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A framework for N-of-1 trials of individualized gene-targeted therapies for genetic diseases.

Individualized genetic therapies-medicines that precisely target a genetic variant that may only be found in a small number of individuals, as few as only one-offer promise for addressing unmet needs in genetic disease, but present unique challenges for trial design. By nature these new individualized medicines require testing in individualized N-of-1 trials. Here, we provide a framework for maintaining scientific rigor in N-of-1 trials. Building upon best practices from traditional clinical trial design, recent guidance from the United States Food and Drug Administration, and our own clinical

'I Could Trust It': Experiences of Reciprocal Translocation Carriers and Their Partners With Prenatal Cell-Free DNA Screening for Unbalanced Translocations.

OBJECTIVE: To explore the experiences of people having cfDNA screening to detect unbalanced translocations, and to understand motivations for choosing this option. METHODS: We used a qualitative approach with in-depth semi-structured interviews with reciprocal translocation carriers and their partners. People who underwent cfDNA screening with translocation analysis through Victorian Clinical Genetics Services between 2015 and 2019 were invited to take part. Purposive sampling based on the participant's geographic location, requesting practitioner specialty and cfDNA screening result was used

Global research on Fabry's disease: Demands for a rare disease.

BACKGROUND: Fabry disease (FD), the second most prevalent lysosomal storage disorder, is classified as a rare disease. It often leads to sig … foster FD research infrastructure in developing and emerging countries with focus on cost-intensive genetic research that is independent from economic interests of big pharmaceutical companies.

Lessons Learned from Translating Genome Sequencing to Clinical Routine: Understanding the Accuracy of a Diagnostic Pipeline.

The potential of genome sequencing (GS), which allows detection of almost all types of genetic variation across nearly the entire genome of an individual, greatly expands the possibility for diagnosing genetic disorders. The opportunities provided with this single test are enticing to researchers and clinicians worldwide for human genetic research as well as clinical application. Multiple studies have highlighted the advantages of GS for genetic variant discovery, emphasizing its added value for routine clinical use. We have implemented GS as first-line genetic testing for patients with rare d…

Calabria as a Genetic Isolate: A Model for the Study of Neurodegenerative Diseases.

Although originally multi-ethnic in its structure, nowadays the Calabria region of southern Italy represents an area with low genetic heterogeneity and a high level of consanguinity that allows rare mutations to be maintained due to the founder effect. A complex research methodology-ranging from clinical activity to the genealogical reconstruction of families/populations across the centuries, the creation of databases, and molecular/genetic research-was modelled on the characteristics of the Calabrian population for more than three decades. This methodology allowed the identification of severa…

Recommendations to encourage participation of individuals from diverse backgrounds in psychiatric genetic studies.

We present innovative research practices in psychiatric genetic studies to ensure representation of individuals from diverse ancestry, sex assigned at birth, gender identity, age, body shape and size, and socioeconomic backgrounds. Due to histories of inappropriate and harmful practices against marginalized groups in both psychiatry and genetics, people of certain identities may be hesitant to participate in research studies. Yet their participation is essential to ensure diverse representation, as it is incorrect to assume that the same genetic and environmental factors influence the risk for

Genomic Medicine: Lessons Learned From Monogenic and Complex Bone Disorders.

Current genetic studies of monogenic and complex bone diseases have broadened our understanding of disease pathophysiology, highlighting the need for medical interventions and treatments tailored to the characteristics of patients. As genomic research progresses, novel insights into the molecular mechanisms are starting to provide support to clinical decision-making; now offering ample opportunities for disease screening, diagnosis, prognosis and treatment. Drug targets holding mechanisms with genetic support are more likely to be successful. Therefore, implementing genetic information to the

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… Before the GWAS era, genetic research was mainly driven by typically underpowered and ill-defined candidate gene studies. …

Disease Modeling To Understand the Pathomechanisms of Human Genetic Kidney Disorders.

The class of human genetic kidney diseases is extremely broad and heterogeneous. Accordingly, the range of associated disease phenotypes is highly variable. Many children and adults affected by inherited kidney disease will progress to ESKD at some point in life. Extensive research has been performed on various different disease models to investigate the underlying causes of genetic kidney disease and to identify disease mechanisms that are amenable to therapy. We review some of the research highlights that, by modeling inherited kidney disease, contributed to a better understanding of the und

"It's all very well reading the letters in the genome, but it's a long way to being able to write": Men's interpretations of undergoing genetic profiling to determine future risk of prostate cancer.

A family history of prostate cancer (PC) is one of the main risk factors for the disease. A number of common single nucleotide polymorphisms (SNPs) that confer small but cumulatively substantial risks of PC have been identified, opening the possibility for the use of SNPs in PC risk stratification for targeted screening and prevention in the future. The objective of this study was to explore the psychosocial impact of receiving information about genetic risk of PC. The participants were men who had a family history of PC and were enrolled in a screening study providing research genetic profili

Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD).

Several genetic causes have been recently described for neurological diseases, increasing our knowledge of the common pathological mechanisms involved in these disorders. Mutation analysis has shown common causative factors for two major neurodegenerative disorders, ALS and FTD. Shared pathological and genetic markers as well as common neurological signs between these diseases have given rise to the notion of an ALS/FTD spectrum. This overlap among genetic factors causing ALS/FTD and the coincidence of mutated alleles (including causative, risk and modifier variants) have given rise to the not

A cost-benefit analysis of the Quebec Network of Genetic Medicine.

Certain serious diseases, including several major genetic disorders, cannot be treated effectively unless they are detected before symptoms appear. In such cases, only systematic population screening can ensure that the necessary preventive treatment can be administered to affected individuals. The question of whether to establish such screening programs, which may be relatively costly, is a pressing problem for many public administrations. This study of the costs and benefits of the Quebec Network of Genetic Medicine has as its main objective the development of an analytical framework which c

Clinical, immunologic, and genetic characteristics of 148 patients with natural killer cell deficiency.

BACKGROUND: Natural killer (NK) cell deficiency (NKD) is an immunodeficiency phenotype in which abnormality of NK cells is the major clinically relevant immune defect. OBJECTIVE: We sought to define the clinical, immunologic, and genetic characteristics of patients with NKD to aid in the understanding of these individuals and this cell type and guide future research and clinical practice. METHODS: During 2006-2022, 168 individuals with a suspected diagnosis of NKD were enrolled, with comprehensive clinical, immunologic, and genetic data collected and analyzed. Research exome sequencing was p

Cardiovascular therapy and pharmacogenetics in 2007.

John Carlquist received a PhD from the Department of Cellular Viral and Molecular Biology at the University of Utah School of Medicine (UT, … ntinues to serve as Technical Director; he also directs the Intermountain Heart Study Molecular and Genetic Research Laboratory. Current research interests include the genetics of lipid metabolism as related to coronary heart disease and the genetic factors influencing drug treatment outcomes.

Generalist Genes: Genetic Links Between Brain, Mind, and Education.

Genetics contributes importantly to learning abilities and disabilities-not just to reading, the target of most genetic research, but also to mathematics and other academic areas as well. One of the most important recent findings from quantitative genetic research such as twin studies is that the same set of genes is largely responsible for genetic influence across these domains. We call these "generalist genes" to highlight their pervasive influence. In other words, most genes found to be associated with a particular learning ability or disability (such as reading) will also be associated wit…

Mapping themes, trends, and knowledge structure of Behcet syndrome: a bibliometric analysis from 2010 to 2021.

This study employed bibliometric analysis to examine the current literature on Behcet Syndrome, an autoimmune disorder with complex pathophysiology and inadequate therapeutic options. The researchers collected 3,462 publications related to Behcet Syndrome from 2010 to 2021 via PubMed and conducted co-word and social network analyses to identify research hotspots and potential future directions. The co-word analysis produced a bibliographic data matrix, which revealed 72 high-frequency medical topic title (MeSH) terms. Using repeated dichotomy in the gCLUTO software, the researchers created a v

Osteoarthritis year in review 2023: genetics, genomics, and epigenetics.

OBJECTIVE: To elucidate the scientific advances made in the last 12 months within the realm of osteoarthritis genetics, genomics, and epigenetics. This review paper highlights major research publications that enhance our current understanding of the role of genetics, genomics, and epigenetics in osteoarthritis. METHODS: A systematic literature search was conducted on pubmed.ncbi.nlm.nih.gov on "March 17, 2023", using the following keywords: "osteoarthritis" in combination with any of these terms: "genetic(s)", "mutation(s)", "genomic(s)", "epigenetic(s)", "DNA methylation", "noncoding RNA", "

Editorial: Exploring Rare Genetic Variation in Pediatric-Onset Obsessive-Compulsive Disorder.

Genetic factors play a central role in the risk for developing obsessive-compulsive disorder (OCD), a finding established through twin, family, and large-scale cohort studies. Current genetic research aims to identify the specific genetic and genomic variants contributing to OCD risk.1 This involves investigating both common genetic variation-studied through genome-wide association studies (GWAS)-and rare genetic and genomic variation-studied through genome/exome sequencing or chromosomal microarray.

Implications of genetic findings for understanding schizophrenia.

From the perspective of those of us working on the genetics of schizophrenia, recent progress in identifying specific genetic risk factors at highly robust levels of statistical significance has been striking. However, the prevailing response among other schizophrenia researchers and some funders, families, and sufferers is often one of disappointment. In particular, it is often claimed that these discoveries explain only a small proportion of the genetic risk and hence tell us little about the nature of schizophrenia. The purpose of this article is to persuade you that recent genetic findings

The Process of Disclosure: Mothers' Experiences of Communicating X-Linked Carrier Risk Information to At-Risk Daughters.

When a boy is diagnosed with an X-linked condition such as Duchenne or Becker muscular dystrophy (D/BMD), the mother learns not only of her own potential carrier risk but also that of her daughters. Before the daughters are seen in the Genetics Clinic, responsibility for disclosing carrier risk information falls mainly to their mothers. We know little about if when and how these daughters are being told about their risk, and how mothers find the experience. Should we be doing more to help and support them? Using qualitative methods, six mothers known to the Manchester Centre for Genomic Medici

Medical genetics in Zulia, a State of Venezuela.

Zulia is a state located in the northwest of Venezuela. Congenital malformations, deformities and chromosomal anomalies are the second cause of infant and neonatal mortality. There are seven public and private groups providing genetic services, the most important of which, the Medical Genetic Unit at the Zulia University was created in 1973. So far, this unit has provided genetic services to 12,000 families, and has been responsible for undergraduate and postgraduate education in human and medical genetics. Prenatal diagnosis is performed at the Unit and a private practice group, the most freq