A highly sensitive and specific workflow for detecting rare copy-number variants from exome sequencing data
Exome sequencing (ES) is a first-tier diagnostic test for many suspected Mendelian disorders. While it is routine to detect small sequence variants, it is not a standard practice in clinical settings to detect...Genome Medicine 2020 12:14A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused by vari...Genome Medicine 2020 12:13Interactions between the gut microbiome and host gene regulation in cystic fibrosis
Cystic fibrosis is the most common autosomal recessive genetic disease in Caucasians. It is caused by mutations in the CFTR gene, leading to poor hydration of mucus and impairment of the respiratory, digestive, a...Genome Medicine 2020 12:12Stepwise evolution and convergent recombination underlie the global dissemination of carbapenemase-producing Escherichia coli
Carbapenem-resistant Enterobacteriaceae are considered by WHO as “critical” priority pathogens for which novel antibiotics are urgently needed. The dissemination of carbapenemase-producing Escherichia coli (CP-EcGenome Medicine 2020 12:10Genomic surveillance for hypervirulence and multi-drug resistance in invasive Klebsiella pneumoniae from South and Southeast Asia
Klebsiella pneumoniae is a leading cause of bloodstream infection (BSI). Strains producing extended-spectrum beta-lactamases (ESBLs) or carbapenemases are considered global priority pathogens for which new treatm...Genome Medicine 2020 12:11De novo variants in exomes of congenital heart disease patients identify risk genes and pathways
Congenital heart disease (CHD) affects ~ 1% of live births and is the most common birth defect. Although the genetic contribution to the CHD has been long suspected, it has only been well established recently....Genome Medicine 2020 12:9Molecular profiling for precision cancer therapies
The number of druggable tumor-specific molecular aberrations has grown substantially in the past decade, with a significant survival benefit obtained from biomarker matching therapies in several cancer types. ...Genome Medicine 2020 12:8An unsupervised learning approach to identify novel signatures of health and disease from multimodal data
Modern medicine is rapidly moving towards a data-driven paradigm based on comprehensive multimodal health assessments. Integrated analysis of data from different modalities has the potential of uncovering nove...Genome Medicine 2020 12:7Strains used in whole organism Plasmodium falciparum vaccine trials differ in genome structure, sequence, and immunogenic potential
Plasmodium falciparum (Pf) whole-organism sporozoite vaccines have been shown to provide significant protection against controlled human malaria infection (CHMI) in clinical trials. Initial CHMI studies showed si...Genome Medicine 2020 12:6- Genome Medicine 2019 12:5
Digital twins to personalize medicine
Personalized medicine requires the integration and processing of vast amounts of data. Here, we propose a solution to this challenge that is based on constructing Digital Twins. These are high-resolution model...Genome Medicine 2019 12:4Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework
The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria for different types of evidence. This incl...Genome Medicine 2019 12:3Exome sequencing reveals a high prevalence of BRCA1 and BRCA2 founder variants in a diverse population-based biobank
Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little...Genome Medicine 2019 12:2An epigenome-wide association study of sex-specific chronological ageing
Advanced age is associated with cognitive and physical decline and is a major risk factor for a multitude of disorders. There is also a gap in life expectancy between males and females. DNA methylation differe...Genome Medicine 2019 12:1Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4
The efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden. However, ...Genome Medicine 2019 11:87Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression
Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) are characterised by abnormal epigenetic repression and differentiation of bone marrow haematopoietic stem cells (HSCs). Drugs that reverse epi...Genome Medicine 2019 11:86Recommendations for the collection and use of multiplexed functional data for clinical variant interpretation
Variants of uncertain significance represent a massive challenge to medical genetics. Multiplexed functional assays, in which the functional effects of thousands of genomic variants are assessed simultaneously...Genome Medicine 2019 11:85A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation
Maternal effect mutations in the components of the subcortical maternal complex (SCMC) of the human oocyte can cause early embryonic failure, gestational abnormalities and recurrent pregnancy loss. Enigmatical...Genome Medicine 2019 11:84Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases
Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnos...Genome Medicine 2019 11:83Genomics of circadian rhythms in health and disease
Circadian clocks are endogenous oscillators that control 24-h physiological and behavioral processes. The central circadian clock exerts control over myriad aspects of mammalian physiology, including the regul...Genome Medicine 2019 11:82FIREVAT: finding reliable variants without artifacts in human cancer samples using etiologically relevant mutational signatures
Accurate identification of real somatic variants is a primary part of cancer genome studies and precision oncology. However, artifacts introduced in various steps of sequencing obfuscate confidence in variant ...Genome Medicine 2019 11:81Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants
We investigated the features of the genomic rearrangements in a cohort of 50 male individuals with proteolipid protein 1 (PLP1) copy number gain events who were ascertained with Pelizaeus-Merzbacher disease (PMD;...Genome Medicine 2019 11:80Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants
Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients carrying de novo SVs are frequently unknown.Genome Medicine 2019 11:79Text-mining clinically relevant cancer biomarkers for curation into the CIViC database
Precision oncology involves analysis of individual cancer samples to understand the genes and pathways involved in the development and progression of a cancer. To improve patient care, knowledge of diagnostic,...Genome Medicine 2019 11:78Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels
The 2015 American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines for clinical sequence variant interpretation state that “well-established” functio...Genome Medicine 2019 11:77Standard operating procedure for curation and clinical interpretation of variants in cancer
Manually curated variant knowledgebases and their associated knowledge models are serving an increasingly important role in distributing and interpreting variants in cancer. These knowledgebases vary in their ...Genome Medicine 2019 11:76Genomic screening and genomic diagnostic testing—two very different kettles of fish
Genomic testing can be misunderstood as being determinative, when in reality it is the same as all other tests and context is essential for its correct interpretation. Two hypothetical cases of testing for Mar...Genome Medicine 2019 11:75Low coverage whole genome sequencing enables accurate assessment of common variants and calculation of genome-wide polygenic scores
Inherited susceptibility to common, complex diseases may be caused by rare, pathogenic variants (“monogenic”) or by the cumulative effect of numerous common variants (“polygenic”). Comprehensive genome interpr...Genome Medicine 2019 11:74Immune receptor repertoires in pediatric and adult acute myeloid leukemia
Acute myeloid leukemia (AML), caused by the abnormal proliferation of immature myeloid cells in the blood or bone marrow, is one of the most common hematologic malignancies. Currently, the interactions between...Genome Medicine 2019 11:73Is ‘likely pathogenic’ really 90% likely? Reclassification data in ClinVar
In 2015, professional guidelines defined the term ‘likely pathogenic’ to mean with a 90% chance of pathogenicity. To determine whether current practice reflects this definition, ClinVar classifications were tr...Genome Medicine 2019 11:72Neoantigens and genome instability: impact on immunogenomic phenotypes and immunotherapy response
The resurgence of immune therapies in cancer medicine has elicited a corresponding interest in understanding the basis of patient response or resistance to these treatments. One aspect of patient response clea...Genome Medicine 2019 11:71Artificial intelligence in clinical and genomic diagnostics
Artificial intelligence (AI) is the development of computer systems that are able to perform tasks that normally require human intelligence. Advances in AI software and hardware, especially deep learning algor...Genome Medicine 2019 11:70Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension
Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, ri...Genome Medicine 2019 11:69From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability
Since different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) ra...Genome Medicine 2019 11:68pTuneos: prioritizing tumor neoantigens from next-generation sequencing data
Cancer neoantigens are expressed only in cancer cells and presented on the tumor cell surface in complex with major histocompatibility complex (MHC) class I proteins for recognition by cytotoxic T cells. Accur...Genome Medicine 2019 11:67Inflammatory cytokines and organ dysfunction associate with the aberrant DNA methylome of monocytes in sepsis
Sepsis, a life-threatening organ dysfunction caused by a dysregulated systemic immune response to infection, associates with reduced responsiveness to subsequent infections. How such tolerance is acquired is n...Genome Medicine 2019 11:66Dissecting the genetic basis of comorbid epilepsy phenotypes in neurodevelopmental disorders
Neurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability, developmental disability, and epilepsy are characterized by abnormal brain development that may affect cognition, ...Genome Medicine 2019 11:65NARD: whole-genome reference panel of 1779 Northeast Asians improves imputation accuracy of rare and low-frequency variants
Here, we present the Northeast Asian Reference Database (NARD), including whole-genome sequencing data of 1779 individuals from Korea, Mongolia, Japan, China, and Hong Kong. NARD provides the genetic diversity...Genome Medicine 2019 11:64Advances in omics-based methods to identify novel targets for malaria and other parasitic protozoan infections
A major advance in antimalarial drug discovery has been the shift towards cell-based phenotypic screening, with notable progress in the screening of compounds against the asexual blood stage, liver stage, and ...Genome Medicine 2019 11:63Mapping genetic interactions in cancer: a road to rational combination therapies
The discovery of synthetic lethal interactions between poly (ADP-ribose) polymerase (PARP) inhibitors and BRCA genes, which are involved in homologous recombination, led to the approval of PARP inhibition as a...Genome Medicine 2019 11:62Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis
Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease, and gene expression profiling has identified several molecular subtypes with distinct biological and clinicopathological characteristics. While...Genome Medicine 2019 11:60Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients
Recent evidence suggests that immunotherapy efficacy in melanoma is modulated by gut microbiota. Few studies have examined this phenomenon in humans, and none have incorporated metatranscriptomics, important f...Genome Medicine 2019 11:61Identifying Crohn’s disease signal from variome analysis
After years of concentrated research efforts, the exact cause of Crohn’s disease (CD) remains unknown. Its accurate diagnosis, however, helps in management and preventing the onset of disease. Genome-wide asso...Genome Medicine 2019 11:59Genetic underpinnings of recovery after stroke: an opportunity for gene discovery, risk stratification, and precision medicine
As the number of stroke survivors continues to increase, identification of therapeutic targets for stroke recovery has become a priority in stroke genomics research. The introduction of high-throughput genotyp...Genome Medicine 2019 11:58The relationship between insomnia and complex diseases—insights from genetic data
Insomnia is a common condition whose pathophysiology is poorly understood. Large genetic studies have provided insights into the etiology of insomnia, highlighting biological pathways that are shared with othe...Genome Medicine 2019 11:57Best practices for bioinformatic characterization of neoantigens for clinical utility
Neoantigens are newly formed peptides created from somatic mutations that are capable of inducing tumor-specific T cell recognition. Recently, researchers and clinicians have leveraged next generation sequenci...Genome Medicine 2019 11:56Comprehensive characterization of circular RNAs in ~ 1000 human cancer cell lines
Human cancer cell lines are fundamental models for cancer research and therapeutic strategy development. However, there is no characterization of circular RNAs (circRNAs) in a large number of cancer cell lines.Genome Medicine 2019 11:55Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing
DNA methylation changes with age. Chronological age predictors built from DNA methylation are termed ‘epigenetic clocks’. The deviation of predicted age from the actual age (‘age acceleration residual’, AAR) h...Genome Medicine 2019 11:54Variant Interpretation for Cancer (VIC): a computational tool for assessing clinical impacts of somatic variants
Clinical laboratories implement a variety of measures to classify somatic sequence variants and identify clinically significant variants to facilitate the implementation of precision medicine. To standardize t...Genome Medicine 2019 11:53Identifying chemogenetic interactions from CRISPR screens with drugZ
Chemogenetic profiling enables the identification of gene mutations that enhance or suppress the activity of chemical compounds. This knowledge provides insights into drug mechanism of action, genetic vulnerab...Genome Medicine 2019 11:52
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