-
European Journal of Human Genetics :... Jul 2023The UK National Diagnostic Service for Ehlers-Danlos Syndromes (EDS) was established in 2009 for the rare types of EDS. Vascular EDS (vEDS) is an inherited connective... (Review)
Review
The UK National Diagnostic Service for Ehlers-Danlos Syndromes (EDS) was established in 2009 for the rare types of EDS. Vascular EDS (vEDS) is an inherited connective tissue disorder caused by pathogenic variants in the COL3A1 gene. Associated tissue fragility affects multiple organ systems, increasing the risk of blood vessel dissection and rupture, with potentially fatal consequences. The diagnosis of vEDS has improved with advances in genetic testing, however this is most often suspected following an acute event. We provide data on the clinical features of vEDS for 180 patients (full cohort) seen in our service with confirmed molecular diagnoses. Increased awareness of this rare condition will prompt genetic testing essential to confirm the diagnosis. Outcomes are improved by early diagnosis followed by appropriate management. Fragile connective tissues make invasive procedures potentially dangerous, particularly in an emergency setting. Lifestyle advice from a young age can help acceptance and understanding of the diagnosis and inform choices. There is currently limited evidence for the use of drug therapy to reduce vascular events. We report on the incidence of vascular events in 126 patients (statistical analysis cohort) in our care and the use of medication. Our retrospective data showed that those patients on a long-term angiotensin II receptor blocker and/or beta-blocker had fewer vascular events than those not on cardiac medication who received the same lifestyle and emergency care advice.
Topics: Humans; Ehlers-Danlos Syndrome, Type IV; Retrospective Studies; Ehlers-Danlos Syndrome; Genetic Testing; United Kingdom; Collagen Type III
PubMed: 36977837
DOI: 10.1038/s41431-023-01343-7 -
Current Opinion in Infectious Diseases Aug 2023Nucleic acid sequence-based organism identification plays an important role in the diagnosis and management of transplant and cancer-associated infectious diseases.... (Review)
Review
PURPOSE OF REVIEW
Nucleic acid sequence-based organism identification plays an important role in the diagnosis and management of transplant and cancer-associated infectious diseases. Here, we provide a high-level overview of advanced sequencing technologies, discuss test performance, and highlight unmet research needs with a focus on immunocompromised hosts.
RECENT FINDINGS
Next-generation sequencing (NGS) technologies are powerful tools with a growing role in managing immunocompromised patients with suspected infection. Targeted NGS (tNGS) can identify pathogens directly from patient specimens, especially for mixed samples, and has been used to detect resistance mutations in transplant-related viruses (e.g. CMV). Whole-genome sequencing (WGS) is increasingly used for outbreak investigations and infection control. Metagenomic NGS (mNGS) is useful for hypothesis-free testing and can simultaneously assess pathogens and host response to infection.
SUMMARY
NGS testing increases diagnostic yield relative to standard culture and Sanger sequencing but may be limited by high cost, turnaround times, and detection of unexpected organisms or commensals of uncertain significance. Close collaboration with the clinical microbiology laboratory and infectious diseases is recommended when NGS testing is considered. Additional research is required to understand which immunocompromised patients are most likely to benefit from NGS testing, and when testing should ideally be performed.
Topics: Humans; Precision Medicine; Virus Diseases; High-Throughput Nucleotide Sequencing; Clinical Laboratory Services; Communicable Diseases
PubMed: 37431553
DOI: 10.1097/QCO.0000000000000936 -
Pediatric Clinics of North America Oct 2023Although genetics has traditionally been associated with pregnancy, birth defects, and newborn screening, almost every disease is influenced in part by an individual's... (Review)
Review
Although genetics has traditionally been associated with pregnancy, birth defects, and newborn screening, almost every disease is influenced in part by an individual's genetic makeup. Therefore, it is important to consider the impact of genetics in health and disease throughout an individual's lifetime.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Neonatal Screening; Referral and Consultation
PubMed: 37704348
DOI: 10.1016/j.pcl.2023.05.004 -
Journal of the National Cancer Institute May 2024
Topics: Humans; Genetic Testing; Patient Rights; Genomics
PubMed: 38412308
DOI: 10.1093/jnci/djae043 -
Genome Medicine Nov 2023Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those...
BACKGROUND
Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome.
METHODS
We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants.
RESULTS
Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving.
CONCLUSIONS
Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.
Topics: Humans; Genetic Variation; Rare Diseases; Whole Genome Sequencing; Genetic Testing; Mutation; Cell Cycle Proteins
PubMed: 37946251
DOI: 10.1186/s13073-023-01240-0 -
American Journal of Medical Genetics.... Sep 2023The transition from analog to digital technologies in clinical laboratory genomics is ushering in an era of "big data" in ways that will exceed human capacity to rapidly... (Review)
Review
The transition from analog to digital technologies in clinical laboratory genomics is ushering in an era of "big data" in ways that will exceed human capacity to rapidly and reproducibly analyze those data using conventional approaches. Accurately evaluating complex molecular data to facilitate timely diagnosis and management of genomic disorders will require supportive artificial intelligence methods. These are already being introduced into clinical laboratory genomics to identify variants in DNA sequencing data, predict the effects of DNA variants on protein structure and function to inform clinical interpretation of pathogenicity, link phenotype ontologies to genetic variants identified through exome or genome sequencing to help clinicians reach diagnostic answers faster, correlate genomic data with tumor staging and treatment approaches, utilize natural language processing to identify critical published medical literature during analysis of genomic data, and use interactive chatbots to identify individuals who qualify for genetic testing or to provide pre-test and post-test education. With careful and ethical development and validation of artificial intelligence for clinical laboratory genomics, these advances are expected to significantly enhance the abilities of geneticists to translate complex data into clearly synthesized information for clinicians to use in managing the care of their patients at scale.
Topics: Humans; Artificial Intelligence; Laboratories, Clinical; Genomics; Genetic Testing; Phenotype
PubMed: 37507620
DOI: 10.1002/ajmg.c.32057 -
Lancet (London, England) Aug 2023
Topics: Humans; Artificial Intelligence; Early Detection of Cancer; Mass Screening; Neoplasms
PubMed: 37544321
DOI: 10.1016/S0140-6736(23)01576-3 -
The Urologic Clinics of North America Aug 2023Differences of sex development (DSD) encompass a broad range of conditions in which the development of chromosomal, gonadal, or anatomic sex is not typically male or... (Review)
Review
Differences of sex development (DSD) encompass a broad range of conditions in which the development of chromosomal, gonadal, or anatomic sex is not typically male or female. Terms used to describe DSD are controversial, and continuously evolving. An individualized, multidisciplinary approach is key to both the diagnosis and management of DSD. Recent advances in DSD care include expanded genetic testing options, a more nuanced approach to gonadal management, and an emphasis on shared decision-making, particularly related to external genital surgical procedures. The timing of DSD surgery is currently being questioned and debated in both medical and advocacy/activism spheres.
Topics: Humans; Female; Male; Decision Making, Shared; Genetic Testing
PubMed: 37385705
DOI: 10.1016/j.ucl.2023.04.010 -
The New Zealand Medical Journal Jul 2023Positive screening tests require investigation, usually by specialists. Specialist services are known to be limited. The planning of screening programmes must first...
Positive screening tests require investigation, usually by specialists. Specialist services are known to be limited. The planning of screening programmes must first include a model of existing diagnostic and follow-up services of symptomatic patients so that the added impact of the extra referrals required for screening can be estimated. This is fundamental to the planning of screening programmes; inevitable diagnostic delay, impeded access to services for symptomatic patients, and resulting harm or increased mortality from disease can thus be avoided.
Topics: Humans; Early Detection of Cancer; Delayed Diagnosis; New Zealand; Mass Screening; Neoplasms
PubMed: 37414081
DOI: No ID Found -
Journal of Cardiovascular Translational... Dec 2023
Topics: Humans; Cardiomyopathies; Genetic Testing
PubMed: 38015357
DOI: 10.1007/s12265-023-10464-9