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Pediatric Research Jan 2024The aim of the study was to characterize molecular diagnoses in patients with childhood-onset progressive neurological disorders of suspected genetic etiology.
BACKGROUND
The aim of the study was to characterize molecular diagnoses in patients with childhood-onset progressive neurological disorders of suspected genetic etiology.
METHODS
We studied 48 probands (age range from newborn to 17 years old) with progressive neurological disorders of unknown etiology from the largest pediatric neurology clinic in Finland. Phenotypes included encephalopathy (54%), neuromuscular disorders (33%), movement disorders (11%), and one patient (2%) with hemiplegic migraine. All patients underwent whole-exome sequencing and disease-causing genes were analyzed.
RESULTS
We found 20 (42%) of the patients to have variants in genes previously associated with disease. Of these, 12 were previously reported disease-causing variants, whereas eight patients had a novel variant on a disease-causing gene: ATP7A, CHD2, PURA, PYCR2, SLC1A4, SPAST, TRIT1, and UPF3B. Genetics also enabled us to define atypical clinical presentations of Rett syndrome (MECP2) and Menkes disease (ATP7A). Except for one deletion, all findings were single-nucleotide variants (missense 72%, truncating 22%, splice-site 6%). Nearly half of the variants were de novo.
CONCLUSIONS
The most common cause of childhood encephalopathies are de novo variants. Whole-exome sequencing, even singleton, proved to be an efficient tool to gain specific diagnoses and in finding de novo variants in a clinically heterogeneous group of childhood encephalopathies.
IMPACT
Whole-exome sequencing is useful in heterogeneous pediatric neurology cohorts. Our article provides further evidence for and novel variants in several genes. De novo variants are an important cause of childhood encephalopathies.
Topics: Infant, Newborn; Humans; Child; Adolescent; Nervous System Diseases; Rett Syndrome; Phenotype; Neurology; Brain Diseases; Spastin; RNA-Binding Proteins
PubMed: 37563452
DOI: 10.1038/s41390-023-02767-z -
Cureus Nov 2023Durvalumab is an immune checkpoint inhibitor (ICI) belonging to the anti-programmed death-ligand 1 (PD-L1) class, and it is used in the treatment of various end-stage...
Durvalumab is an immune checkpoint inhibitor (ICI) belonging to the anti-programmed death-ligand 1 (PD-L1) class, and it is used in the treatment of various end-stage malignancies. Immune checkpoint inhibitors are associated with various systemic and cutaneous adverse events. Psoriasiform drug eruptions have been clinically observed in patients who have a personal history of psoriasis being treated with ICIs. We present a unique case of de novo psoriasis in a patient being treated for poorly differentiated adenocarcinoma of the lung. The patient responded well to topical treatment and did not require discontinuation of durvalumab. Our case highlights the importance of clinician familiarity with psoriasis presentation, its association with durvalumab therapy, and treatment options for durvalumab-induced psoriasis.
PubMed: 38074037
DOI: 10.7759/cureus.48453 -
Clinical Genetics Mar 2024Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease, although 10%-30% of cases are sporadic. However, this percentage may include truly de novo...
Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease, although 10%-30% of cases are sporadic. However, this percentage may include truly de novo patients (carrying a reduced D4Z4 allele that is not present in either of the parents) and patients with apparently sporadic disease resulting from mosaicism, non-penetrance, or complex genetic situations in either patients or parents. In this study, we characterized the D4Z4 Reduced Alleles (DRA) and evaluated the frequency of truly de novo cases in FSHD1 in a cohort of DNA samples received consecutively for FSHD-diagnostic from 100 Italian families. The D4Z4 testing revealed that 60 families reported a DRA compatible with FSHD1 (1-10 RU). The DRA co-segregated with the disease in most cases. Five families with truly de novo cases were identified, suggesting that this condition may be slightly lower (8%) than previously reported. In addition, D4Z4 characterization in the investigated families showed 4% of mosaic cases and 2% with translocations. This study further highlighted the importance of performing family studies for clarifying apparently sporadic FSHD cases, with significant implications for genetic counseling, diagnosis, clinical management, and procreative choices for patients and families.
Topics: Humans; Muscular Dystrophy, Facioscapulohumeral; Alleles; Mosaicism; Italy; Chromosomes, Human, Pair 4
PubMed: 38041579
DOI: 10.1111/cge.14466 -
JACC. Cardiovascular Interventions Jul 2023
Topics: Humans; Treatment Outcome; Coronary Artery Disease; Angioplasty, Balloon, Coronary; Paclitaxel; Coronary Angiography; Coronary Restenosis; Cardiovascular Agents
PubMed: 37495353
DOI: 10.1016/j.jcin.2023.05.046 -
Frontiers in Zoology Jun 2024Many questions in biology benefit greatly from the use of a variety of model systems. High-throughput sequencing methods have been a triumph in the democratization of... (Review)
Review
Many questions in biology benefit greatly from the use of a variety of model systems. High-throughput sequencing methods have been a triumph in the democratization of diverse model systems. They allow for the economical sequencing of an entire genome or transcriptome of interest, and with technical variations can even provide insight into genome organization and the expression and regulation of genes. The analysis and biological interpretation of such large datasets can present significant challenges that depend on the 'scientific status' of the model system. While high-quality genome and transcriptome references are readily available for well-established model systems, the establishment of such references for an emerging model system often requires extensive resources such as finances, expertise and computation capabilities. The de novo assembly of a transcriptome represents an excellent entry point for genetic and molecular studies in emerging model systems as it can efficiently assess gene content while also serving as a reference for differential gene expression studies. However, the process of de novo transcriptome assembly is non-trivial, and as a rule must be empirically optimized for every dataset. For the researcher working with an emerging model system, and with little to no experience with assembling and quantifying short-read data from the Illumina platform, these processes can be daunting. In this guide we outline the major challenges faced when establishing a reference transcriptome de novo and we provide advice on how to approach such an endeavor. We describe the major experimental and bioinformatic steps, provide some broad recommendations and cautions for the newcomer to de novo transcriptome assembly and differential gene expression analyses. Moreover, we provide an initial selection of tools that can assist in the journey from raw short-read data to assembled transcriptome and lists of differentially expressed genes.
PubMed: 38902827
DOI: 10.1186/s12983-024-00538-y -
BMC Bioinformatics Sep 2023The study of de novo variation is important for assessing biological characteristics of new variation and for studies related to human phenotypes. Software programs...
BACKGROUND
The study of de novo variation is important for assessing biological characteristics of new variation and for studies related to human phenotypes. Software programs exist to call de novo variants and programs also exist to test the burden of these variants in genomic regions; however, I am unaware of a program that fits in between these two aspects of de novo variant assessment. This intermediate space is important for assessing the quality of de novo variants and to understand the characteristics of the callsets. For this reason, I developed an R package called acorn.
RESULTS
Acorn is an R package that examines various features of de novo variants including subsetting the data by individual(s), variant type, or genomic region; calculating features including variant change counts, variant lengths, and presence/absence at CpG sites; and characteristics of parental age in relation to de novo variant counts.
CONCLUSIONS
Acorn is an R package that fills a critical gap in assessing de novo variants and will be of benefit to many investigators studying de novo variation.
Topics: Humans; Genomics; Phenotype; Software
PubMed: 37660114
DOI: 10.1186/s12859-023-05457-z -
BioRxiv : the Preprint Server For... Oct 2023Lipogenesis is a vital but often dysregulated metabolic pathway. We report super-resolution multiplexed vibrational imaging of lipogenesis rates and pathways using...
Lipogenesis is a vital but often dysregulated metabolic pathway. We report super-resolution multiplexed vibrational imaging of lipogenesis rates and pathways using isotopically labelled oleic acid and glucose as probes in live adipocytes and hepatocytes. These findings suggest oleic acid inhibits lipogenesis (DNL), but not total lipogenesis, in hepatocytes. No significant effect is seen in adipocytes. These differential effects may be due to alternate regulation of DNL between cell types and could help explain the complicated role oleic acid plays in metabolism.
PubMed: 37873279
DOI: 10.1101/2023.10.04.560581 -
Nucleic Acids Research Jan 2024Most of the transcribed eukaryotic genomes are composed of non-coding transcripts. Among these transcripts, some are newly transcribed when compared to outgroups and are...
Most of the transcribed eukaryotic genomes are composed of non-coding transcripts. Among these transcripts, some are newly transcribed when compared to outgroups and are referred to as de novo transcripts. De novo transcripts have been shown to play a major role in genomic innovations. However, little is known about the rates at which de novo transcripts are gained and lost in individuals of the same species. Here, we address this gap and estimate the de novo transcript turnover rate with an evolutionary model. We use DNA long reads and RNA short reads from seven geographically remote samples of inbred individuals of Drosophila melanogaster to detect de novo transcripts that are gained on a short evolutionary time scale. Overall, each sampled individual contains around 2500 unspliced de novo transcripts, with most of them being sample specific. We estimate that around 0.15 transcripts are gained per year, and that each gained transcript is lost at a rate around 5× 10-5 per year. This high turnover of transcripts suggests frequent exploration of new genomic sequences within species. These rate estimates are essential to comprehend the process and timescale of de novo gene birth.
Topics: Animals; Humans; Biological Evolution; Drosophila melanogaster; Genome; Genomics; RNA; Transcription, Genetic; RNA, Untranslated; Geography; Evolution, Molecular
PubMed: 38000384
DOI: 10.1093/nar/gkad1079 -
Heliyon Feb 2024Drug-coated balloon (DCB) is a novel approach to avoiding stent-related complications and has proven effective for the treatment of in-stent restenosis (ISR) and small...
BACKGROUND
Drug-coated balloon (DCB) is a novel approach to avoiding stent-related complications and has proven effective for the treatment of in-stent restenosis (ISR) and small vessels. However, its role in the treatment of de novo lesions in large vessels is less settled.
AIMS
To estimate the efficacy and safety of drug-coated balloon versus stent in the treatment of de novo lesions in large coronary arteries.
METHODS
We searched the literature until April 2023. We judged the safety of DCB based on major adverse cardiovascular events (MACEs), cardiac death, all-cause mortality, non-fatal myocardial infarction, target lesion revascularization (TLR), and bleeding event; and efficacy according to late lumen loss (LLL), minimum lumen diameter (MLD). We conducted subgroup analyses according to stent type and whether urgent PCI was required.
RESULTS
A total of 10 RCTs were included. Overall, LLL (mean difference (MD) = -0.19, 95 % confidence interval (CI): -0.32 to -0.06, P = 0.003) was lower in the DCB group than in the Stent arm. This effect was consistent in subgroup analysis regardless of stent type and disease type. In terms of safety indicators, there were no significant differences between DCB and stent. The subgroup analyses found that safety indicators showed no significant differences between DCB and drug-eluting stent (DES), but TLR was lower in the DCB than in the bare metal stent (BMS). Moreover, in ST-elevation myocardial infarction (STEMI), safety indicators and LLL showed no significant differences between DCB and DES, but MLD in the DCB was smaller. While in patients with excluded STEMI, MACE and TLR was lower in the DCB compared with the overall stent.
CONCLUSIONS
DCB could be a promising alternative for treating de novo lesions in large coronary arteries with satisfactory efficacy and low risk, superior to BMS and not inferior to DES, with a trend toward lower late lumen loss.
PubMed: 38333846
DOI: 10.1016/j.heliyon.2024.e25264 -
Frontiers in Cell and Developmental... 2023
PubMed: 37645249
DOI: 10.3389/fcell.2023.1241606