Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing.

Hereditary adult-onset ataxias are a heterogeneous group of phenotypically overlapping conditions, often caused by pathogenic expansions of short tandem repeats. Currently, 18 repeat disorders with a core phenotype of adult-onset ataxia are known. Diagnosis typically relies on sequential PCR-based methods, which are labour-intensive and lack precision.

Evaluation of Different National Comprehensive Cancer Network Clinical Practice Guidelines in Prostate Cancer for Germline Genetic Testing in Localized and Locally Recurrent Prostate Cancer.

Background And Objective: Germline genetic testing (GGT) is useful for identifying prostate cancer (PCa). This study aims to evaluate the GGT criteria according to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines on oncology (NCCN guidelines) for PCa, version 1.2022, for identifying PCa patients to whom GGT at a nonmetastatic stage should be offered.

Does every body matter? The relationship between engagement with body-positive and appearance-ideal content on instagram and aspects of positive and negative body image.

Body-positive content is prevalent on social networking sites (SNS). Research shows that engagement with body-positive content reduces aspects of negative body image and increases aspects of positive body image. However, the mechanisms accounting for the impact of body-positive content on body image are not well understood.

Dual STAT3/STAT5 inhibition as a novel treatment strategy in T-prolymphocytic leukemia.

T-prolymphocytic leukemia (T-PLL) is a rare, aggressive T-cell malignancy with poor outcomes and an urgent need for new therapeutic approaches. Integrating genomic data and new transcriptomic profiling, we identified recurrent JAK/STAT mutations (predominantly in JAK3 and STAT5B) as hallmarks in a cohort of 335 T-PLL cases. In line, transcriptomic and protein analyses revealed constitutive JAK/STAT activation in virtually all samples.

and Other Predisposition Genes in High-Risk Hormone Receptor+/Human Epidermal Growth Factor Receptor 2- Breast Cancer Treated With Endocrine Therapy With or Without Palbociclib: A Secondary PENELOPE-B Study Analysis.

Purpose: The PENELOPE-B trial (ClinicalTrials.gov identifier: NCT01864746) recruited patients with hormone receptor+/human epidermal growth factor receptor 2- early breast cancer without a pathological complete response after taxane-containing neoadjuvant chemotherapy and at a high risk of relapse. Patients were randomly assigned (1:1) to receive 13 cycles of palbociclib once daily or placebo on days 1-21 in a 28-day cycle in addition to endocrine therapy (ET).

Multidimensional OMICs reveal ARID1A orchestrated control of DNA damage, splicing, and cell cycle in normal-like and malignant urothelial cells.

Epigenetic regulators, such as the SWI/SNF complex, with important roles in tissue development and homeostasis, are frequently mutated in cancer. ARID1A, a subunit of the SWI/SNF complex, is mutated in approximately 20% of all bladder tumors; however, the consequences of this remain poorly understood. Finding truncations to be the most common mutation, we generated loss- and gain-of-function models to conduct RNA-Seq, interactome analyses, Omni-ATAC-Seq, and functional studies to characterize ARID1A-affected pathways potentially suitable for the treatment of ARID1A-deficient bladder cancers.

Joint analysis of germline genetic data from over 29,000 cases with suspected hereditary breast and ovarian cancer (HBOC) as part of the NASGE initiative.

As multigene panel testing is becoming routine in clinical care, there are recommendations at national and international level, as to which genes should be analyzed in the context of a hereditary breast and ovarian cancer (HBOC). However, the individual composition of gene panels offered by testing laboratories vary, resulting in a different variant diagnostic rate. Therefore, we performed a retrospective NGS dataset analysis of suspected HBOC patients who had been tested at different German diagnostic laboratories that are part of the NASGE network.

Chromosome-scale genome dynamics reveal signatures of independent haplotype evolution in the ancient asexual mite .

Some unique asexual species persist over time and contradict the consensus that sex is a prerequisite for long-term evolutionary survival. How they escape the dead-end fate remains enigmatic. Here, we generated a haplotype-resolved genome assembly on the basis of a single individual and collected genomic data from worldwide populations of the parthenogenetic diploid oribatid mite to identify signatures of persistence without sex.

Systematic assessment of COVID-19 host genetics using whole genome sequencing data.

Courses of SARS-CoV-2 infections are highly variable, ranging from asymptomatic to lethal COVID-19. Though research has shown that host genetic factors contribute to this variability, cohort-based joint analyses of variants from the entire allelic spectrum in individuals with confirmed SARS-CoV-2 infections are still lacking. Here, we present the results of whole genome sequencing in 1,220 mainly vaccine-naïve individuals with confirmed SARS-CoV-2 infection, including 827 hospitalized COVID-19 cases.

Updated Structure of Repeat Expansions in Patients With Myotonic Dystrophy Type 2 and Its Implication for Standard Diagnostics.

Background And Objectives: Myotonic dystrophy type 2 (DM2) is a multisystemic repeat disorder caused by the expansion of an unstable CCTG tetranucleotide repeat in the noncoding region of the gene. Standard diagnostic is based on Southern blot analysis or a unidirectional RP-PCR that amplifies the repeat from the downstream end.

Methods: Our study reevaluated 80 patients (cohort 1) with clinical suspicion of DM2 but homozygous negative results using the standard diagnostic repeat-primed PCR (RP-PCR).

High quality genome assembly and annotation (v1) of the eukaryotic freshwater microalga Coccomyxa elongata SAG 216-3b.

Unicellular green algae of the genus Coccomyxa are recognized for their worldwide distribution and ecological versatility. Coccomyxa elongata is a freshwater species of the Coccomyxa simplex clade, which also includes lichen symbionts. To facilitate future molecular and phylogenomic studies of this versatile clade of algae, we generated a high-quality genome assembly for C.

Analysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR.

Lesional focal epilepsy (LFE) is a common and severe seizure disorder caused by epileptogenic lesions, including malformations of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT). Understanding the genetic etiology of these lesions can inform medical and surgical treatment. We conducted a somatic variant enrichment mega-analysis in brain tissue from 1386 individuals who underwent epilepsy surgery, including 599 previously unpublished individuals with ultra-deep ( > 1600x) targeted panel sequencing.

NCBench: providing an open, reproducible, transparent, adaptable, and continuous benchmark approach for DNA-sequencing-based variant calling.

We present the results of the human genomic small variant calling benchmarking initiative of the German Research Foundation (DFG) funded Next Generation Sequencing Competence Network (NGS-CN) and the German Human Genome-Phenome Archive (GHGA). In this effort, we developed NCBench, a continuous benchmarking platform for the evaluation of small genomic variant callsets in terms of recall, precision, and false positive/negative error patterns. NCBench is implemented as a continuously re-evaluated open-source repository.

Long-read transcriptome sequencing of CLL and MDS patients uncovers molecular effects of mutations.

Mutations in splicing factor 3B subunit 1 () frequently occur in patients with chronic lymphocytic leukemia (CLL) and myelodysplastic syndromes (MDSs). These mutations have different effects on the disease prognosis with beneficial effect in MDS and worse prognosis in CLL patients. A full-length transcriptome approach can expand our knowledge on mutation effects on RNA splicing and its contribution to patient survival and treatment options.

Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.

Repeat expansions in FGF14 cause autosomal dominant late-onset cerebellar ataxia (SCA27B) with estimated pathogenic thresholds of 250 (incomplete penetrance) and 300 AAG repeats (full penetrance), but the sequence of pathogenic and non-pathogenic expansions remains unexplored. Here, we demonstrate that STRling and ExpansionHunter accurately detect FGF14 expansions from short-read genome data using outlier approaches. By combining long-range PCR and nanopore sequencing in 169 patients with cerebellar ataxia and 802 controls, we compare FGF14 expansion alleles, including interruptions and flanking regions.

Causes and consequences of a complex recombinational landscape in the ant .

Eusocial Hymenoptera have the highest recombination rates among all multicellular animals studied so far, but it is unclear why this is and how this affects the biology of individual species. A high-resolution linkage map for the ant corroborates genome-wide high recombination rates reported for ants (8.1 cM/Mb).

Olaparib Addition to Maintenance Bevacizumab Therapy in Ovarian Carcinoma With BRCA-Like Genomic Aberrations.

Importance: Testing for homologous recombination deficiency is required for the optimal treatment of high-grade epithelial ovarian cancer. The search for accurate biomarkers is ongoing.

Objective: To investigate whether progression-free survival (PFS) and overall survival (OS) of patients with high-grade epithelial ovarian cancer treated with maintenance olaparib or placebo differed between patients with a tumor BRCA-like genomic profile and patients without a tumor BRCA-like profile.

Evolutionary trajectories of small cell lung cancer under therapy.

The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity.

Noninvasive minimal residual disease assessment in relapsed/refractory large B-cell lymphoma using digital droplet PCR.

Although several promising approaches for the treatment of relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) have been approved recently, it remains unclear which patients will ultimately achieve long-term responses. Circulating tumor (ct)DNA sequencing has emerged as a valuable tool to assess minimal residual disease (MRD). Correlations between MRD and outcomes have been shown in previously untreated DLBCL, but data on the repeated assessment of MRD in the dynamic course of rrDLBCL is limited.

A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren's disease.

Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders.

Entirely noninvasive outcome prediction in central nervous system lymphomas using circulating tumor DNA.

State-of-the-art response assessment of central nervous system lymphoma (CNSL) by magnetic resonance imaging is challenging and an insufficient predictor of treatment outcomes. Accordingly, the development of novel risk stratification strategies in CNSL is a high unmet medical need. We applied ultrasensitive circulating tumor DNA (ctDNA) sequencing to 146 plasma and cerebrospinal fluid (CSF) samples from 67 patients, aiming to develop an entirely noninvasive dynamic risk model considering clinical and molecular features of CNSL.