Usher syndrome (USH) should no longer be considered a fixed diagnosis limited to syndromic early-onset sensorineural hearing loss and progressive vision decline due to rod-cone retinal dystrophy. Patients increasingly present with partial or delayed retinal manifestations, often lacking a clinically relevant audiological history. Concurrently, genomic testing uncovers variants that challenge the practical relevance of the traditional definition of type I, II, and III subclassifications. This review argues for a paradigm shift toward genotype-first diagnosis led by ophthalmologists, integrating retinal findings and audiological evaluations with comprehensive genetic information. The rise of gene-specific molecular therapies, including antisense oligonucleotides and CRISPR-mediated gene editing for USH2A and MYO7A , demands timely and accurate molecular categorization for each patient. Delays in precise molecular diagnosis may risk excluding patients from potentially vision-saving trials. Diagnostic gaps persist, including limited variant interpretation tools, underrepresentation of non-Caucasian populations in reference databases, and a lack of standardized retinal imaging protocols. The establishment of centralized, real-time Usher registries and interdisciplinary diagnostic models is essential. The future of USH management lies in anticipatory, individualized care that begins in the retina clinic.
Circular RNAs (circRNAs), a new star of noncoding RNAs, are a group of endogenous RNAs that form a covalently closed circle and occur widely in the mammalian genome. Most circRNAs are conserved throughout species and frequently show stage-specific expression during various stages of tissue development. CircRNAs were a mystery discovery, as they were initially believed to be a product of splicing errors; however, subsequent research has shown that circRNAs can perform various functions and help in the regulation of splicing and transcription, including playing a role as microRNA (miRNA) sponges. With the application of high throughput next-generation technologies, circRNA hotspots were discovered. There are emerging indications that explain the association of circRNAs with human diseases, like cancers, developmental disorders, and inflammation, and circRNAs may be a new potential biomarker for the diagnosis and treatment outcome of various diseases, including cancer. After the discoveries of miRNAs and long noncoding RNAs, circRNAs are now acting as a novel research entity of interest in the field of RNA disease biology. In this review, we aim to focus on major updates on the biogeny and metabolism of circRNAs, along with their possible/established roles in major human diseases.
BACKGROUND Pharmacogenomics (PG) testing is under-utilised in Australia. Our research provides Australia-specific data on the perspectives of patients who have had PG testing and those of the clinicians involved in their care, with the aim to inform wider adoption of PG into routine clinical practice. AIM To investigate the frequency of actionable drug gene interactions and assess the perceived utility of PG among patients and clinicians METHODS We conducted a retrospective audit of PG undertaken by 100 patients at an Australian public hospital genetics service from 2018 to 2021. Via electronic surveys we compared and contrasted the experience, understanding and usage of results between these patients and their clinicians. RESULTS Of 100 patients who had PG, 84% were taking prescription medications, of which 67% were taking medications with actionable drug-gene interactions. Twenty-five out of 81 invited patients and 17 out of 89 invited clinicians completed the surveys. Sixty-eight percent of patients understood their PG results and 48% had medications changed following testing. Paired patient-clinician surveys showed patient-perceived utility and experience was positive, contrasting their clinicians’ hesitancy on PG adoption who identified insufficient education/training, lack of clinical support, test turnaround time and cost as barriers to adoption. CONCLUSION Our dichotomous findings between the perspectives of our patient and clinician cohorts suggest the uptake of PG is likely to be driven by patients and clinicians need to be prepared to provide information and guidance to their patients.
Interleukin-2 (IL-2) is an important cytokine that plays a key role in the immune response. The IL-2 receptor (IL-2R) is composed of three subunits, alpha, beta, and gamma, with the alpha subunit having the highest affinity for IL-2. Several studies reported that immune dysregulation of IL-2 may cause tissue injury as well as damage leading to the pathogenesis of various autoimmune diseases such as acute necrotizing vasculitis in systemic lupus erythematosus (SLE), inflammatory synovitis in rheumatoid arthritis (RA), salivary and lacrimal gland dys-function in Sjogren syndrome (SS), obliterative vasculopathy fibrosis in systemic sclerosis (SSc), and inflammatory demyelination in multiple sclerosis (MS). The aim of this review paper was to examine the role of IL-2/IL-2R in various autoimmune disorders, taking into account recent advancements and discoveries, gaps in the current literature, ongoing debates, and potential avenues for future research. The focus of this review is on systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, sjogren syndrome, and multiple sclerosis, which are all linked to the malfunctioning of IL-2/IL-2R. In genetic studies, gene polymorphisms of IL-2 such as IL-2 330/T, IL-2 330/G, and rs2069763 are involved in increasing the risk of SLE. Furthermore, genetic associations of IL-2/IL-2R such as rs791588, rs2281089, rs2104286, rs11594656, and rs35285258 are significantly associated with RA susceptibility. The IL-2 polymorphism including rs2069762A, rs6822844T, rs6835457G, and rs907715T are significant connections with systemic sclerosis. In addition, rs2104286 (IL-2), rs11594656 (IL-2RA), rs35285258 (IL-2RB) gene polymorphism significant increases the risk of multiple sclerosis. In therapeutic approaches, low-dose IL-2 therapy could regulate Tfr and Tfh cells, resulting in a reduction in disease activity in the SLE patients. In addition, elevated sIL-2R levels in the peripheral blood of SLE patients could be linked to an immunoregulatory imbalance, which may contribute to the onset and progression of SLE. Consequently, sIL-2R could potentially be a target for future SLE therapy. Moreover, Low dose-IL2 was well-tolerated, and low levels of Treg and high levels of IL-21 were associated with positive responses to Ld-IL2 suggested to be a safe and effective treatment for RA. Additionally, low-dose IL-2 treatment improves the exocrine glands' ability to secrete saliva in SS-affected mice. Whereas, Basiliximab targets the alpha chain of the IL-2 receptor suggested as a potential treatment for SSc. Also, pre-and post-treatment with Tregs, MDSCs, and IL-2 may have the potential to prevent EAE induction in patients with MS. It is suggested that further studies should be conducted on IL-2 polymorphism in Sjogren syndrome.
BACKGROUND Tetrasomy 18p is a rare chromosome abnormality disorder known to have considerable variability in clinical features and gathering data from different cases will help clinicians and researchers learn about its genotype-phenotype relationship and diagnosis.CASE SUMMARY Herein, we have reviewed the literature on phenotypic features of this disorder and described the phenotypic and cytogenetic features of a girl of early childhood with tetrasomy 18p for the first time from Iran. This patient showed a strong sense of smell（a unique feature not reported previously for this syndrome）, had clenched hand, pes planus, forward head posture in walking and hirsutism（dysmorphic features less reported）, and showed 10 clinical features that are generally observed in previously reported cases, including developmental delay/intellectual disability, triangular face, smooth philtrum, feeding difficulties, hypotonia, epicanthus, strabismus, history of constipation, growth retardation and foot anomalies. G-banding chromosome analysis from peripheral blood revealed an abnormal female karyotype with a small marker chromosome（47,XX, +mar）, and oligo-array comparative genomic hybridization displayed a gain of 14Mb of the 18p arm containing 56 Online Mendelian Inheritance in Man（OMIM） genes in this patient. Overall, this patient seems to have mild phenotypes.CONCLUSION This Iranian tetrasomy 18p child displays a uniquely strong sense of smell, some less reported dysmorphic features and ten features generally reported.
Chronic occupational stress and an individual’s reaction to that stress often lead to burnout syndrome. We sought to use genetics to evaluate what, if any, interactions exist between John Henryism (JH) and cynicism in hopes of clarifying holistic risk factors of burnout syndrome. We performed genome-wide association studies in a discover phase with 1,852 samples and validated associations in a replication phase of 465 samples, both from the CARDIA study, and used supervised machine learning to developing genetic risk algorithms. We identified 933 genetic associations and developed a classification algorithm for high cynicism using machine learning with areas under the receiver operator characteristics curve greater than 0.7. We found significant genetic components to these traits but no evidence of an interaction between JH and cynicism, so while there may be a genetic risk component, JH does not appear to contribute to burnout risk.
BACKGROUND Epigenetic disruptions have been implicated in some cases of infertility and can serve as therapeutic targets. However, the involvement of epigenetics in infertility has not received adequate attention.AIM This study aimed to determine the epigenetic basis of infertility in order to enhance public knowledge.METHODS Relevant articles on the subject were collected from PubMed, RCA, Google Scholar, Springer Link, and Scopus. The articles were pooled together and duplicates were removed using Endnote software.RESULTS Available information shows that epigenetic mechanisms, mainly DNA methylation, histone modification, and microRNA interference are necessary for normal gametogenesis and embryogenesis. As a result, epigenetic disruptions in genes that control gametogenesis and embryogenesis, such as DDX3X, ADH4, AZF, PLAG1, D1RAS3, CYGB, MEST, JMJD1A, KCNQ1, IGF2, H19, and MTHFR may result in infertility. Aberrant DNA methylation during genomic imprinting and parental epigenetic mark erasures, in particular, may affect the DNA epigenomes of sperm and oocytes, resulting in reproductive abnormalities.Histone epigenetic dysregulation during oocyte development and histone-protamine replacement in the sperm may also cause reproductive abnormalities. Furthermore, overexpression or repression of certain micro RNAs embedded in the ovary, testis, embryo, as well as granulosa cells and oocytes may impair reproduction. Male infertility is characterized by spermatogenesis failure, which includes oligozoospermia, asthenozoospermia, and teratozoospermia, while female infertility is characterized by polycystic ovary syndrome. Some epigenetic modifications can be reversed by deactivating the regulatory enzymes, implying that epigenetic reprogramming could help treat infertility in some cases. For some disorders, epigenetic drugs are available, but none have been formulated for infertility.CONCLUSION Some cases of infertility have an epigenetic etiology and can be treated by reversing the same epigenetic mechanism that caused it. As a result, medical practitioners are urged to come up with epigenetic treatments for infertility that have an epigenetic cause.
BACKGROUND Celiac sprue, or celiac disease, is a relatively common disease whereby many are unaware that they have it. It often manifests with symptoms outside of the digestive system. Many health care providers are unaware of the wide variety of symptoms of celiac disease as well as diseases that are associated with it, often delaying diagnosis and treatment.CASE SUMMARY The following case indicates an otherwise healthy 20-year-old female who presents with a variety of symptoms and is ultimately diagnosed with shingles, infectious mononucleosis, and celiac disease CONCLUSION Although it is known that risk-factors are genetic as well as environmental, much more research is needed to better understand the relationship of potential causes. In addition, continuing education is needed in health care so that more practitioners better understand celiac disease.
Clinical and molecular spectrum of Wiedemann-Steiner syndrome, an emerging member of the chromatinopathy family
Pedigree analysis supports a correlation between an AXIN2 variant and polyposis/colorectal cancer
Despite its apparently simple genetics,cystic fibrosis（CF） is a rather complex genetic disease.A lot of variability in the steps of the path from the cystic fibrosis transmembrane conductance regulator（CFTR） gene to the clinical manifestations originates an uncertain genotype- phenotype relationship.A major determinant of this uncertainty is the incomplete knowledge of the CFTR mutated genotypes,due to the high number of CFTR mutations and to the higher number of their combinations in trans and in cis.Also the very limited knowledge of functional effects of CFTR mutated alleles severely impairs our diagnostic and prognostic ability.The final phenotypic modulation exerted by CFTR modifier genes and interactome further complicates the framework.The next generation sequencing approach is a rapid,lowcost and high-throughput tool that allows a near complete structural characterization of CFTR mutated genotypes,as well as of genotypes of several other genes cooperating to the final CF clinical manifestations.This powerful method perfectly complements the new personalized therapeutic approach for CF.Drugs active on specific CFTR mutational classes are already available for CF patients or are in phase 3 trials.A complete genetic characterization has been becoming crucial for a correct personalized therapy.However,the need of a functional classification of each CFTR mutation potently arises.Future big efforts towards an ever more detailed knowledge of both structural and functional CFTR defects,coupled to parallel personalized therapeutic interventions decisive for CF cure can be foreseen.
Atrial fibrillation（AF）is the most frequent arrhythmogenic syndrome in humans.With an estimate incidence of1%-2%in the general population,AF raises up to almost10%-12%in 80+years.Thus,AF represents nowadays a highly prevalent medical problem generating a large economic burden.At the electrophysiological level,distinct mechanisms have been elucidated.Yet,despite its prevalence,the genetic and molecular culprits of this pandemic cardiac electrophysiological abnormality have remained largely obscure.Molecular genetics of AF familiar cases have demonstrated that single nucleotide mutations in distinct genes encoding for ion channels underlie the onset of AF,albeit such alterations only explain a minor subset of patients with AF.In recent years,analyses by means of genome-wide association studies have unraveled a more complex picture of the etiology of AF,pointing out to distinct cardiac-enriched transcription factors,as well as to other regulatory genes.Furthermore a new layer of regulatory mechanisms have emerged,i.e.,post-transcriptional regulation mediated by non-coding RNA,which have been demonstrated to exert pivotal roles in cardiac electrophysiology.In this manuscript,we aim to provide a comprehensive review of the genetic regulatory networks that if impaired exert electrophysiological abnormalities that contribute to the onset,and subsequently,on self-perpetuation of AF.
Gene therapy is a promising technology with potential applications in the treatment of medical conditions, both congenital and acquired. Despite its label as breakthrough technology for the 21 st century, the simple concept of gene therapy- the introduction of a functional copy of desired genes in affected individuals- is proving to be more challenging than expected. Oral gene delivery has shown intriguing results and warrants further exploration. In particular, oral administration of chitosan DNA nanoparticles, one the most commonly used formulations of therapeutic DNA, has repeatedly demonstrated successful in vitro and in vivo gene transfection. While oral gene therapy has shown immense promise as treatment options in a variety of diseases, there are still significant barriers to overcome before it can be considered for clinical applications. In this review we provide an overview of the physiologic challenges facing the use of chitosan DNA nanoparticles for oral gene delivery at both the extracellular and intracellular level. From administration at the oral cavity, chitosan nanoparticles must traverse the gastrointestinal tract and protect its DNA contents from significant jumps in pH levels, various intestinal digestive enzymes, thick mucus layers with high turnover, and a proteinaceous glycocalyx meshwork. Once these extracellular barriers are overcome, chitosan DNA nanoparticles must enter intestinal cells, escape endolysosomes, and disassociate from genetic material at the appropriate time allowing transport of genetic material into the nucleus to deliver a therapeutic effect. The properties of chitosan nanoparticles and modified nanoparticles are discussed in this review. An understanding of the barriers to oral gene delivery and how to overcome them would be invaluable for future gene therapy development.
We report a 28-year-old female who presented with severe joint pain, chronic muscle weakness, Raynaud’s phenomenon, and hypermobility. She was found to have a 6074A > T nucleotide transition in the TNXB gene causing an amino acid protein change at Asp2025Val classified as likely pathogenic. We add this clinical report to the literature and classical human disease gene catalogs to identify this specific mutation as disease-causing. This gene variant was reported previously in a different 36-year-old patient who shared our patient’s symptoms of joint hypermobility, skeletal and joint pain, skin elasticity and musculoskeletal problems, thereby causing a more severe presentation than seen in the hypermobility type of Ehlers-Danlos syndrome (EDS). At the time of writing, a few mutations in the TNXB gene have been recognized as pathogenic causing EDS due to tenascin-X deficiency, but the variant identified in our patient has not been recognized as pathogenic in online genetic databases. Our case study in combination with peer-reviewed literature suggests that the 6074A > T nucleotide transition in the TNXB gene may be classified as disease-causing for EDS due to tenascin-X deficiency.
Adeno-associated virus（AAV） is a small,non-enveloped virus that contains a single-stranded DNA genome. It was the first gene therapy drug approved in the Western world in November 2012 to treat patients with lipoprotein lipase deficiency. AAV made history and put human gene therapy in the forefront again. More than four decades of research on AAV vector biology and human gene therapy has generated a huge amount of valuable information. Over 100 AAV serotypes and variants have been isolated and at least partially characterized. A number of them have been used for preclinical studies in a variety of animal models. Several AAV vector production platforms,especially the baculovirus-based system have been established for commercial-scale AAV vector production. AAV purification technologies such as density gradient centrifugation,column chromatography,or a combination,have been well developed. More than 117 clinical trials have been conducted with AAV vectors. Although there are still challenges down the road,such as crossspecies variation in vector tissue tropism and gene transfer efficiency,pre-existing humoral immunity to AAV capsids and vector dose-dependent toxicity in patients,the gene therapy community is forging ahead with cautious optimism. In this review I will focus on the properties and applications of commonly used AAV serotypes and variants,and the technologies for AAV vector production and purification. I will also discuss the advancement of several promising gene therapy clinical trials.
Comparison of next generation sequencing-based and methylated DNA immunoprecipitation-based approaches for fetal aneuploidy non-invasive prenatal testing
The genetic diagnosis of inherited retinal dystrophies has been deeply hampered by the extreme genetic and allelic heterogeneity of this group of disorders, with most families bearing rare or private pathogenic variants. Clinicians, patients, and the affected families are becoming aware of the benefits of a reliable molecular diagnosis: it facilitates genetic counseling and prenatal screening, improves the clinical diagnosis – providing prognostic information as genotype–phenotype correlations are being drawn, opens new venues for basic research, and guides therapy as the current clinical trials for retinal disorders are mainly gene-specific. The wide range of high-throughput techniques, now increasingly available and affordable for most laboratories, poses new questions to the clinical geneticists concerning the best approach to accurate genotyping on the basis of efficiency and cost-effectiveness. The comparison between available molecular diagnosis methodologies, in this rapidly moving field, leads to the conclusion that there is not an obvious preferential approach, but a combination of prioritized strategies is at present the optimal choice.
Adolescents and young adults（AYA）with a cancer diagnosis or those at risk for cancer due to hereditary cancer syndromes may benefit from genetic counseling and testing not only to manage personal risk but also to address reproductive concerns,especially fertility.The opportunity for genetic counselors to provide important risk information is relevant to both the newly diagnosed as well as to unaffected carriers and survivors.However,genetic counselors may need additional training in reproductive options related to AYA cancer to provide this valuable counsel.This commentary uses hereditary breast and ovarian cancer syndrome as a model to highlight important considerations when discussing preimplanatation genetic diagnosis and prenatal diagnosis,particularly in the context of expanded testing for hereditary cancer risk including multigene panels or whole exome or whole genome sequencing.Other hereditary cancers are also addressed;however,less is known about the psychosocial and fertility concerns in these AYA populations.Additionally,we provide an overview of the concept of"oncofertility"-the linkage between cancer care and reproductive medicine that aims to expand the reproductive opportunities of cancer patients-and offer support for the expansion of guidelines to include genetic counselors in AYA cancer patients’treatment planning related to reproductive health and fertility.
Typically,inherited metabolic diseases arise from point mutations in genes encoding metabolic enzymes. Although some of these mutations directly affect amino acid residues in the active sites of these enzymes,the majority do not. It is now well accepted that the majority of these disease-associated mutations exert their effects through alteration of protein stability,which causes a reduction in enzymatic activity. This finding suggests a way to predict the severity of newly discovered mutations. In silico prediction of the effects of amino acid sequence alterations on protein stability often correlates with disease severity. However,no stability prediction tool is perfect and,in general,better results are obtained if the predictions from a variety of tools are combined and then interpreted. In addition to predicted alterations to stability,the degree of conservation of a particular residue can also be a factor which needs to be taken into account: alterations to highly conserved residues are more likely to be associated with severe forms of the disease. The approach has been successfully applied in a variety of inherited metabolic diseases,but further improvements are necessary to enable robust translation into clinically useful tools.
