Search Results (34)

Advances in artificial intelligence (AI), multi-omic profiling, and sophisticated imaging technologies have significantly advanced personalized medicine in gastrointestinal surgical oncology. These technological innovations enable precise patient stratification, tailored surgical strategies, and individualized therapeutic approaches, thereby significantly enhancing clinical outcomes. Despite remarkable progress, challenges persist, including the standardization and integration of diverse data types, ethical concerns regarding patient privacy, and rigorous clinical validation of predictive models. Addressing these challenges requires establishing international standards for data interoperability, such as Fast Healthcare Interoperability Resources, and adopting advanced security methods, such as homomorphic encryption, to facilitate secure multi-institutional data sharing. Moreover, ensuring model transparency and explainability through techniques such as explainable AI is critical for fostering trust among clinicians and patients. The successful integration of these advanced technologies necessitates strong multidisciplinary collaboration among surgeons, radiologists, geneticists, pathologists, and oncologists. Ultimately, the continued development and effective implementation of these personalized medical strategies complemented by human expertise promise a transformative shift toward patient-centered care, improving long-term outcomes for patients with gastrointestinal cancer. Full article

Introduction: Tuberous sclerosis complex (TSC) is a rare multisystemic genetic disorder characterized by the formation of benign tumors in various organs, including the central nervous system, skin, kidneys, and heart. The diagnosis is based on well-defined clinical criteria, such as those from Schwartz (2007) updated in 2012 by the International Tuberous Sclerosis Complex Consensus Group. The study aims to investigate the clinical, imaging, and molecular characteristics of patients diagnosed with tuberous sclerosis and to explore the correlation between specific genetic mutations (TSC1 and TSC2 genes) and the severity of clinical manifestations. Material and Methods: This is a retrospective longitudinal study of 13 patients diagnosed with tuberous sclerosis, identified in the records of the Bihor Regional Center for Medical Genetics (BRCMG) within the Bihor County Emergency Clinical Hospital from 1984 to 2024. Clinical, imaging, and molecular features were assessed. Patients were evaluated by a multidisciplinary team, including a geneticist, pediatrician, neurologist, psychiatrist, and psychologist. Clinical and imaging data were retrospectively collected from the congenital malformations and genetic disease records of BRCMG Bihor and statistically analyzed. Results: All patients showed clinical and imaging signs consistent with the diagnosis of tuberous sclerosis. Neurological manifestations were present in 83% of patients, including epilepsy and cognitive delays. Renal lesions were detected in 46% of cases, and dermatological lesions, such as facial angiofibromas, were observed in 69% of patients. Mutational variants identified in the TSC2 gene correlated with a more severe clinical presentation, including severe intellectual disability and treatment-resistant seizures, compared to variants in the TSC1 gene. Conclusions: Our study, although involving a small number of patients, highlights the clinical heterogeneity of tuberous sclerosis and the importance of a multidisciplinary approach in patient management. Early diagnosis and ongoing monitoring are essential to improving the quality of life for patients. Further studies are needed to assess the impact of therapeutic interventions and genetic correlations within the studied population. Full article

Background/Objectives: Schuurs–Hoeijmakers syndrome (SHMS), also known as PACS1 neurodevelopmental disorder, is a rare condition characterized by intellectual disability, distinctive craniofacial abnormalities, and congenital malformations. SHMS has already been associated with variants in the PACS1 gene in 63 patients. In this study, we describe 10 new Italian SHMS patients all harboring the common de novo p.(Arg203Trp) variant. Methods: The 10 patients we studied were evaluated by clinical geneticists and child neurologists and a detailed description of clinical features was recorded. Data were then coded using the Human Phenotype Ontology (HPO) terms. The recurrent p.(Arg203Trp) variant in PACS1 was identified by clinical exome sequencing or whole exome sequencing in trio using standard methodologies. To facilitate mutation identification, we designed a new PCR-RFLP strategy adopting the endonuclease DpnII. Results: We define a detailed clinical phenotyping in patients with intellectual disability and facial characteristics (thick eyebrows, down-slanting palpebral fissures, ocular hypertelorism, low-set ears, a thin upper lip, and a wide mouth) that can help clinicians form a more efficient diagnosis of SHMS even through neuroimaging and neuropsychological evaluation. Conclusions: Our series of 10 newly affected Italian children highlights specific clinical features that may help clinicians recognize and better manage this syndrome, contributing to precision medicine approaches in medical genetics. Full article

The biomarker-based Dutch Newborn Screening (NBS) panel (as of 2024) comprises 19 inherited metabolic disorders (IMDs). With the use of next-generation sequencing (NGS) as a first-tier screen, NBS could expand to include IMDs that lack a reliable biochemical footprint in dried blood spots, while also reducing secondary findings. To be eligible for inclusion in NBS, an IMD needs to fulfill the Wilson and Jungner criteria, with treatability being one of the most important criteria. In this study, we aimed to identify IMDs eligible for DNA-first NBS when considering only treatability in the context of NBS as a prerequisite. First, three independent reviewers performed a systematic literature review of the 1459 genotypic IMDs and their causative gene(s), as described in the International Classification of Inherited Metabolic Disorders (dated 1 February 2021), applying 16 criteria to exclude non-treatable disorders. Eligible disorders were then discussed in three online meetings with a project group of clinical laboratory geneticists, medical laboratory specialists specialized in IMD, and pediatricians with expertise in IMDs. Based on treatability, we identified 100 genes, causing 95 IMDs, as eligible for NBS, including 42 causal genes for the IMDs in the current biomarker-based NBS. The other 58 genes are primarily associated with treatable defects in amino acid metabolism and fatty acid oxidation. Other IMDs were excluded, most often because of insufficient literature. As the evaluation of treatability was not straightforward, we recommend the development of standardized treatability scores for the inclusion of IMDs in NBS. Full article

Background: Hereditary transthyretin amyloidosis (ATTRv) is an autosomal-dominant systemic disease, where amyloid fibrils accumulate especially in the peripheral and autonomic nervous systems and in the heart. The aim of the present work was to outline the follow-up and type of management received by asymptomatic carriers (ACs) and Coutinho stage 1 ATTRv patients in Spain. Methods: A cross-sectional, non-interventional study was conducted throughout seven experienced hospitals in Spain. A total of 86 ACs without neurological symptoms and 19 Coutinho stage 1 ATTRv patients diagnosed 12 months before their enrollment were included. Clinical and demographic data, red flags, and neurological and cardiological evaluations were gathered. In addition, site variables were collected from four centers to describe the clinical management of ATTRv. Results: ATTRv clinical management varied depending on the center setting but was primarily overseen by neurology and internal medicine, which were responsible for the holistic follow-up of ACs and patients. Routinely, neurologists, neurophysiologists, cardiologists, and internal medicine conducted the follow-up. Specialties involved in initial AC assessment were neurophysiologists and cardiologists in 100% of cases, neurologists (75%), internists and geneticists (50%), and ophthalmologists (25%). A review of the medical tests performed proved an exhaustive management of the study population. Stable patients were followed up every 6 months, while those under evolution were monitored every 3–6 months. The frequency of monitoring of ACs was annual, and carriers classified with doubtful disease onset were visited every 3–6 months. Conclusions: The EMPATIa study provides valuable insights into the management of ATTRv in a real-world clinical setting in highly experienced hospitals in Spain. It demonstrates that multidisciplinary practice and enhanced disease awareness may lead to a reduction in diagnostic delay. Full article

Rare and ultra-rare diseases constitute a significant medical challenge due to their low prevalence and the limited understanding of their origin and underlying mechanisms. These disorders often exhibit phenotypic diversity and molecular complexity that represent a challenge to biomedical research. There are more than 6000 different rare diseases that affect nearly 300 million people worldwide. However, the prevalence of each rare disease is low, and in consequence, the biomedical resources dedicated to each rare disease are limited and insufficient to effectively achieve progress in the research. The use of animal models to investigate the mechanisms underlying pathogenesis has become an invaluable tool. Among the animal models commonly used in research, Drosophila melanogaster has emerged as an efficient and reliable experimental model for investigating a wide range of genetic disorders, and to develop therapeutic strategies for rare and ultra-rare diseases. It offers several advantages as a research model including short life cycle, ease of laboratory maintenance, rapid life cycle, and fully sequenced genome that make it highly suitable for studying genetic disorders. Additionally, there is a high degree of genetic conservation from Drosophila melanogaster to humans, which allows the extrapolation of findings at the molecular and cellular levels. Here, I examine the role of Drosophila melanogaster as a model for studying rare and ultra-rare diseases and highlight its significant contributions and potential to biomedical research. High-throughput next-generation sequencing (NGS) technologies, such as whole-exome sequencing and whole-genome sequencing (WGS), are providing massive amounts of information on the genomic modifications present in rare diseases and common complex traits. The sequencing of exomes or genomes of individuals affected by rare diseases has enabled human geneticists to identify rare variants and identify potential loci associated with novel gene–disease relationships. Despite these advances, the average rare disease patient still experiences significant delay until receiving a diagnosis. Furthermore, the vast majority (95%) of patients with rare conditions lack effective treatment or a cure. This scenario is enhanced by frequent misdiagnoses leading to inadequate support. In consequence, there is an urgent need to develop model organisms to explore the molecular mechanisms underlying these diseases and to establish the genetic origin of these maladies. The aim of this review is to discuss the advantages and limitations of Drosophila melanogaster, hereafter referred as Drosophila, as an experimental model for biomedical research, and the applications to study human disease. The main question to address is whether Drosophila is a valid research model to study human disease, and in particular, rare and ultra-rare diseases. Full article

Community genetic services were introduced in South Africa almost seven decades ago, with medical geneticists and genetic counsellors being formally recognized for the past 30 years. Initial training platforms were established at academic centres countrywide, and posts for relevant healthcare professionals, including medical geneticists and genetic counsellors were created in the public sector. Despite these early advances, the number of these specialists required to address the rising burden of congenital disorders in the country remains far below required targets established by the National Department of Health. The aim of this study was to analyse the retrospective, current and projected number of medical geneticists and genetic counsellors in South Africa. The results indicate the number of practicing medical geneticists (n = 13) and genetic counsellors (n = 28) are currently at 10% and 5% of capacity targets, respectively. There is unequal distribution of these specialists between the public and private healthcare sectors, and geographical maldistribution. An alarming trend of emigration is particularly prevalent among newly qualified genetic counsellors. With the proportion of congenital disorders expected to continue to rise in coming years, together with the increasing proportion of ageing South Africans, it is imperative that health workforce planning addresses the ever-widening gap between the supply, demand and unmet need for these crucial specialists in South Africa. Full article

Brazil is a continent-size country with 203 million inhabitants, classified as a developing upper-middle-income country, although inequities remain significant. Most of the population is assisted by the public Unified Health System (SUS), along with a thriving private health sector. Congenital malformations are the second leading cause of infant mortality and chronic/genetic disorders and a significant burden in hospital admissions. The past two decades have been crucial for formalizing medical genetics as a recognized medical specialty in the SUS, as well as for implementing a new health policy by the Ministry of Health for comprehensive care for rare diseases. These public health policies had the broad support of the Brazilian Society of Medical Genetics and Genomics and patient organizations. Most comprehensive genetic services are concentrated in large urban centers in the South and Southeast regions of Brazil; with this new policy, new services throughout the country are progressively being integrated. The number of medical geneticists increased by 103% in a decade. Details on the policy and an overview of the availability of services, testing, human resources, newborn screening, research projects, patient organizations, and relevant issues regarding medical genetics in this vast and diverse country are presented. Full article

Cardiomyopathies have evolved from being considered rare and idiopathic to being increasingly linked to genetic factors. This shift was enabled by advancements in understanding genetic variants and the widespread use of next generation sequencing (NGS). Current guidelines emphasize the importance of evidence-based gene panels that can offer “clinically actionable results”, which provide diagnostic and prognostic insights. They also advise against indiscriminate family screening after finding variants of uncertain significance (VUS) and recommend collaboration among multidisciplinary teams for an accurate variant pathogenicity assessment. This article presents an innovative “cardiogenetic clinic” approach involving cardiologists and medical geneticists to provide genetic testing and family screening. This study attempts to improve the diagnostic process for suspected genetic cardiomyopathies; this includes direct patient recruitment during cardiology appointments, NGS analysis, and combined consultations with cardiologists and geneticists to assess the results and screen the families. The study cohort of 170 patients underwent genetic testing, which identified 78 gene variants. Positive results (C4 or C5 variants) occurred in 20 (19.8%) cases, with rates varying by cardiomyopathy phenotype, while 57 (73.1%) of the variants found were classified as C3-VUS, causing a significant management issue. This model shortened the time to results, increased patient adherence, and improved patients’ diagnoses. Family screening was pondered depending on the relevance of the detected variants, showing this method’s potential to impact patient management. Full article

The delivery of genetic services in developing countries is faced with significant challenges, despite medical and technological advances globally. The Philippines, being an archipelago, faces even more challenges, with significant disparities in access to healthcare, and tertiary medical centers and specialists being concentrated in the major cities. The utilization of different networks for the integration of genetic services in the existing public health delivery system has been valuable. Using the well-established network of the national newborn screening program, genetic services have been successfully integrated into the delivery of healthcare, even at the grassroot level. Equitable access to healthcare, including genetic services, was highlighted and supported by the enactment of the Rare Disease Law in 2016. The support of the academe to assure the sustainability of services was evident in the establishment of a genetic counseling program to augment the work of a handful of clinical geneticists. Professional societies and support groups have been instrumental in identifying genetic conditions to be prioritized and lobbying for increased public awareness, leading to national programs and policies. This paper primarily discusses the value of networks in the delivery of genetic services, specifically newborn screening, programs for rare diseases, birth defects, and genetic counseling. Full article

Healthcare human resource planning is one of the biggest challenges facing the healthcare systems in many countries. Inadequate decisions in human resource planning can lead to an insufficient number of healthcare professionals then healthcare inequalities. One of the components of resource planning in the healthcare system is long-term data monitoring and the identification of potential trends. Since 1990, the number of physicians in Lithuania has decreased by 15.3% (−2266), but the decrease in the population has led to a 13.61% increase in the number of physicians per 10,000 inhabitants (5.32). During the analyzed period, the largest decrease in the number of physicians workforce by specialty was the number of medical physicians (−73.08%), epidemiology and hygiene (−69.30%), children’s diseases (−49.08%), the most increased number was of family/general practitioners (GPs), geneticists, physical medicine, and rehabilitation specialists. Since 1992, the number of visits to physicians in Lithuania, which has been decreasing for a long time, began increasing, and in 2022 (9.3 visits) it has almost reached the number of visits (9.5) per capita as in 1991. The aim of this research was to collect long-term data from various databases, summarize them, and identify possible trends and the reasons for data changes. The study analyzed data from the Lithuanian healthcare system from the Declaration of Independence of Lithuania to the last 30 years. The data includes or affects the indicators of the healthcare system, changes in population and doctors, the number of visits to doctors, the number of medical students and residents, and data determining inequalities in the healthcare system. Long-term data analysis is useful for developing a model of healthcare human resource planning and for planning healthcare resources. Full article

The advancement of genetic knowledge and the discovery of an increasing number of genetic disorders has made the role of the geneticist progressively more complex and fundamental. However, most genetic disorders present during childhood; thus, their early recognition is a challenge for the pediatrician, who will be also involved in the follow-up of these children, often establishing a close relationship with them and their families and becoming a referral figure. In this review, we aim to provide the pediatrician with a general knowledge of the approach to treating a child with a genetic syndrome associated with dysmorphic features. We will discuss the red flags, the most common manifestations, the analytic collection of the family and personal medical history, and the signs that should alert the pediatrician during the physical examination. We will offer an overview of the physical malformations most commonly associated with genetic defects and the way to describe dysmorphic facial features. We will provide hints about some tools that can support the pediatrician in clinical practice and that also represent a useful educational resource, either online or through apps downloaded on a smartphone. Eventually, we will offer an overview of genetic testing, the ethical considerations, the consequences of incidental findings, and the main indications and limitations of the principal technologies. Full article

Background: In the metastatic setting, cancer patients may not benefit from standard care regimes and their diseases undergo drug resistance due to tumour cell heterogeneity and genomic landscape complexity. In recent years, there have been several attempts to personalise the diagnostic-therapeutic path and to propose novel strategies based on not only histological test results but also on each patient’s clinical history and molecular biology. Profiling molecular tests allows physicians to investigate the single tumour genomic landscape and to promote targeted approaches. The Molecular Tumour Board (MTB) is a multidisciplinary committee dedicated to selecting individualised and targeted therapeutic strategies appropriate for patients suffering from diseases that present resistance to standard care. Materials and Methods: Our MTB settled in “Azienda Ospedaliero Universitaria delle Marche”, Ancona (AN), Italy, and includes oncologists, molecular biologists, geneticists, and other specialists. Clinical cases are referred by physicians to the MTB, through the Cancer and Research Centre of the Marche Region (CORM), through a telemedicine platform. Four possible molecular profiles are available: FoundationOne^® CDx e FoundationOne^®Liquid CDx and two local Next Generation Sequencing (NGS) panels, with 16 DNA genes and 10 RNA genes respectively. The resulting genetic mutations and their analyses are evaluated by all the members of the Board and a report for each patient is provided with medical recommendations. Results: from June 2021 to May 2023, we collected data from 97 referral patients (M: 49, F: 48). The mean age was 60.6 years (range 22–83 years). 90 cases were approved for testing. Only seven patients were not eligible for genomic profiling. In two patients who were eligible, molecular profiling was not performed because a tissue sample was not available. Off-label therapy was recommended for three patients. 5% of cases (5/88) showed addressable driver mutations associated with an existing targeted therapy and were immediately enrolled. Conclusions: MTB presents a powerful tool for offering precise medical goals. Our Department of Clinical Oncology also takes advantage of the important role of multidisciplinary teams, through the establishment of CORM and MTB meetings, within which there is the chance to perform NGS-based analyses. It will be important in the future to implement the use of genomic profiling to improve personalised care and to guide the choice of suitable therapies and more appropriate management of patients. Full article

We have developed MAGI-ACMG, a classification algorithm that allows the classification of sequencing variants (single nucleotide or small indels) according to the recommendations of the American College of Medical Genetics (ACMG) and the Association for Clinical Genomic Science (ACGS). The MAGI-ACMG classification algorithm uses information retrieved through the VarSome Application Programming Interface (API), integrates the AutoPVS1 tool in order to evaluate more precisely the attribution of the PVS1 criterion, and performs the customized assignment of specific criteria. In addition, we propose a sub-classification scheme for variants of uncertain significance (VUS) according to their proximity either towards the “likely pathogenic” or “likely benign” classes. We also conceived a pathogenicity potential criterion (P_POT) as a proxy for segregation criteria that might be added to a VUS after posterior testing, thus allowing it to upgrade its clinical significance in a diagnostic reporting setting. Finally, we have developed a user-friendly web application based on the MAGI-ACMG algorithm, available to geneticists for variant interpretation. Full article

Primary amenorrhea (PA) describes the complete absence of menses by the age of 15 years. It is a devastating diagnosis that can affect the adolescent’s view of her femininity, sexuality, fertility and self-image. A normal menstrual cycle can occur only in the presence of: a properly functioning hypothalamus–pituitary axis, well-developed and active ovaries, outflow tract without abnormalities. Any dysfunction in any of these players can result in amenorrhea. PA evaluation includes the patient’s medical history, physical examination, pelvic ultrasonography and initial hormone evaluation, limited to the serum-follicle-stimulating hormone (FSH) and luteinizing hormone, testosterone and prolactin. A karyotype should be obtained in all adolescents with high FSH serum levels. The main causes of PA, whether or not accompanied by secondary sexual characteristics, include endocrine defects of the hypothalamus–pituitary–ovarian axis, genetic defects of the ovary, metabolic diseases, autoimmune diseases, infections, iatrogenic causes (radiotherapy, chemotherapy), environmental factors and Müllerian tract defects. PA management depends on the underlying causes. Estrogen replacement therapy at puberty has mainly been based on personal experience. PA can be due to endocrine, genetic, metabolic, anatomical and environmental disorders that may have severe implications on reproductive health later in life. In some complex cases, a multidisciplinary team best manages the adolescent, including a pediatrician endocrinologist, gynecologist, geneticist, surgeon, radiologist, and psychologist. Full article