TY  - JOUR
AB  - Background: Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2). MeCP2 is a multi-functional protein involved in many cellular processes, but the mechanisms by which its dysfunction causes disease are not fully understood. The duplication of the MECP2 gene causes a distinct disorder called MECP2 duplication syndrome (MDS), highlighting the importance of tightly regulating its dosage for proper cellular function. Additionally, some patients with mutations in genes other than MECP2 exhibit phenotypic similarities with RTT, indicating that these genes may also play a role in similar cellular functions. The purpose of this study was to characterise the molecular alterations in patients with RTT in order to identify potential biomarkers or therapeutic targets for this disorder. Methods: We used a combination of transcriptomics (RNAseq) and proteomics (TMT mass spectrometry) to characterise the expression patterns in fibroblast cell lines from 22 patients with RTT and detected mutation in MECP2, 15 patients with MDS, 12 patients with RTT-like phenotypes and 13 healthy controls. Transcriptomics and proteomics data were used to identify differentially expressed genes at both RNA and protein levels, which were further inspected via enrichment and upstream regulator analyses and compared to find shared features in patients with RTT. Results: We identified molecular alterations in cellular functions and pathways that may contribute to the disease phenotype in patients with RTT, such as deregulated cytoskeletal components, vesicular transport elements, ribosomal subunits and mRNA processing machinery. We also compared RTT expression profiles with those of MDS seeking changes in opposite directions that could lead to the identification of MeCP2 direct targets. Some of the deregulated transcripts and proteins were consistently affected in patients with RTT-like phenotypes, revealing potentially relevant molecular processes in patients with overlapping traits and different genetic aetiology. Conclusions: The integration of data in a multi-omics analysis has helped to interpret the molecular consequences of MECP2 dysfunction, contributing to the characterisation of the molecular landscape in patients with RTT. The comparison with MDS provides knowledge of MeCP2 direct targets, whilst the correlation with RTT-like phenotypes highlights processes potentially contributing to the pathomechanism leading these disorders.
AU  - Pascual-Alonso, A.*
AU  - Xiol, C.*
AU  - Smirnov, D.
AU  - Kopajtich, R.
AU  - Prokisch, H.
AU  - Armstrong, J.*
C1  - 68273
C2  - 54798
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Identification of molecular signatures and pathways involved in Rett syndrome using a multi-omics approach.
JO  - Hum. Genomics
VL  - 17
IS  - 1
PB  - Bmc
PY  - 2023
SN  - 1473-9542
ER  - 

TY  - JOUR
AU  - Silvaieh, S.*
AU  - König, T.*
AU  - Wurm, R.*
AU  - Parvizi, T.*
AU  - Berger-Sieczkowski, E.*
AU  - Goeschl, S.*
AU  - Hotzy, C.*
AU  - Wagner, M.
AU  - Berutti, R.*
AU  - Sammler, E.*
AU  - Stogmann, E.*
AU  - Zimprich, A.*
C1  - 67939
C2  - 54417
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Correction: Comprehensive genetic screening of early-onset dementia patients in an Austrian cohort-suggesting new disease-contributing genes.
JO  - Hum. Genomics
VL  - 17
IS  - 1
PB  - Bmc
PY  - 2023
SN  - 1473-9542
ER  - 

TY  - JOUR
AB  - Early-onset dementia (EOD), with symptom onset before age 65, has a strong genetic burden. Due to genetic and clinical overlaps between different types of dementia, whole-exome sequencing (WES) has emerged as an appropriate screening method for diagnostic testing and novel gene-finding approaches. We performed WES and C9orf72 repeat testing in 60 well-defined Austrian EOD patients. Seven patients (12%) carried likely disease-causing variants in monogenic genes, PSEN1, MAPT, APP, and GRN. Five patients (8%) were APOE4 homozygote carriers. Definite and possible risk variants were detected in the genes TREM2, SORL1, ABCA7 and TBK1. In an explorative approach, we cross-checked rare gene variants in our cohort with a curated neurodegeneration candidate gene list and identified DCTN1, MAPK8IP3, LRRK2, VPS13C and BACE1 as promising candidate genes. Conclusively, 12 cases (20%) carried variants relevant to patient counseling, comparable to previously reported studies, and can thus be considered genetically resolved. Reduced penetrance, oligogenic inheritance and not yet identified high-risk genes might explain the high number of unresolved cases. To address this issue, we provide complete genetic and phenotypic information (uploaded to the European Genome-phenome Archive), enabling other researchers to cross-check variants. Thereby, we hope to increase the chance of independently finding the same gene/variant-hit in other well-defined EOD patient cohorts, thus confirming new genetic risk variants or variant combinations.
AU  - Silvaieh, S.*
AU  - König, T.*
AU  - Wurm, R.*
AU  - Parvizi, T.*
AU  - Berger-Sieczkowski, E.*
AU  - Goeschl, S.*
AU  - Hotzy, C.*
AU  - Wagner, M.
AU  - Berutti, R.*
AU  - Sammler, E.*
AU  - Stogmann, E.*
AU  - Zimprich, A.*
C1  - 68607
C2  - 54678
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Comprehensive genetic screening of early-onset dementia patients in an Austrian cohort-suggesting new disease-contributing genes.
JO  - Hum. Genomics
VL  - 17
IS  - 1
PB  - Bmc
PY  - 2023
SN  - 1473-9542
ER  - 

TY  - JOUR
AB  - In recent years, a growing interest in the characterization of the molecular basis of psoriasis has been observed. However, despite the availability of a large amount of molecular data, many pathogenic mechanisms of psoriasis are still poorly understood. In this study, we performed an integrated analysis of 23 public transcriptomic datasets encompassing both lesional and uninvolved skin samples from psoriasis patients. We defined comprehensive gene co-expression network models of psoriatic lesions and uninvolved skin. Moreover, we curated and exploited a wide range of functional information from multiple public sources in order to systematically annotate the inferred networks. The integrated analysis of transcriptomics data and co-expression networks highlighted genes that are frequently dysregulated and show aberrant patterns of connectivity in the psoriatic lesion compared with the unaffected skin. Our approach allowed us to also identify plausible, previously unknown, actors in the expression of the psoriasis phenotype. Finally, we characterized communities of co-expressed genes associated with relevant molecular functions and expression signatures of specific immune cell types associated with the psoriasis lesion. Overall, integrating experimental driven results with curated functional information from public repositories represents an efficient approach to empower knowledge generation about psoriasis and may be applicable to other complex diseases.
AU  - Federico, A.*
AU  - Pavel, A.*
AU  - Möbus, L.*
AU  - McKean, D.*
AU  - Del Giudice, G.*
AU  - Fortino, V.*
AU  - Niehues, H.*
AU  - Rastrick, J.*
AU  - Eyerich, K.*
AU  - Eyerich, S.
AU  - van den Bogaard, E.H.*
AU  - Smith, C.*
AU  - Weidinger, S.*
AU  - de Rinaldis, E.*
AU  - Greco, D.*
C1  - 66880
C2  - 53343
TI  - The integration of large-scale public data and network analysis uncovers molecular characteristics of psoriasis.
JO  - Hum. Genomics
VL  - 16
IS  - 1
PY  - 2022
SN  - 1473-9542
ER  - 

TY  - JOUR
AB  - BackgroundIncreasing evidence is demonstrating that a patient's unique genetic profile can be used to detect the disease's onset, prevent its progression, and optimize its treatment. This led to the increased global efforts to implement personalized medicine (PM) and pharmacogenomics (PG) in clinical practice. Here we investigated the perceptions of students from different universities in Bosnia and Herzegovina (BH) towards PG/PM as well as related ethical, legal, and social implications (ELSI). This descriptive, cross-sectional study is based on the survey of 559 students from the Faculties of Medicine, Pharmacy, Health Studies, Genetics, and Bioengineering and other study programs.ResultsOur results showed that 50% of students heard about personal genome testing companies and 69% consider having a genetic test done. A majority of students (57%) agreed that PM represents a promising healthcare model, and 40% of students agreed that their study program is well designed for understanding PG/PM. This latter opinion seems to be particularly influenced by the field of study (7.23, CI 1.99-26.2, p=0.003). Students with this opinion are also more willing to continue their postgraduate education in the PM (OR=4.68, CI 2.59-8.47, p<0.001). Furthermore, 45% of students are aware of different ethical aspects of genetic testing, with most of them (46%) being concerned about the patient's privacy.ConclusionsOur results indicate a positive attitude of biomedical students in Bosnia and Herzegovina towards genetic testing and personalized medicine. Importantly, our results emphasize the key importance of pharmacogenomic education for more efficient translation of precision medicine into clinical practice.
AU  - Mahmutovic, L.*
AU  - Akcesme, B.*
AU  - Durakovic, C.*
AU  - Akcesme, F.B.*
AU  - Maric, A.*
AU  - Adilovic, M.*
AU  - Hamad, N.*
AU  - Wjst, M.
AU  - Feeney, O.*
AU  - Semiz, S.*
C1  - 54740
C2  - 45805
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Perceptions of students in health and molecular life sciences regarding pharmacogenomics and personalized medicine.
JO  - Hum. Genomics
VL  - 12
IS  - 1
PB  - Bmc
PY  - 2018
SN  - 1473-9542
ER  -