different physiological or pathological processes. Our results also suggest that bioactive chitooligosaccharides can be obtained conveniently using homogenously deacetylated chitosan and Chia for various biomedical applications.
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http://dx.doi.org/10.3390/molecules26216706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8587675PMC
November 2021

Biallelic ZNFX1 variants are associated with a spectrum of immuno-hematological abnormalities.

Clin Genet 2022 02 6;101(2):247-254. Epub 2021 Nov 6.

Genomic Research & Medical Reporting, CENTOGENE GmbH, Rostock, Germany.

Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55 000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense changes, two variants predicted to result in complete protein loss through nonsense-mediated decay, and two frameshift changes that likely introduce a truncation. Our findings (i) independently confirm the role of ZNFX1 in primary genetic immunodeficiency, (ii) expand the genetic and clinical spectrum of ZNFX1-related disease, and (iii) illustrate the utility of large, well-curated, and continually updated genotype-phenotype databases in resolving molecular diagnoses of patients with initially negative genetic testing findings.
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http://dx.doi.org/10.1111/cge.14081DOI Listing
February 2022

Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility.

NPJ Genom Med 2020 Oct 5;5(1):44. Epub 2020 Oct 5.

CENTOGENE AG, Rostock, Germany.

We implemented a collaborative diagnostic program in Lahore (Pakistan) aiming to establish the genetic diagnosis, and to asses diagnostic yield and clinical impact in patients with suspected genetic diseases. Local physicians ascertained pediatric patients who had no previous access to genetic testing. More than 1586 genetic tests were performed in 1019 individuals (349 index cases, 670 relatives). Most frequently performed tests were exome/genome sequencing (ES/GS, 284/78 index cases) and specific gene panels (55 index cases). In 61.3% of the patients (n = 214) a genetic diagnosis was established based on pathogenic and likely pathogenic variants. Diagnostic yield was higher in consanguineous families (60.1 vs. 39.5%). In 27 patients, genetic diagnosis relied on additional biochemical testing, allowing rapid assessment of the functional effect of the variants. Remarkably, the genetic diagnosis had a direct impact on clinical management. Most relevant consequences were therapy related such as initiation of the appropriated treatment in a timely manner in 51.9% of the patients (n = 111). Finally, we report 12 candidate genes among 66 cases with no genetic diagnosis. Importantly, three of these genes were validated as 'diagnostic' genes given the strong evidence supporting causality derived from our data repository (CAP2-dilated cardiomyopathy, ITFG2-intellectual disability and USP53-liver cholestasis). The high diagnostic yield, clinical impact, and research findings demonstrate the utility of genomic testing, especially when used as first-line genetic test. For patients with suspected genetic diseases from resource-limited regions, ES can be considered as the test of choice to achieve genetic diagnosis.
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http://dx.doi.org/10.1038/s41525-020-00150-zDOI Listing
October 2020

An international comparison of age and sex dependency of COVID-19 deaths in 2020: a descriptive analysis.

Sci Rep 2021 09 27;11(1):19143. Epub 2021 Sep 27.

Section for Medical Statistics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.

The number of reported coronavirus disease (COVID-19) deaths per 100,000 persons observed so far in 2020 is described in 15 European countries and the USA as dependent on age groups and sex. It is compared with the corresponding historic all-cause mortality per year depending on age and sex observed in these countries. Some common features exist although substantial differences in age and sex dependency of COVID-19 mortality were noted between countries. An exponential increase with age is a good model to describe and analyze both COVID-19 and all-cause mortality above 40 years old, where almost all COVID-19 deaths occur. Moreover, age dependency is stronger for COVID-19 mortality than for all-cause mortality, and males have an excess risk compared with women, which is less pronounced in the higher age groups. Additionally, concerning calendar time, differences in the age and sex dependency between countries were noted with the common tendency that male excess risk for COVID-19 mortality was smaller in the second half of the year.
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http://dx.doi.org/10.1038/s41598-021-97711-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476584PMC
September 2021

Whole Exome Sequencing in a Series of Patients with a Clinical Diagnosis of Tuberous Sclerosis Not Confirmed by Targeted Sequencing.

Genes (Basel) 2021 09 10;12(9). Epub 2021 Sep 10.

Department of Medical Genetics, Medical School, Szentagothai Research Center, University of Pecs, 7624 Pecs, Hungary.

Background: Approximately fifteen percent of patients with tuberous sclerosis complex (TSC) phenotype do not have any genetic disease-causing mutations which could be responsible for the development of TSC. The lack of a proper diagnosis significantly affects the quality of life for these patients and their families.

Methods: The aim of our study was to use Whole Exome Sequencing (WES) in order to identify the genes responsible for the phenotype of nine patients with clinical signs of TSC, but without confirmed tuberous sclerosis complex 1/ tuberous sclerosis complex 2 ( mutations using routine molecular genetic diagnostic tools.

Results: We found previously overlooked heterozygous nonsense mutations in , and a heterozygous intronic variant in . In one patient, two heterozygous missense variants were found in polycystic kidney and hepatic disease 1 (, confirming polycystic kidney disease type 4. A heterozygous missense mutation in solute carrier family 12 member 5 ( was found in one patient, which is linked to cause susceptibility to idiopathic generalized epilepsy type 14. Heterozygous nonsense variant ring finger protein 213 ( was identified in one patient, which is associated with susceptibility to Moyamoya disease type 2. In the remaining three patients WES could not reveal any variants clinically relevant to the described phenotypes.

Conclusion: Patients without appropriate diagnosis due to the lack of sensitivity of the currently used routine diagnostic methods can significantly profit from the wider application of next generation sequencing technologies in order to identify genes and variants responsible for their symptoms.
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http://dx.doi.org/10.3390/genes12091401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471884PMC
September 2021

LIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort.

Front Neurol 2021 9;12:710572. Epub 2021 Aug 9.

Department of Neurology, University Hospital Würzburg, Würzburg, Germany.

Pathogenic variants in the Leucine-rich repeat kinase 2 ( gene are the most common known monogenic cause of Parkinson's disease (PD). -linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions. To systematically assess clinical signs and symptoms including non-motor features, comorbidities, medication and environmental factors in PD patients, unaffected pathogenic variant carriers, and controls. A further focus is to enable the investigation of modifiers of penetrance and expressivity of pathogenic variants using genetic and environmental data. Eligible participants are invited for a personal or online examination which comprises completion of a detailed eCRF and collection of blood samples (to obtain DNA, RNA, serum/plasma, immune cells), urine as well as household dust. We plan to enroll 1,000 participants internationally: 300 with -linked PD, 200 with pathogenic variants but without PD, 100 PD patients with pathogenic variants in the or genes, 200 patients with idiopathic PD, and 200 healthy persons without pathogenic variants. The eCRF consists of an investigator-rated (1 h) and a self-rated (1.5 h) part. The first part includes the Movement Disorder Society Unified Parkinson's Disease Rating, Hoehn &Yahr, and Schwab & England Scales, the Brief Smell Identification Test, and Montreal Cognitive Assessment. The self-rating part consists of a PD risk factor, food frequency, autonomic dysfunction, and quality of life questionnaires, the Pittsburgh Sleep Quality Inventory, and the Epworth Sleepiness as well as the Hospital Anxiety and Depression Scales. The first 15 centers have been initiated and the first 150 participants enrolled (as of March 25th, 2021). LIPAD is a large-scale international scientific effort focusing on deep phenotyping of -linked PD and healthy pathogenic variant carriers, including the comparison with additional relatively frequent genetic forms of PD, with a future perspective to identify genetic and environmental modifiers of penetrance and expressivity ClinicalTrials.gov, NCT04214509.
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http://dx.doi.org/10.3389/fneur.2021.710572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406937PMC
August 2021

Robust chitinolytic activity of crab-eating monkey (Macaca fascicularis) acidic chitinase under a broad pH and temperature range.

Sci Rep 2021 07 29;11(1):15470. Epub 2021 Jul 29.

Department of Chemistry and Life Science, Kogakuin University, Hachioji, Tokyo, 192-0015, Japan.

Diet of the crab-eating monkey (Macaca fascicularis) consists of both plants and animals, including chitin-containing organisms such as crabs and insects. This omnivorous monkey has a high expression of acidic chitinase (CHIA) in the stomach and here, we report on its enzymatic properties under different conditions. When we compared with Mus musculus CHIA (Mm-CHIA), Macaca fascicularis CHIA (Mf-CHIA) exhibits higher chitinolytic activity at broad pH (1.0-7.0) and temperature (30-70 ℃) range. Interestingly, at its optimum pH (5.0), Mf-CHIA showed the highest activity at 65 °C while maintaining it at robust levels between 50 and 70 °C. The degradation efficiency of Mf-CHIA was superior to Mm-CHIA toward both polymeric chitin as well as an artificial chromogenic substrate. Our results show that unique features of Mf-CHIA including its thermostability warrant the nomination of this enzyme for potential agricultural and biomedical applications.
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http://dx.doi.org/10.1038/s41598-021-95010-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322401PMC
July 2021

Nearly Identical Plasmids Encoding VIM-1 and Mercury Resistance in Enterobacteriaceae from North-Eastern Germany.

Microorganisms 2021 Jun 22;9(7). Epub 2021 Jun 22.

Pharmaceutical Microbiology, University of Greifswald, 17489 Greifswald, Germany.

The emergence of carbapenemase-producing Enterobacteriaceae limits therapeutic options and presents a major public health problem. Resistances to carbapenems are mostly conveyed by metallo-beta-lactamases (MBL) including VIM, which are often encoded on resistance plasmids. We characterized four VIM-positive isolates that were obtained as part of a routine diagnostic screening from two laboratories in north-eastern Germany between June and August 2020. Whole-genome sequencing was performed to address (a) phylogenetic properties, (b) plasmid content, and (c) resistance gene carriage. In addition, we performed phenotypic antibiotic and mercury resistance analyses. The genomic analysis revealed three different bacterial species including , and with four different sequence types. All isolates were geno- and phenotypically multidrug-resistant (MDR) and the phenotypic profile was explained by the underlying resistance gene content. Three isolates of four carried nearly identical VIM-1-resistance plasmids, which in addition encoded a mercury resistance operon and showed some similarity to two publicly available plasmid sequences from sources other than the two laboratories above. Our results highlight the circulation of a nearly identical IncN-type VIM-1-resistance plasmid in different Enterobacteriaceae in north-eastern Germany.
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http://dx.doi.org/10.3390/microorganisms9071345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305640PMC
June 2021

Dried Blood Spot (DBS) Methodology Study for Biomarker Discovery in Lysosomal Storage Disease (LSD).

Metabolites 2021 Jun 13;11(6). Epub 2021 Jun 13.

Centogene GmbH, Am Strande 7, 18055 Rostock, Germany.

Lysosomal storage diseases (LSDs) are a heterogeneous group of inherited metabolic diseases caused by mutations in genes encoding for proteins involved in the lysosomal degradation of macromolecules. They occur in approximately 1 in 5000 live births and pose a lifelong risk. Therefore, to achieve the maximum benefit from LSDs therapies, a fast and early diagnosis of the disease is required. In this framework, biomarker discovery is a significant factor in disease diagnosis and in predicting its outcomes. On the other hand, the dried blood spot (DBS) based metabolomics platform can open up new pathways for studying non-directional hypothesis approaches to biomarker discovery. This study aims to increase the efficiency of the developed methods for biomarker development in the context of rare diseases, with an improved impact on the reliability of the detected compounds. Thereby, we conducted two independent experiments and integrated them into the screening of the human blood metabolome: (1) comparison of EDTA blood and filter cards in terms of their suitability for metabolomics studies; (2) optimization of the extraction method: a side-by-side comparison of a series of buffers to the best utility to the disease of interest. The findings were compared to previous studies across parameters such as metabolite coverage, sample type suitability, and stability. The results indicate that measurements of metabolites are susceptible to differences in pre-analytical conditions and extraction solvents. This proposed approach can increase the positive rate of the future development of biomarkers. Altogether, the procedure can be easily adapted and applied to other studies, where the limited number of samples is a common barrier.
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http://dx.doi.org/10.3390/metabo11060382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231917PMC
June 2021

The Leukodystrophy Spectrum in Saudi Arabia: Epidemiological, Clinical, Radiological, and Genetic Data.

Front Pediatr 2021 13;9:633385. Epub 2021 May 13.

Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.

Leukodystrophies (LDs) are inherited heterogeneous conditions that affect the central nervous system with or without peripheral nerve involvement. They are individually rare, but collectively, they are common. Thirty disorders were included by the Global Leukodystrophy Initiative Consortium (GLIA) as LDs. We conducted a retrospective chart review of a consecutive series of patients diagnosed with different types of LD from four large tertiary referral centers in Riyadh, Saudi Arabia. Only those 30 disorders defined by GLIA as LDs were included. In total, 83 children from 61 families were identified and recruited for this study. The male-to-female ratio was 1.5:1, and a consanguinity rate of 58.5% was observed. An estimated prevalence of 1:48,780 or 2.05/100,000 was observed based on the clinical cohort, whereas a minimum of 1:32,857 or 3.04/100,000 was observed based on the local genetic database. The central region of the country exhibited the highest prevalence of LDs (48.5%). The most common LD was metachromatic leukodystrophy (MLD), and it accounted for 25.3%. The most common disorder based on carrier frequency was AGS. Novel variants were discovered in 51% of the cases, but 49% possessed previously reported variants. Missense variants were high in number and accounted for 73% of all cases. Compared with other disorders, MLD due to saposin b deficiency was more common than expected, Pelizaeus-Merzbacher-like disease was more prevalent than Pelizaeus-Merzbacher disease, and X-linked adrenoleukodystrophy was less common than expected. The mortality rate among our patients with LD was 24%. To the best of our knowledge, this is the largest cohort of patients with LD from Saudi Arabia. We present epidemiological, clinical, radiological, and genetic data. Furthermore, we report 18 variants that have not been reported previously. These findings are of great clinical and molecular utility for diagnosing and managing patients with LD.
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http://dx.doi.org/10.3389/fped.2021.633385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155587PMC
May 2021

Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism.

Nat Commun 2021 05 28;12(1):3216. Epub 2021 May 28.

Institute of Medical Biometry and Statistics, University of Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany.

X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset (p < 5 × 10). The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to MSH3 and PMS2, the genes that were recently implicated in modifying age at onset in Huntington's disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in X-linked dystonia-parkinsonism that likely affect the DNA mismatch repair pathway.
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http://dx.doi.org/10.1038/s41467-021-23491-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163740PMC
May 2021

Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy.

Am J Hum Genet 2021 07 25;108(7):1301-1317. Epub 2021 May 25.

Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore.

Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.
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http://dx.doi.org/10.1016/j.ajhg.2021.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322802PMC
July 2021

Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders.

Genet Med 2021 08 19;23(8):1551-1568. Epub 2021 Apr 19.

King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, MNGHA, Riyadh, Saudi Arabia.

Purpose: Within this study, we aimed to discover novel gene-disease associations in patients with no genetic diagnosis after exome/genome sequencing (ES/GS).

Methods: We followed two approaches: (1) a patient-centered approach, which after routine diagnostic analysis systematically interrogates variants in genes not yet associated to human diseases; and (2) a gene variant centered approach. For the latter, we focused on de novo variants in patients that presented with neurodevelopmental delay (NDD) and/or intellectual disability (ID), which are the most common reasons for genetic testing referrals. Gene-disease association was assessed using our data repository that combines ES/GS data and Human Phenotype Ontology terms from over 33,000 patients.

Results: We propose six novel gene-disease associations based on 38 patients with variants in the BLOC1S1, IPO8, MMP15, PLK1, RAP1GDS1, and ZNF699 genes. Furthermore, our results support causality of 31 additional candidate genes that had little published evidence and no registered OMIM phenotype (56 patients). The phenotypes included syndromic/nonsyndromic NDD/ID, oral-facial-digital syndrome, cardiomyopathies, malformation syndrome, short stature, skeletal dysplasia, and ciliary dyskinesia.

Conclusion: Our results demonstrate the value of data repositories which combine clinical and genetic data for discovering and confirming gene-disease associations. Genetic laboratories should be encouraged to pursue such analyses for the benefit of undiagnosed patients and their families.
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http://dx.doi.org/10.1038/s41436-021-01159-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354858PMC
August 2021

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult-onset disorder.

Ann Clin Transl Neurol 2021 04 19;8(4):774-789. Epub 2021 Mar 19.

Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Juelich, Germany.

Objectives: Genetic variant classification is a challenge in rare adult-onset disorders as in SCA-PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA-PRKCG a comprehensive phenotype description from a German multi-center cohort, including standardized 3D MR imaging.

Methods: This cross-sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS).

Results: Our sample included 25 cases confirmed as SCA-PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA-PRKCG included slowly progressive ataxia (onset at 4-50 years), preceded in some by early-onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive-affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA-PRKCG cases but in none of the controls.

Interpretation: In this largest cohort to date, SCA-PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non-ataxia movement disorders and cognitive-affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA-PRKCG.
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http://dx.doi.org/10.1002/acn3.51315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045942PMC
April 2021

Accuracy Investigation of the Pose Determination of a VR System.

Sensors (Basel) 2021 Feb 25;21(5). Epub 2021 Feb 25.

Institute of Engineering Geodesy and Measurement Systems, Graz University of Technology, 8010 Graz, Austria.

The usage of VR gear in mixed reality applications demands a high position and orientation accuracy of all devices to achieve a satisfying user experience. This paper investigates the system behaviour of the VR system HTC Vive Pro at a testing facility that is designed for the calibration of highly accurate positioning instruments like geodetic total stations, tilt sensors, geodetic gyroscopes or industrial laser scanners. Although the experiments show a high reproducibility of the position readings within a few millimetres, the VR system has systematic effects with magnitudes of several centimetres. A tilt of about 0.4∘ of the reference plane with respect to the horizontal plane was detected. Moreover, our results demonstrate that the tracking algorithm faces problems when several lighthouses are used.
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http://dx.doi.org/10.3390/s21051622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956487PMC
February 2021

Reply letter to Battke et al.

Eur J Hum Genet 2021 05 17;29(5):724-725. Epub 2021 Feb 17.

CENTOGENE GmbH, Rostock, Germany.

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http://dx.doi.org/10.1038/s41431-021-00819-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110564PMC
May 2021

A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features.

Genet Med 2021 06 2;23(6):1158-1162. Epub 2021 Feb 2.

Centogene AG, Rostock, Germany.

Purpose: The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10.

Methods: Using exome, genome, and Sanger sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry.

Results: A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein.

Conclusion: We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.
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http://dx.doi.org/10.1038/s41436-021-01097-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187145PMC
June 2021

Genetic characterization of the Albanian Gaucher disease patient population.

JIMD Rep 2021 Jan 17;57(1):52-57. Epub 2020 Nov 17.

CENTOGENE GmbH Rostock Germany.

Gaucher disease (GD) is a recessive metabolic disorder caused by a deficiency of the gene-encoded enzyme β-glucocerebrosidase. We characterized a cohort of 36 Albanian GD patients, 31 with GD type 1 and 5 affected by GD types 2, 3, and an intermediate GD phenotype between type 2 and type 3. Of the 12 different alleles that we detected, the most frequently observed was p.Asn409Ser, followed by p.[Asp448His;His294Gln]. The prevalence of the p.Leu483Pro allele was approximately 10-fold lower than reported in other populations. We identified a novel pathogenic missense variant (c.1129G>A; p.Ala377Thr). All five of our non-type 1 patients had genotypes consisting of the p.[Asp448His;His294Gln] allele in combination with another severe allele. The median Lyso-Gb1 level of treated patients carrying the p.[Asp448His;His294Gln] and no p.Asn409Ser allele was significantly higher than that of treated individuals homozygous or compound heterozygous for the p.Asn409Ser allele. In conclusion, the most important distinguishing features of the Albanian GD patient population are the underrepresentation of the p.Leu483Pro allele and an unusually high number of p.[Asp448His;His294Gln] alleles originating from a common Balkan founder event. The presence of at least one p.Asn409Ser allele is associated with mild disease and low Lyso-Gb1 biomarker levels, while compound heterozygosity involving p.[Asp448His;His294Gln] and no p.Asn409Ser entails severe phenotypes and high Lyso-Gb1 levels.
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http://dx.doi.org/10.1002/jmd2.12167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802630PMC
January 2021
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