Clinical interpretation of genome variation
Guest Editors: Heidi Rehm and Douglas Fowler
Genome Medicine is pleased to present a special issue entitled ‘Clinical interpretation of genome variation’, guest edited by Dr Heidi Rehm from the Broad Institute and MGH and Dr Douglas Fowler from the University of Washington. As next-generation sequencing enters the clinic, research and clinical communities still face major challenges in characterizing genome variation including accurate variant classification, interpretation of variants of uncertain significance, understanding non-coding variants, assessing causality for diagnosis as well as addressing incidental findings. This special issue aims to capture the advances made in understanding genome variation in the clinical context covering the breadth of human disease including Mendelian and complex diseases and rare and common diseases, highlighting novel approaches for accurate variant classification, genome-guided diagnostics and prognostics as well as insights into disease mechanisms.This collection of articles has not been sponsored and articles will undergo the journal’s standard peer-review process. The Guest Editors declare that they have no competing interests. Guest Editors serve an advisory role to guide the scope of the special issue and commissioned content; final editorial decisions lie with the Editor.
Polygenic risk scores: from research tools to clinical instruments
Genome-wide association studies have shown unequivocally that common complex disorders have a polygenic genetic architecture and have enabled researchers to identify genetic variants associated with diseases. ...Genome Medicine 2020 12:44Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders
Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous ge...Genome Medicine 2020 12:28The paradox of cancer genes in non-malignant conditions: implications for precision medicine
Next-generation sequencing has enabled patient selection for targeted drugs, some of which have shown remarkable efficacy in cancers that have the cognate molecular signatures. Intriguingly, rapidly emerging d...Genome Medicine 2020 12:16A 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 12:13De 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 12:8- Genome Medicine 2019 12:5
Recommendations 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 12:2Recommendations 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 11:85Re-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 11:83Distinct 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 11:75Is ‘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 11:72Artificial 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 11:70From 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 11:68Long 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 11:60Variant 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 11:53
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