4078 results for "*geneti*"

in 46.53 milliseconds.

• Identification_of_the_underlying_causal_variant_in_a_multi_generational_family_with_autosomal_dominant_common_variable_immunodeficiency

  Common variable immunodeficiency (CVID) is the most common form of primary immunodeficiency with an estimated incidence of 1:10,000. It has been apparent for many years that CVID has a genetic component, occurs frequently in families and can have both a recessive or dominant mode of inheritance. In recent years, 4 genes underlying CVID have been identified; however, mutations within in them are estimated to account for no more than 10% of all cases of CVID.We have identified a multi-generational family with autosomal dominant CVID. Genome-wide linkage analysis has mapped the locus underlying CVID in this family to an approximately 9.2 Mb interval on chromosome 3q27.3-q29, between the markers D3S3570 and D3S1265. This locus is distinct from any of the previously mapped susceptibility loci suggesting a novel genetic variant is responsible for disease in this family. The aim of this study is to use exome sequencing of affected (n = 4) and unaffected (n = 4) individuals, in tandem with the available genetic mapping data, to identify the causal variant underlying CVID in this family.

  Study EGAS00001000269

• AfricanNeo aDNA Study

  With the largest genomic dataset to date of Bantu-speaking populations, including newly generated data of modern-day and ancient DNA from previously unsampled regions in Africa, we shed fresh light on the expansion of peoples speaking Bantu languages that started ~4000 years ago in western Africa. We have generated whole-genome sequences from 12 Late Iron Age individuals. Our comprehensive genetic analysis of the expansion of people speaking Bantu languages reveals a complex history of serial founder events, variable levels of contact with local groups, and spread-over-spread events.

  Study EGAS00001007519

• Whole-genome sequencing analysis of low-grade astrocytomas within the ICGC PedBrain Tumor Project

  In order to investigate the full range of genetic alterations contributing to the tumourigenesis of low-grade astrocytoma, we have conducted a next-generation sequencing-based analysis on a large series of matched tumor-normal pairs. This study, conducted by the International Cancer Genome Consortium PedBrain Tumor Project (ICGC PedBrain, http://www.pedbraintumor.org/), has revealed multiple new insights into the biological basis of this tumor entity.

  Study EGAS00001000381

• Comprehensive Deep Sequencing Atlas in HCC tumors

  Establishment of a comprehensive deep sequencing atlas focused on Hepatocellular Carcinoma (HCC) tumors, employing Whole Genome Sequencing (WGS), RNA Sequencing (RNAseq), and Whole Exome Sequencing (WES). The atlas aims to unravel the intricate genetic landscape of HCC, providing a detailed characterization of genomic alterations, transcriptomic profiles, and key mutations associated with this liver cancer. The integration of WGS, RNAseq, and WES data offers a holistic perspective, facilitating a deeper understanding of the molecular mechanisms driving HCC pathogenesis. The resulting atlas serves as a valuable resource for researchers, clinicians, and the broader scientific community, contributing to advancements in HCC diagnostics, prognostics, and therapeutic interventions.

  Study EGAS00001007694

• RB Loss in Resistant EGFR Mutant Lung Adenocarcinomas that Transform to Small Cell Lung Cancer

  Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs typically occurs afterafter an average of one year of continuous treatment. In a subset of patients, aA fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in resistant EGFR mutant cancers that transformed to SCLC. Consistent Further, with their similarities to classical SCLC at the genetic and gene expression levelincreased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared to resistant NSCLCs. , cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to Bcl-2 family inhibition with ABT-263 compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.

  Study EGAS00001001102

• Breast_Cancer_Matched_Pair_Cell_Line_Whole_Genomes

  We propose to definitively characterise the somatic genetics of matched pair breast cancer cell lines through generation of comprehensive catalogues of somatic mutations by high coverage genome sequencing coupled with integrated transcriptomic and methylation analyses.

  Study EGAS00001000166

• Genetic heterogeneity and dynamics of transcriptional subtypes in matched primary and recurrent head and neck squamous cell carcinomas

  To get a better understanding of different HNSCC subtypes, whole-exome (matched tumor-normal paits) and whole transcriptome sequencing to to elucidate underlying molecular processes. Here, we present the matched whole-exome sequencing data from 28 patients (normal tissue, tumor tissue, relapse).

  Study EGAS00001005005

• Whole-exome and targeted sequencing of pediatric hyperdiploid B-cell precursor acute lymphoblastic leukemia

  High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.

  Study EGAS00001001113

• Exome sequencing reveals pathogenic variants in known and novel candidate genes for severe sperm motility disorders

  STUDY QUESTION: What are the causative genetic variants in patients with male infertility due to severe sperm motility disorders? SUMMARY ANSWER: We identified high confidence disease-causing variants in multiple genes previously associated with severe sperm motility disorders in 9 out of 21 patients (43%). We also identified variants in novel candidate genes in 8 additional patients (38%). WHAT IS KNOWN ALREADY: Severe sperm motility disorders are a form of male infertility characterised by vital, but immotile sperm often in combination with a spectrum of structural abnormalities of the sperm flagellum. Examples of this spectrum of disorders include dysplasia of the fibrous sheath / multiple morphological abnormalities of the sperm flagella (DFS-MMAF) and severe forms of asthenozoospermia associated to non-specific structural defects. These disorders frequently recur in families and may include chronic respiratory disease. As such, genetic causes are suspected and many genes have recently been reported. Currently, depending on the clinical sub-categorisation, up to 50% of causality in patients with severe sperm motility disorders can be explained by pathogenic variants in at least 21 known genes. STUDY DESIGN, SIZE, DURATION: We performed exome sequencing in patients with severe sperm motility disorders from two different clinics, aiming to identify the underlying genetic defects and establishing a diagnostic yield in both. PARTICIPANTS/MATERIALS, SETTING, METHOD: Two groups of infertile men, one from Argentina (n= 9) and one from Australia (n=12), with clinically defined sperm motility disorders were included. All patients in the Argentine cohort were diagnosed with DFS-MMAF, based on transmission electron microscopy. Exome sequencing was performed in all 21 patients and variants with an allele frequency of <1% in the gnomAD population were prioritised and interpreted. MAIN RESULTS AND ROLE OF CHANCE: In 9/21 patients (43%), we identified pathogenic variants in known sperm motility disorder genes: CFAP43 (3 patients); CFAP44 (2 patients), QRICH2 (2 patients), DNAH1 (1 patient) and DNAH6 (1 patient). The diagnostic rate did not differ markedly between the Argentinian and the Australian cohort (44% and 42%, respectively). Furthermore, we identified patients with variants in the novel candidate sperm motility genes CFAP58, DNAH12, DRC1, MDC1, PACRG, SSPL2C and TPTE2. One patient presented with two possibly damaging variants in four candidate genes and it remains unclear which variants were responsible for the severe sperm motility defect in this patient. LIMITATIONS, REASONS FOR CAUTION: In this study, we described patients with potential bi-allelic variants in known and novel candidate genes for severe sperm motility disorders. Due to unavailability of parental DNA, we have not assessed de novo or maternally inherited dominant variants and could not phase the mutations to establish in all cases that the mutations occur on both alleles. WIDER IMPLICATIONS OF THE FINDINGS: Our results confirm an important role for five known genes for sperm motility and we demonstrate that exome sequencing is an effective method to diagnose patients with severe sperm motility defects (9/21 diagnosed; 43%). Furthermore, our analysis revealed seven novel candidate genes for severe sperm motility disorders. Genome-wide sequencing of additional patient cohorts and re-analysis of exome data of currently unsolved cases may reveal additional variants in these novel candidate genes.

  Study EGAS00001005018

• Fixation effects on variant-calling in a clinical resequencing panel

  Formalin fixation is the standard method for preservation of tissue for diagnostic purposes, including pathological review and molecular assays. However, this method is known to cause artifacts that can affect the accuracy of molecular genetic tests. We assessed the applicability of alternative fixatives to determine whether these perform significantly better on next-generation sequencing assays, and whether adequate morphology is retained for primary diagnosis, in a prospective study using a clinical-grade laboratory-developed targeted resequencing assay. We examined and quantified several parameters relating to sequencing quality and variant-calling from tumor and normal colon epithelial tissues. We identify one alterative fixative, Sakura Universal Molecular Fixative that suppresses many formalin-related artifacts while retaining adequate morphology for pathological review.

  Study EGAS00001003507