genomics, WGS, WES, Whole Genome Sequencing, Whole Exome Sequencing, Clinical Utility

PURPOSE: This meta-analysis aims to compare the diagnostic and clinical utility of exome sequencing (ES) vs genome sequencing (GS) in pediatric and adult patients with rare diseases across diverse populations. METHODS: A meta-analysis was conducted to identify studies from 2011 to 2021. RESULTS: One hundred sixty-one studies across 31 countries/regions were eligible, featuring 50,417 probands of diverse populations. Diagnostic rates of ES (0...

Many clinical decisions in oncology practice rely on the presence or absence of an alteration in a single genetic locus, be it a pathogenic variant in a hereditary cancer gene or activating mutation in a drug target. In addition, there are integrative tests that produce continuous variables and evaluate complex characteristics of the entire tumor genome. Microsatellite instability (MSI) analysis identifies tumors with the accumulation of mutations in short repetitive nucleotide sequences. This procedure is utilized in Lynch syndrome diagnostic pipelines and for the selection of patients for immunotherapy...

The diagnosis of inherited neuromuscular disorders is challenging due to their genetic and phenotypic variability. Traditionally, neurophysiology and histopathology were primarily used in the initial diagnostic approach to these conditions. Sanger sequencing for molecular diagnosis was less frequently utilized as its application was a time-consuming and cost-intensive process. The advent and accessibility of next-generation sequencing (NGS) has revolutionized the evaluation process of genetically heterogenous neuromuscular disorders...

Introduction: Comprehensive genetic testing with whole-exome (WES) or whole-genome (WGS) sequencing facilitates diagnosis, can optimize treatment, and may improve outcomes in critically ill neonates, including those requiring extracorporeal membrane oxygenation (ECMO) for respiratory failure. Our objective was to describe practice variation and barriers to the utilization of comprehensive genetic testing for neonates on ECMO. Methods: We performed a cross-sectional survey of Level IV neonatal intensive care units in the United States across the Children's Hospitals Neonatal Consortium (CHNC)...

Children with genetic diseases endure a prolonged and costly "diagnostic odyssey." The use of whole exome sequencing (WES) and whole genome sequencing (WGS) has improved the diagnosis rate, ending the odyssey. However, the additional costs associated WES/WGS has impeded their adoption in Asian settings. We aim to estimate the expected change to the mean number of diagnostic tests used, and the associated costs from a decision to use WES early in the diagnostic pathways of pediatric phenotypes, as compared to Existing Practice...

BACKGROUND: Genetic causes that lead to spermatogenetic failure in patients with nonobstructive azoospermia (NOA) have not been yet completely established. OBJECTIVE: To identify low-frequency NOA-associated single nucleotide variants (SNVs) using whole-genome sequencing (WGS). MATERIALS AND METHODS: Men with various types of NOA (n = 39), including samples that had been previously tested with whole-exome sequencing (WES; n = 6) and did not result in diagnostic conclusions...

Congenital heart disease (CHD) is the most common congenital malformation in fetuses and neonates, which also represents a leading cause of mortality. Although significant progress has been made by emerging advanced technologies in genetic etiology diagnosis, the causative genetic mechanisms behind CHD remain poorly understood and more than half of CHD patients lack a genetic diagnosis. Unlike carefully designed large case-control cohorts by multicenter trials, we designed a reliable strategy to analyze case-only cohorts to utilize clinical samples sufficiently...

Rare diseases impact all socio-economic, geographic, and racial groups indiscriminately. Newborn screening (NBS) is an exemplary international public health initiative that identifies infants with rare conditions early in life to reduce morbidity and mortality. NBS theoretically promotes equity through universal access, regardless of financial ability. There is however heterogeneity in access to newborn screening and conditions that are screened throughout the world. In the United States and some other developed countries, NBS is provided to all babies, subsidized by the local or federal government...

BACKGROUND AND OBJECTIVES: Genetic white matter disorders (GWMD) are of heterogeneous origin, with more than a hundred causal genes identified to date. Classical targeted approaches achieve a molecular diagnosis in only half of all patients. Here we aim to determine the clinical utility of singleton whole-exome sequencing and whole-genome sequencing (sWES-WGS) interpreted with a phenotype- and interactome-driven prioritization algorithm to diagnose GWMD patients, while identifying novel phenotypes and candidate genes...

Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that lead to secondary defects in the synthesis, catabolism, transport, and metabolism of biogenic amines can lead to neurotransmitter abnormalities, which can present with similar features. Eleven patients with secondary neurotransmitter abnormalities were enrolled between 2011 and 2015. All patients underwent research-based whole exome and/or whole genome sequencing (WES/WGS)...

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare, highly heterogeneous genetic disorder involving the impairment of motile cilia. With no single gold standard for PCD diagnosis and complicated multiorgan dysfunction, the diagnosis of PCD can be difficult in clinical settings. Some methods for diagnosis, such as nasal nitric oxide measurement and digital high-speed video microscopy with ciliary beat pattern analysis, can be expensive or unavailable. To confirm PCD diagnosis, we used a strategy combining assessment of typical symptoms with whole-exome sequencing (WES) and/or low-pass whole-genome sequencing (WGS) as an unbiased detection tool to identify known pathogenic mutations, novel variations, and copy number variations...

Whole genome sequencing (WGS) is a powerful tool for postnatal genetic diagnosis, but relevant clinical studies in the field of prenatal diagnosis are limited. The present study aimed to prospectively evaluate the utility of WGS compared with chromosomal microarray (CMA) and whole exome sequencing (WES) in the prenatal diagnosis of fetal structural anomalies. We performed trio WGS (≈40-fold) in parallel with CMA in 111 fetuses with structural or growth anomalies, and sequentially performed WES when CMA was negative (CMA plus WES)...

Genetic variants are major determinants of susceptibility to disease, response to therapy, and clinical outcomes. Advances in the short-read sequencing technologies, despite some shortcomings, have enabled identification of the vast majority of the genetic variants in each genome. The major challenge is in identifying the pathogenic variants in cardiovascular diseases. The yield of the genetic testing has been limited because of technological shortcomings and our incomplete understanding of the genetic basis of cardiovascular disorders...

OBJECTIVE: Use next-generation sequencing (NGS) technology to improve our diagnostic yield in patients with suspected genetic disorders in the Asian setting. DESIGN: A diagnostic study conducted between 2014 and 2019 (and ongoing) under the Singapore Undiagnosed Disease Program. Date of last analysis was 1 July 2019. SETTING: Inpatient and outpatient genetics service at two large academic centres in Singapore. PATIENTS: Inclusion criteria: patients suspected of genetic disorders, based on abnormal antenatal ultrasound, multiple congenital anomalies and developmental delay...

BACKGROUND: Homozygous Familial Hypercholesterolemia (HoFH) is an inherited recessive condition associated with extremely high levels of low-density lipoprotein (LDL) cholesterol in affected individuals. It is usually caused by homozygous or compound heterozygous functional mutations in the LDL receptor (LDLR). A number of mutations causing FH have been reported in literature and such genetic heterogeneity presents great challenges for disease diagnosis. OBJECTIVE: We aim to determine the likely genetic defects responsible for three cases of pediatric HoFH in two kindreds...

Precision medicine (PM) informed by next-generation sequencing (NGS) poses challenges for health technology assessment (HTA). To date, there has been limited reimbursement of genomic testing with NGS in Canada, particularly for whole-genome and whole-exome sequencing (WGS/WES). Through a structured literature review, we examine Canadian economic evidence and evidentiary challenges for the adoption of genomic testing. We searched Medline (PubMed) for published Canadian studies generating economic evidence for PM informed by NGS...

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited monogenic renal disease characterised by the accumulation of clusters of fluid-filled cysts in the kidneys and is caused by mutations in PKD1 or PKD2 genes. ADPKD genetic diagnosis is complicated by PKD1 pseudogenes located proximal to the original gene with a high degree of homology. The next generation sequencing (NGS) technology including whole exome sequencing (WES) and whole genome sequencing (WGS), is becoming more affordable and its use in the detection of ADPKD mutations for diagnostic and research purposes more widespread...

There is a growing attention toward personalized medicine. This is led by a fundamental shift from the 'one size fits all' paradigm for treatment of patients with conditions or predisposition to diseases, to one that embraces novel approaches, such as tailored target therapies, to achieve the best possible outcomes. Driven by these, several national and international genome projects have been initiated to reap the benefits of personalized medicine. Exome and targeted sequencing provide a balance between cost and benefit, in contrast to whole genome sequencing (WGS)...

Whole exome and whole genome sequencing (WES/WGS) is increasingly utilized in inpatient settings such as neonatal and pediatric intensive care units (ICU), but no research has explored the process of informed consent in this setting. My experience as an inpatient genetic counselor has illuminated factors unique to the ICU that may threaten elements of informed consent such as voluntariness, disclosure, understanding, and capacity. I present three cases that exemplify elements complicating consent counseling for WES/WGS in the ICU, including the emotional state of the parents, involvements of other healthcare providers, environmental distractions and competing clinical priorities...

Objective: The clinical diagnosis of genetic disorders is undergoing transformation, driven by whole exome sequencing and whole genome sequencing (WES/WGS). However, such nucleotide-level resolution technologies create an interpretive challenge. Prior literature suggests that clinicians may employ characteristic cognitive processes during WES/WGS investigations to identify disruptions in genes causal for the observed disease. Based on cognitive ergonomics, we designed and evaluated a gene prioritization workflow that supported these cognitive processes...