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Plain language summary: Expanded carrier screening (ECS) is a genetic screening test carried out by analysing a blood sample. This screen can be used to detect whether the individual unknowingly carries gene variants associated with common genetic conditions, such as cystic fibrosis, that may be passed on to their children. It is typically performed in reproductive medicine for those who are considering having a family either naturally or via fertility treatment. Many donor sperm and egg banks, particularly in the USA and Europe, also perform blanket ECS testing on all their prospective sperm and egg donors. ECS is not currently routine practice in the UK, but a growing number of patients are requesting it before treatment. All of us carry gene variants of some sort that may cause autosomal recessive disease in their children if their partner or donor also carry a variant in the same gene. An autosomal recessive disease means two copies of an abnormal gene must be present in order for the disease or trait (such as cystic fibrosis or sickle cell disease) to develop. One copy of the variant means the person is a carrier but does not have the condition. Two copies, i.e. from the mother and father, means the child has a 25% chance of having the genetic disease. Carrying a gene variant does not mean that the individual would necessarily have any symptoms of the disease or any features of the condition. Genetic tests for specific conditions are currently available either before or during pregnancy for prospective parents who have a family or personal history of a genetic condition, or for those from ethnic backgrounds where certain conditions – such as haemoglobinopathies (blood disorders) – are common, prompting referral to a clinical genetics department. Expanded carrier screens may test for more than 100 genetic conditions. The list of conditions screened for is called a panel. Common panels are 250 or 600 genes. Not all expanded carrier screens that are available analyse the same genes. Some may test for genes that do not cause serious disease, or cause diseases that occur in later life; others test for genes that cause severe conditions in childhood. There is no agreement as to which panel of genes should be tested for in an ECS. Understanding the screening that is being offered, and the meaning of any results, is complicated and requires support from appropriately trained professionals to best inform the prospective parent or parents. [ABSTRACT FROM AUTHOR]

Genetic testing, including whole genome, whole exome, and other next‐generation sequencing technologies, has evolved vastly in the past decade. With this, the number of identified genes and genetic variants is constantly increasing. Although a variety of databases and online tools exist that summarize, categorize, and classify genes, a clear guideline of which information is needed when reporting a gene and what to do when identifying a new gene is lacking. This includes the correct nomenclature, descriptive information about genetic loci and genetic variation, aliases, and correlated phenotypes. This tutorial is meant to serve as an introduction to reporting genes in a paper and provides an overview of available databases and tools to obtain all necessary information on the genes of interest. [ABSTRACT FROM AUTHOR]

Paragangliomas are rare tumors originating from the paraventricular bodies of the autonomic nervous system located in the adrenal glands, chest, abdomen, pelvis and head and neck. Tumors of this type account for 0.5% of head and neck cancers, 0.03% of all cancers and their incidence is estimated at 1–30/100,000 per year. Head and Neck Paragangliomas (HNPGL) are localized in carotid body, tympanic cavity or jugular foramen. It is established that HNPGL may be associated with mutations of the SDH complex, with SDHD being the most prevalent. However, SDHB, SDHC and SDHAF are also potential causes. The aforementioned mutations are influenced by various risk factors, including young age, a positive family history of paraganglioma, the presence of metastases and gender The purpose of this study is to summarize the results of genetic testing performed on patients with head and neck paraganglioma and to create an up-to-date genetic diagnosis algorithm for patients with HNPGL based on previous studies published in the literature that can be used in daily practice. Several papers observed that among SDHD mutation carriers, most or all of those studied had HNPGL, and SDHB mutations were more frequently found in the presence of metastasis. Based on the results, it was concluded that there is no basis for genetic testing for VHL in patients without a positive family history. In each algorithm proposed by different authors, proposals for rational genetic diagnosis were analyzed based on the studies cited by the author and the analyses included in our paper. For the analysis of the treatment algorithms, the following were included: Martin, Mannelli, Neumann, Gupta. Subsequently, publications related to the genetic diagnosis of HNPGL were analyzed to verify the proposed algorithms in light of the latest genetic studies and to establish an updated diagnostic management scheme. [ABSTRACT FROM AUTHOR]

Background: Sequencing-based genetic testing is widely used in biomedical research, including pathogenic microorganism detection with metagenomic next-generation sequencing (mNGS). The application of sequencing results to clinical diagnosis and treatment relies on various interpretation knowledge bases. Currently, the existing knowledge bases are primarily built through manual knowledge extraction. This method requires professionals to read extensive literature and extract relevant knowledge from it, which is time-consuming and costly. Furthermore, manual extraction unavoidably introduces subjective biases. In this study, we aimed to automatically extract knowledge for interpreting mNGS results. Method: We propose a novel approach to automatically extract pathogenic microorganism knowledge based on the question-answer (QA) model. First, we construct a MicrobeDB dataset since there is no available pathogenic microorganism QA dataset for training the model. The created dataset contains 3,161 samples from 618 published papers covering 224 pathogenic microorganisms. Then, we fine-tune the selected baseline model based on MicrobeDB. Finally, we utilize ChatGPT to enhance the diversity of training data, and employ data expansion to increase training data volume. Results: Our method achieves an Exact Match (EM) and F1 score of 88.39% and 93.18%, respectively, on the MicrobeDB test set. We also conduct ablation studies on the proposed data augmentation method. In addition, we perform comparative experiments with the ChatPDF tool based on the ChatGPT API to demonstrate the effectiveness of the proposed method. Conclusions: Our method is effective and valuable for extracting pathogenic microorganism knowledge. [ABSTRACT FROM AUTHOR]

Background: Although, there is a wealth of information in the medical literature on the usefulness of genomic testing in assessing risk and its application in medical oncology decision making, there are no theoretical reflections in the nursing field. Aim: To understand the implications of molecular biology in nursing practice and highlight the role of Nursing Theory in guiding nurses' reasoning. Materials and Methods: Searching literature published between 2000 and 2022 in Medline and Google Scholar. Scientific evidence was analysed by the authors expert in different fields. Results: Based on the findings of the literature, concerns have been raised about the proper care of cancer patients who have a genomic risk profile determination. In particular, the absence of theoretical thinking and conceptual models that consider developments in molecular biology and their impact on nursing, in addition to the prevalence of heuristic thinking and the application of clinical patterns in nursing practice, could induce patient misjudgement with inadequate planning of preventive, curative, rehabilitative and educational nursing interventions. Nurses working in the field of oncology should be aware that the risk profile determined by genomics tests is merely the visible and stated portion of the cancer patient: the tip of iceberg. Discussion: This study demonstrates how genomic testing takes into account a fraction of genes discovered in tumour tissue to establish a risk profile. This subset differs, for example, from the social genome, which can determine the risk of dementia, cancer and cardiovascular disease, but in response to social adversity. Nursing theory, which views the environment as a metaparadigm, must consider a conceptual model that can integrate the findings of genomic testing with recommendations from studies on the social genome of humans to make it easier to build nursing treatments that can better reduce these risks. Conclusion: A nursing theoretical discourse on genomics is a paramount requirement for developing effective nursing care. [ABSTRACT FROM AUTHOR]

If I decide to disclose information about myself, this act may undermine other people's ability to conceal information about them. Such dependencies are called privacy dependencies in the literature. Some say that privacy dependencies generate moral duties to avoid sharing information about oneself. If true, we argue, then it is sometimes justified for others to impose harm on the person sharing information to prevent them from doing so. In this paper, we first show how such conclusions arise. Next, we show that the existence of such a dependency between the moral significance you are inclined to attribute to privacy dependencies and judgments about permissible self-defense puts pressure on at least some ways of spelling out the idea that privacy dependencies ought to constrain our data-sharing conduct. [ABSTRACT FROM AUTHOR]

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BACKGROUND The genetic composition of embryos generated by in vitro fertilization (IVF) can be examined with preimplantation genetic testing (PGT). Until recently, PGT was limited to detecting single-gene, high-risk pathogenic variants, large structural variants, and aneuploidy. Recent advances have made genome-wide genotyping of IVF embryos feasible and affordable, raising the possibility of screening embryos for their risk of polygenic diseases such as breast cancer, hypertension, diabetes, or schizophrenia. Despite a heated debate around this new technology, called polygenic embryo screening (PES; also PGT-P), it is already available to IVF patients in some countries. Several articles have studied epidemiological, clinical, and ethical perspectives on PES; however, a comprehensive, principled review of this emerging field is missing. OBJECTIVE AND RATIONALE This review has four main goals. First, given the interdisciplinary nature of PES studies, we aim to provide a self-contained educational background about PES to reproductive specialists interested in the subject. Second, we provide a comprehensive and critical review of arguments for and against the introduction of PES, crystallizing and prioritizing the key issues. We also cover the attitudes of IVF patients, clinicians, and the public towards PES. Third, we distinguish between possible future groups of PES patients, highlighting the benefits and harms pertaining to each group. Finally, our review, which is supported by ESHRE, is intended to aid healthcare professionals and policymakers in decision-making regarding whether to introduce PES in the clinic, and if so, how, and to whom. SEARCH METHODS We searched for PubMed-indexed articles published between 1/1/2003 and 1/3/2024 using the terms 'polygenic embryo screening', 'polygenic preimplantation', and 'PGT-P'. We limited the review to primary research papers in English whose main focus was PES for medical conditions. We also included papers that did not appear in the search but were deemed relevant. OUTCOMES The main theoretical benefit of PES is a reduction in lifetime polygenic disease risk for children born after screening. The magnitude of the risk reduction has been predicted based on statistical modelling, simulations, and sibling pair analyses. Results based on all methods suggest that under the best-case scenario, large relative risk reductions are possible for one or more diseases. However, as these models abstract several practical limitations, the realized benefits may be smaller, particularly due to a limited number of embryos and unclear future accuracy of the risk estimates. PES may negatively impact patients and their future children, as well as society. The main personal harms are an unindicated IVF treatment, a possible reduction in IVF success rates, and patient confusion, incomplete counselling, and choice overload. The main possible societal harms include discarded embryos, an increasing demand for 'designer babies', overemphasis of the genetic determinants of disease, unequal access, and lower utility in people of non-European ancestries. Benefits and harms will vary across the main potential patient groups, comprising patients already requiring IVF, fertile people with a history of a severe polygenic disease, and fertile healthy people. In the United States, the attitudes of IVF patients and the public towards PES seem positive, while healthcare professionals are cautious, sceptical about clinical utility, and concerned about patient counselling. WIDER IMPLICATIONS The theoretical potential of PES to reduce risk across multiple polygenic diseases requires further research into its benefits and harms. Given the large number of practical limitations and possible harms, particularly unnecessary IVF treatments and discarded viable embryos, PES should be offered only within a research context before further clarity is achieved regarding its balance of benefits and harms. The gap in attitudes between healthcare professionals and the public needs to be narrowed by expanding public and patient education and providing resources for informative and unbiased genetic counselling. [ABSTRACT FROM AUTHOR]

Pregnancy planning and genetic testing (PPGT) has emerged as a tool in reproductive healthcare, offering parents-to-be insight in their risks of having a child with a genetic disorder. This paper reviews the advantages, drawbacks and challenges associated with PPGT, providing some practical guidance for health care professionals. Advantages include identification of genetic risks, a possibility to informed reproductive decision-making, and the potential to reduce the parents-to-be risk for an affected child. Challenges and drawbacks include provision of service, ethical considerations, genetic counselling complexities, and the need to increase public and professional awareness by comprehensive education and accessibility. Practical guidance involves considerations for selecting appropriate candidates, counselling strategies, and how to integrate PPGT into existing healthcare frameworks. By addressing these factors, PPGT can offer an increased reproductive informed choice for the individual and the couple reducing the burden of disease in the family. [ABSTRACT FROM AUTHOR]

The article "The people behind the papers -- Juan Moriano and Cedric Boeckx" discusses the molecular mechanisms underlying the evolution of the human cortex, focusing on genetic changes that may have played a role in human brain evolution. The authors, Juan Moriano and Cedric Boeckx, identified a zinc-finger transcription factor, KLF6, as a regulator of a cholesterol biosynthesis program in outer radial glia cells, shedding light on the recent evolution of the human brain. The research aligns well with previous work in Development, and the authors plan to validate their findings through functional experiments using brain organoids. [Extracted from the article]

Background: Mutations in PDE6A and PDE6B are known to cause autosomal recessive RP in humans, On the other hand, mutations in PDE6G are rare but can lead to severe early-onset RP. Case presentation: An 8-year-old Chinese boy was referred to our hospital for poor vision issues. Refraction with cycloplegia showed high hyperopia with astigmatism both eyes. Funduscopic examination revealed typical bone spicule-type pigment deposits in the periphery and midperiphery. The patient was given glasses and a whole exome sequencing containing mitochondrial genes was performed. The results of genetic testing showed that there was a heterozygous frameshift mutation and a segment deletion in the proband's PDE6G gene. Analysis of the parental genes showed that frameshift mutation was inherited from the proband's mother and segment deletion from his father. Conclusions: In this paper, we give a firsthand report that the complex heterozygous mutations of PDE6G gene can causes autosomal recessiveRP (arRP), which expands the understanding of the pathogenic genes of RP. [ABSTRACT FROM AUTHOR]

Bones and teeth represent a common finding in ancient DNA studies and in forensic casework, even after a long burial. Genetic typing is the gold standard for the personal identification of skeletal remains, but there are two main factors involved in the successful DNA typing of such samples: (1) the set-up of an efficient DNA extraction method; (2) the identification of the most suitable skeletal element for the downstream genetic analyses. In this paper, a protocol based on the processing of 0.5 g of bone powder decalcified using Na2EDTA proved to be suitable for a semi-automated DNA extraction workflow using the Maxwell® FSC DNA IQ™ Casework Kit (Promega, Madison, WI, USA). The performance of this method in terms of DNA recovery and quality was compared with a full demineralisation extraction protocol based on Qiagen technology and kits. No statistically significant differences were scored according to the DNA recovery and DNA degradation index (p-values ≥ 0.176; r ≥ 0.907). This new DNA extraction protocol was applied to 88 bone samples (41 femurs, 19 petrous bones, 12 metacarpals and 16 molars) allegedly belonging to 27 World War II Italian soldiers found in a mass grave on the isle of Cres (Croatia). The results of the qPCR performed by the Quantifiler Human DNA Quantification kit showed values above the lowest Limit of Quantification (lLOQ; 23 pg/µL) for all petrous bones, whereas other bone types showed, in most cases, lower amounts of DNA. Replicate STR-CE analyses showed successful typing (that is, >12 markers) in all tests on the petrous bones, followed by the metacarpals (83.3%), femurs (52.2%) and teeth (20.0%). Full profiles (22/22 autosomal markers) were achieved mainly in the petrous bones (84.2%), followed by the metacarpals (41.7%). Stochastic amplification artefacts such as drop-outs or drop-ins occurred with a frequency of 1.9% in the petrous bones, whereas they were higher when the DNA recovered from other bone elements was amplified (up to 13.9% in the femurs). Overall, the results of this study confirm that petrous bone outperforms other bone elements in terms of the quantity and quality of the recovered DNA; for this reason, if available, it should always be preferred for genetic testing. In addition, our results highlight the need for accurate planning of the DVI operation, which should be carried out by a multi-disciplinary team, and the tricky issue of identifying other suitable skeletal elements for genetic testing. Overall, the results presented in this paper support the need to adopt preanalytical strategies positively related to the successful genetic testing of aged skeletal remains in order to reduce costs and the time of analysis. [ABSTRACT FROM AUTHOR]

Intraglandular dissemination is an important pathological feature of thyroid cancer, yet the biological characteristics of this phenomenon remain relatively underexplored. This paper aims to provide a comprehensive overview of its biological behaviors, protein expressions, and identification methods. Several retrospective studies have found that thyroid cancers with intraglandular dissemination have higher rates of lymph node metastasis, capsule invasion, and vascular invasion, exhibiting more aggressive biological behavior. Immunohistochemistry results show abnormal expression of proteins such as FKBP5, CENPF, CX26, KIF11, PTK7, which are associated with poor prognosis in thyroid cancers with intraglandular dissemination, offering potential guidance for specific targeted therapy in the future. Moreover, adjunctive techniques including ultrasound, fine-needle aspiration, and genetic testing offer valuable support in accurately identifying these cases, facilitating moreproactive treatment and closer follow-up. [ABSTRACT FROM AUTHOR]

Hereditary breast/ovarian cancer (HBOC) syndrome is caused by the inheritance of monoallelic germline BRCA1/2 gene mutations. If BRCA1/2 mutation carriers are identified before the disease develops, effective actions against HBOC can be taken, including intensive screening, risk-reducing mastectomy and salpingo-oophorectomy, and risk-reducing medications. The Italian National Prevention Plan mandates the creation of regional BRCA genetic testing programmes. So far, however, only informal data have been reported on their implementation. We have designed a study aimed at evaluating the results of a population-based programme for risk assessment and genetic counselling and testing for BRCA1/2-related HBOC that is underway in the Emilia-Romagna region (northern Italy). The programme—which is entirely free—includes basic screening with an estimate of the likelihood of carrying a BRCA1/2 mutation using a familial risk assessment tool, a closer examination of women with suspected risk increase, an assessment of the need for further genetic counselling and, if needed, genetic testing and risk-reducing interventions. In this paper, the design of the programme and the protocol of the study are presented. The study has an observational, historical cohort design. Eligible are the women found to be at an increased risk of HBOC (profile 3 women). The main objectives are (i) to determine the precision of the programme in measuring the level of risk of HBOC for profile 3 women; (ii) to determine the characteristics of profile 3 women and their association with the risk management strategy chosen; (iii) to compare the age at onset, histologic type, tumour stage, molecular subtype, and prognosis of breast/ovarian cancers observed in the cohort of profile 3 women with the features of sporadic cancers observed in the general female population; (iv) to determine the level and the determinants of adherence to recommendations; and (v) to determine the appropriateness and timing of risk-reducing surgery and medications. Investigating the quality and results of the programme is necessary because the best practices in risk assessment and genetic counselling and testing for BRCA1/2-related cancer and the challenges they encounter should be identified and shared. The study has the potential to provide sound empirical evidence for the factors affecting the effectiveness of this type of service. [ABSTRACT FROM AUTHOR]

Science should provide students an accurate and contemporary education on genetic influence, particularly how it impacts trait variability and developmental norms. Stories involving familial, racial, and sexual differences routinely appear in the popular media and sales of over‐the‐counter genetic tests are mounting. Unfortunately, research suggests genetic curricula in secondary education and university courses have little impact on genetic literacy; instead they appear to amplify genetic essentialism. This position paper reports on genetic essentialism, the impact of three components of science education (teachers, students, curriculum), and critiques existing genetic lessons in two prevalent scientific disciplines, biology and psychology. Two entrenched 19th century genetic paradigms (e.g., Mendelian inheritance and behavioral genetics) are specifically examined. The paper closes with specific recommendations for improving students' genetic literacy including important contemporary genetic science (e.g., epigenetics) and instructional approaches (e.g., learning progression, refutational teaching). [ABSTRACT FROM AUTHOR]

Background and aim: Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal dominant syndrome characterized by fundic gland polyps (FGP) as well as an increased risk of gastric cancer. The syndrome has been recognized as a clinical entity for less than a decade. A clinical suspicion may be complex and can vary from incidental findings of FGPs at gastroscopy to obstructive symptoms with dyspepsia and vomiting. The diagnosis is established by genetic detection of a pathogenic variant in the promotor 1B region of the APC gene. As of yet there are no established clinical criteria for the diagnosis. To increase knowledge of the condition and to discuss possible genetic testing and surveillance strategies, we performed a systematic review of all reported patients with GAPPS. Methods: This review was organized according to PRISMA guidelines. The search, which was conducted on September 7th, 2023, was applied to MEDLINE and restricted to only humans and papers in the English language. Only the studies on patients/families with GAPPS verified by identification of a pathogenic variant in the APC promoter 1B were included. Results: Twelve publications with a total of 113 patients were identified. In all instances the diagnosis was genetically verified with reports of four different variants within the APC promotor 1B region. Eighty-eight patients (90.1%) had gastric polyps, of these seven patients had low-grade dysplasia and five patients had both low- and high-grade dysplasia. Thirty-seven patients (45.7%) underwent gastrectomy. There were no reports of duodenal polyps (0%). Gastric cancer was found in 31 patients (30.1%) with a median age of 48 years (range 19–75). Twenty-six patients died (23.2%) of which 19 had developed gastric cancer (73.1%). One patient was diagnosed with metastatic colorectal cancer (2.2%) and died at 73 years of age. Nineteen patients had colorectal manifestations with < 20 polyps (41.3%). Conclusion: Patients with a pathogenic variant in the APC promoter 1B region have an increased risk of gastric polyposis and early-onset gastric cancer. However, there is considerable variation in clinical expression and penetrance, which makes decisions on surveillance and the timing of prophylactic gastrectomy challenging. [ABSTRACT FROM AUTHOR]

Cancer genomic services (CGS) can support genetic risk‐stratified cancer prevention and treatment. Racial/ethnic minority groups are less likely to access and utilize CGS compared with non‐Hispanic Whites. Little research has described characteristics of interventions targeted at CGS among Latinos. This scoping review aimed to (1) describe interventions promoting uptake of CGS among Latinos in the United States and Latin America, (2) describe intervention adaptations for Latino participants, and (3) summarize intervention implementation factors suggested by reach, effectiveness, adoption, implementation, and maintenance (RE‐AIM) framework. We conducted a search in English and Spanish of literature published between 2005 and 2022 across PubMed and Latin American and Caribbean Health Sciences Literature databases. Sixteen of 2344 papers met the inclusion criteria of the analysis. Efforts to promote CGS among Latino communities were limited in the US and lower in Latin America. This review highlights the need for in‐depth exploration of acculturation‐informed interventions and better reporting on implementation factors to enhance their scalability across diverse settings. [ABSTRACT FROM AUTHOR]

Aim: This paper determines the polymorphism distribution of the VDR BsmI gene in 350 patients and provides medication recommendations for osteoporosis based on detection results. Materials & methods: Chi-square tests compared genotype and allele frequencies with other populations. Results: Genotype frequencies were 91.66 bb, 8.72 Bb and 0.21% BB, with allelic frequencies of 95.43 b and 4.57% B, adhering to Hardy–Weinberg equilibrium. These findings suggest that VDR gene polymorphisms, particularly at the BsmIlocus, play an essential role in bone health and osteoporosis treatment. Genotype-based drug selection reduced adverse reactions from 14 to two cases. Conclusion: These findings improve clinical treatment efficacy and guide rational drug use for osteoporosis patients. Article highlights Objective To determine the polymorphism distribution of the vitamin D receptor (VDR) BsmI locus gene in osteoporosis patients and provide medication recommendations. Methods Genetic testing of 350 patients for VDR BsmI gene polymorphisms, comparison of genotype and allele frequencies, and assessment of the impact on drug selection. Significance Understanding the role of VDR gene polymorphisms in bone health and treatment response, and the potential for genotype-based drug selection. Results Genotype distribution: The study identified three genotypes at the BsmI locus: bb (91.66%), Bb (8.72%) and BB (0.21%), with allele frequencies of 95.43% for b and 4.57% for B. This distribution aligns with the Hardy–Weinberg equilibrium, indicating a representative sample. Comparison with other populations: The VDR gene allele frequencies in the Guangdong Han population significantly differ from those in South Asia, America, Europe and Africa but are similar to other East Asian populations. Impact on bone mineral density: There was no significant difference in bone mineral density T-scores before and after treatment across the different VDR genotypes, but patients with the b allele showed better responses to osteoporosis treatments, particularly with bisphosphonates. Adverse drug reactions (ADRs): before genetic testing, there were 14 ADRs, which reduced to only two cases post implementation, indicating improved treatment outcomes and reduced side effects through genotype-based drug selection. Conclusions The study supports the importance of genetic testing in guiding osteoporosis treatment as VDR gene polymorphisms, particularly at the BsmI locus, significantly influence treatment efficacy and the occurrence of ADRs. Genotype-based drug selection can improve clinical outcomes and minimize side effects. The findings suggest the need for further research on the distribution and impact of VDR BsmI locus polymorphism in different Chinese populations. Large-scale, multicenter studies are recommended to validate these results and enhance the precision of genotype-based drug recommendations. Integrating pharmacogenomics into clinical practice promises to improve the effectiveness of osteoporosis treatments, minimize adverse reactions, and advance personalized medicine, ultimately enhancing patient outcomes and quality of life. [ABSTRACT FROM AUTHOR]

Objective: Few studies have been conducted on the association between gut microbes and gastric ulcers. This paper aims to investigate the causal relationship between gut flora and gastric ulcer development using a two-sample Mendelian randomization method. Methods: Relevant single nucleotide polymorphisms were screened as instrumental genetic variables (SNPs) from the genetic variation database of the gut microbiota (MiBioGen), and the weighted median estimator of random effects (WME), inverse variance weighting (IVW) and MR-Egger regression three Mendelian randomization methods were used to study the causal association between gut microbes and gastric ulcer development. Results and Discussion: Family Lachnospiraceae, genus Eubacterium ventriosum group, genus Olsenella were risk factors for gastric ulcer, while genus Butyrivibrio, genus Odoribacter, genus Sutterella had a suggestive protective effect on gastric ulcer, but the mechanism of intestinal flora and gastric ulcer needs to be further verified, but this study still provides some theoretical basis for future studies between gastric ulcer and intestinal flora. Conclusions: In this study, a potentially positive and negative causal relationship between intestinal flora and the gastric ulcer was derived by a two-sample Mendelian analysis, from which it was known that the family Lachnospiraceae, genus Eubacterium ventricose group, genus Olsenella are risk factors for gastric ulcer. In contrast, the genus Butyrivibrio, genus Odoribacter, and genus Sutterella had suggestive protective effects against gastric ulcers. [ABSTRACT FROM AUTHOR]

This manuscript discusses the critical need for advancing genetic testing capabilities for neurological disorders (NDs) in Tanzania, emphasizing the importance, challenges, and strategies for implementation. Neurological disorders, often caused by a complex interplay of genetic and environmental factors, disproportionately affect low and middle-income countries like Tanzania. Patients with neurogenetic diagnoses in Tanzania face substantial obstacles, including lack of trust in medical professionals, stigmatization, and limited access to proper care. The manuscript underscores the infancy of genetic testing implementation for NDs in Tanzania, citing challenges such as high costs, limited availability, and the absence of routine testing in diagnostic procedures. The paper recommends establishing well-characterized cohorts, conducting a nationwide emergency census survey, and enhancing diagnostic services and healthcare financing. The paper stresses on the importance of collaboration, research, public awareness, and advocacy to address the challenges posed by NDs in Tanzania. The manuscript proposes a comprehensive plan, including training and capacity building in molecular diagnosis and bioinformatics, to establish genetic testing capabilities and reduce the burden of NDs in the country. Overall, the manuscript calls for a collaborative effort involving government support, stakeholder engagement, and international partnerships to advance genetic testing and improve healthcare outcomes for individuals with neurological disorders in Tanzania. [ABSTRACT FROM AUTHOR]

Simple Summary: Neurofibromatosis Type 1 is an inherited tumour predisposition syndrome with a varied clinical phenotype. Long-term monitoring through imaging is inconsistent and varies in high- and low-income countries. Implementation of a clinical practice guideline through a multidisciplinary clinic is instrumental to the care of adult Neurofibromatosis Type 1 patients. This systematic review aims to evaluate the association between a country's socioeconomic status and diagnostic modalities and strategies used for adult Neurofibromatosis Type 1 patients. Our results show multiple imaging modalities are used in high-income countries; however, there is limited use in low-income countries. The two most common diagnostic modalities used in developed countries are WB MRI and FDG PET/CT. Background: Neurofibromatosis Type 1 is an autosomal dominant tumour-predisposition condition commonly diagnosed in childhood and fully penetrant by adulthood. Long-term monitoring through imaging is inconsistent and varies between high- and low-income countries. Implementation of a clinical practice guideline through a multidisciplinary clinic is instrumental to the care of adult Neurofibromatosis Type 1 patients. We aim to systematically review international diagnostic modalities and strategies to evaluate any association between a country's socioeconomic status and diagnostic modalities or strategies used for Neurofibromatosis Type 1 patients. Methods: We searched PubMed, Embase, Web of Science, and Cochrane. Relevant clinical information on the surveillance of adult Neurofibromatosis Type 1 patients worldwide was reviewed, extracted, and synthesised. Results: We identified 51 papers reporting on 7724 individuals. Multiple imaging modalities are actively employed in high-income and upper-middle-income countries for surveying adult Neurofibromatosis Type 1 patients. We did not find any relevant papers from low- and middle-income countries. Conclusions: This systematic review suggests that there is robust data on diagnostic modalities for adult Neurofibromatosis Type 1 patients in high-income countries, but not for low- and middle-income countries. There is a lack of data on consolidated diagnostic strategies from both high- and low-income countries. Efforts should be made to publish data on usual clinical practice in low- and middle-income countries to develop clinical practice guidelines describing best medical practice to fit a local context. [ABSTRACT FROM AUTHOR]

Alexander disease (ALXDRD) is a rare neurodegenerative disorder of astrocytes resulting from pathogenic variants in the GFAP gene. The genotype-phenotype correlation remains elusive due to the variable expressivity of clinical manifestations. In an attempt to clarify the effects of GFAP variants in ALXDRD, numerous studies were collected and analyzed. In particular, we systematically searched for GFAP variants associated with ALXDRD and collected information on the location within the gene and protein, prediction of deleteriousness/pathogenicity, occurrence, sex and country of origin of patients, DNA source, genetic testing, and clinical signs. To identify possible associations, statistical analyses and meta-analyses were applied, thus revealing a higher than expected percentage of adult patients with ALXDRD. Furthermore, substitution of Arginine, the most frequently altered residue among the 550 predominantly missense causative GFAP variants collected, were mostly de novo and more prevalent in early-onset forms of ALXDRD. The effect of defective splicing in modifying the impact of GFAP variants on the age of onset of ALXDRD was also postulated after evaluating the distribution of the corresponding deleterious predictive values. In conclusion, not only previously unrecognized genotype-phenotype correlations were revealed in ALXDRD, but also subtle mechanisms could explain the variable manifestations of the ALXDRD clinical phenotype. [ABSTRACT FROM AUTHOR]

This study was designed to screen 6 lysosomal storage diseases (LSDs) in neonates using tandem mass spectrometry (MS/MS), and establish cutoff values for these LSDs with 3000 dried blood spots (DBS) samples. Cutoff values for α-L-iduronidase (IDUA), α-galactosidase (GLA), acid beta glucosidase (ABG), β-galactocerebrosidase (GALC), acid sphingomyelinase (ASM), and acid alpha glucosidase (GAA) were as follows: GLA, > 2.06 μmol/L·h; ABG, > 1.78 μmol/L·h; ASM, > 0.99 μmol/L·h; IDUA, > 1.33 μmol/L·h; GALC, > 0.84 μmol/L·h; and GAA, > 2.06 μmol/L·h. There were 30 positives in initial MS/MS screening test, and 15 samples were still positive with repeat testing. Their parents/guardians were recontacted and DBS samples were collected again for test. Only 1 child showed abnormal GAA enzyme activity after recontacting process, and was diagnosed with Pompe disease after genetic screening. Eventually, cutoff values of 6 specific enzyme activities were established and MS/MS is effective for early LSDs screening. [ABSTRACT FROM AUTHOR]

The field of genetic testing has experienced significant growth in medical practice since 1956, when the first genetic analysis was introduced. Persistent proteinuria has long been considered a strong risk factor for the progression of chronic renal failure, though, paradoxically, it can also be a benign process, as seen in individuals with mutations in the cubilin (CUBN) protein, specifically the C-terminal. CUBN is a peripheral protein that plays a crucial role in the receptor-mediated endocytotic reabsorption of albumin in the proximal tubule. In the past, there have been misinterpretations of CUBN variants with isolated proteinuria as glomerular injury, leading to unnecessary kidney biopsies and ineffective treatments. This paper discusses two siblings with a homozygous variant of (p.Tyr3018Ser) in the C-terminal of the CUBN protein, inherited from both heterozygous carrier parents. This case presents an opportunity to question our typical approach to proteinuria in an effort to avoid unnecessary kidney biopsies and the subsequent side effects of treatments, particularly for those with proteinuria. [ABSTRACT FROM AUTHOR]

Background: Hidradenitis suppurativa (HS) is a complex, chronic inflammatory skin disorder whose pathophysiology is poorly understood. Genetic studies have shown that HS is predisposed by mutations in the γ-secretase gene, but only a proportion of familial and partial sporadic cases have been shown to possess such mutations. HS has high genetic heterogeneity and is thought to be triggered by a combination of genetics and environmental factors. Aims: The study aimed to investigate the genetic causes of HS in a large cohort of patients and to update the mutation spectrum of γ-secretase complex genes. Methods: We conducted mutational screening of 95 sporadic HS cases and one large family with both HS and acne conglobata (AC) to identify mutations in the coding and splice junction region of γ-secretase complex genes (nicastrin (NCSTN), presenilin 1 (PSEN1), presenilin enhancer 2 (PSENEN), and aph-1 homolog B, gamma-secretase subunit (APH1B)). Results: Our study identified a nucleotide substitution of 1876C>T in the NCSTN gene, which caused a stop codon (p. Arg626X) in the affected members of a large family with HS and AC. No pathogenic variants were detected in 95 sporadic cases of HS, indicating there is possible genetic heterogeneity. Conclusion: We report a new family with a nonsense mutation in the NCSTN gene that supports the role of the γ-secretase complex genes in HS with AC. The updated γ-secretase mutation spectrum for HS now includes 78 mutations. [ABSTRACT FROM AUTHOR]

This document is an editorial titled "Novel applications of ONT technologies in genomics and transcriptomics" published in the journal Frontiers in Genetics. The editorial discusses the rapid development of Oxford Nanopore sequencing technology and its advantages in genomics and transcriptomics research. It highlights the ability of ONT to sequence long reads and detect epigenetic modifications, as well as the challenges in analyzing ONT data. The editorial also provides an overview of research papers included in the Research Topic, which cover various applications of ONT in detecting structural variants, improving variant detection in clinical genetic testing, gene discovery in non-model organisms, whole genome reconstruction, and detection of modified nucleotides. The document acknowledges the progress made in ONT technology while also acknowledging the unresolved technical issues. [Extracted from the article]

Aim: The aim of this study was to investigate the contribution of chromosomal microarray analysis (CMA) and next‐generation sequencing (NGS) to genetic diagnosis in fetuses with normal karyotype who underwent invasive testing for different indications. Methods: The results of invasive genetic testing performed at a tertiary center between September 2020 and March 2022 were retrospectively analyzed. Indications for invasive tests were classified as fetal structural malformation, presence of soft markers, and high risk in screening tests. CMA results were classified as pathogenic or likely pathogenic (pCNVs), benign (bCNVs), and variants of unknown clinical significance (VOUS). Results: A total of 830 invasive tests were performed and aneuploidy was detected in 11.2% of the fetuses. CMA was performed in 465 fetuses with normal karyotype, and pCNVs were detected in 6.9%. pCNVs were detected in 8.2% of fetuses with structural malformations, 6.5% in soft markers, and 4.7% in high risk in screening tests. Pathogenic variants were detected by NGS in 33.8% of fetuses with bCNVs. Conclusions: pCNVs can be significantly detected not only in fetuses with structural malformations, but also in invasive testing with other indications. NGS significantly contributes to genetic diagnosis in fetuses with structural malformations. [ABSTRACT FROM AUTHOR]

Coffin-Siris syndrome (CSS) is a rare autosomal dominant inheritance disorder characterized by distinctive facial features, hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, hypotonia, hirsutism/hypertrichosis, sparse scalp hair and varying kind of congenital anomalies. CSS can easily be misdiagnosed as other syndromes or disorders with a similar clinical picture because of their genetic and phenotypic heterogeneity. We describde the genotype-phenotype correlation of one patient from a healthy Chinese family with a novel genotype underlying CSS, who was first diagnosed in the ophthalmology department as early-onset high myopia (eoHM). Comprehensive ophthalmic tests as well as other systemic examinations were performed on participants to confirm the phenotype. The genotype was identified using whole exome sequencing, and further verified the results among other family members by Sanger sequencing. Real-time quantitative PCR (RT-qPCR) technology was used to detect the relative mRNA expression levels of candidate genes between proband and normal family members. The pathogenicity of the identified variant was determined by The American College of Medical Genetics and Genomics (ACMG) guidelines. STRING protein-protein interactions (PPIs) network analysis was used to detect the interaction of candidate gene-related proteins with high myopia gene-related proteins. The patient had excessive eoHM, cone-rod dystrophy, coarse face, excessive hair growth on the face, sparse scalp hair, developmental delay, intellectual disability, moderate hearing loss, dental hypoplasia, patent foramen ovale, chronic non-atrophic gastritis, bilateral renal cysts, cisterna magna, and emotional outbursts with aggression. The genetic assessment revealed that the patient carries a de novo heterozygous frameshift insertion variant in the ARID1B c.3981dup (p.Glu1328ArgfsTer5), which are strongly associated with the typical clinical features of CSS patients. The test results of RT-qPCR showed that mRNA expression of the ARID1B gene in the proband was approximately 30% lower than that of the normal control in the family, suggesting that the variant had an impact on the gene function at the level of mRNA expression. The variant was pathogenic as assessed by ACMG guidelines. Analysis of protein interactions in the STRING online database revealed that the ARID1A protein interacts with the high myopia gene-related proteins FGFR3, ASXL1, ERBB3, and SOX4, whereas the ARID1A protein antagonizes the ARID1B protein. Therefore, in this paper, we are the first to report a de novo heterozygous frameshift insertion variant in the ARID1B gene causing CSS with excessive eoHM. Our study extends the genotypic and phenotypic spectrums for ARID1B-CSS and supplies evidence of significant association of eoHM with variant in ARID1B gene. As CSS has high genetic and phenotypic heterogeneity, our findings highlight the importance of molecular genetic testing and an interdisciplinary clinical diagnostic workup to avoid misdiagnosis as some disorders with similar manifestations of CSS. [ABSTRACT FROM AUTHOR]

Psychosocial consequences of false-positive results following newborn bloodspot screening have been identified as a potential risk to this highly successful public health initiative. A scoping review was undertaken in October 2023 underpinned by the Arksey and O'Malley framework. Twenty-four papers were included in the review, many of which focused on cystic fibrosis. The results indicated that impact of false-positive results is variable; some studies suggest false-positive results have the potential to result in negative sequelae including increased stress and changes in parental perceptions of their child, while others suggest these impacts are transient and, in some instances, may even lead to positive outcomes. Further evidence is needed to ensure the representation of other conditions included in newborn bloodspot screening and to support strategies to overcome potential negative sequela. [ABSTRACT FROM AUTHOR]

Copyright of Neurologie Pro Praxi is the property of SOLEN sro and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The clinical application of technological progress in the identification of DNA alterations has always led to improvements of diagnostic yields in genetic medicine. At chromosome side, from cytogenetic techniques evaluating number and gross structural defects to genomic microarrays detecting cryptic copy number variants, and at molecular level, from Sanger method studying the nucleotide sequence of single genes to the high-throughput next-generation sequencing (NGS) technologies, resolution and sensitivity progressively increased expanding considerably the range of detectable DNA anomalies and alongside of Mendelian disorders with known genetic causes. However, particular genomic regions (i.e., repetitive and GC-rich sequences) are inefficiently analyzed by standard genetic tests, still relying on laborious, time-consuming and lowsensitive approaches (i.e., southern-blot for repeat expansion or long-PCR for genes with highly homologous pseudogenes), accounting for at least part of the patients with undiagnosed genetic disorders. Third generation sequencing, generating long reads with improved mappability, is more suitable for the detection of structural alterations and defects in hardly accessible genomic regions. Although recently implemented and not yet clinically available, long read sequencing (LRS) technologies have already shown their potential in genetic medicine research that might greatly impact on diagnostic yield and reporting times, through their translation to clinical settings. The main investigated LRS application concerns the identification of structural variants and repeat expansions, probably because techniques for their detection have not evolved as rapidly as those dedicated to single nucleotide variants (SNV) identification: gold standard analyses are karyotyping and microarrays for balanced and unbalanced chromosome rearrangements, respectively, and southern blot and repeat-primed PCR for the amplification and sizing of expanded alleles, impaired by limited resolution and sensitivity that have not been significantly improved by the advent of NGS. Nevertheless, more recently, with the increased accuracy provided by the latest product releases, LRS has been tested also for SNV detection, especially in genes with highly homologous pseudogenes and for haplotype reconstruction to assess the parental origin of alleles with de novo pathogenic variants. We provide a review of relevant recent scientific papers exploring LRS potential in the diagnosis of genetic diseases and its potential future applications in routine genetic testing. [ABSTRACT FROM AUTHOR]

MIRAGE syndrome is a recently described congenital condition characterized genetically by heterozygous gain-of-function missense mutations in the growth repressor sterile alpha domain containing 9 (SAMD9) located on the arm of chromosome 7 (7q21.2). The syndrome is rare and is usually diagnosed in newborns and children with myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy, hence the acronym MIRAGE. The aims of this paper are (1) to present fetal ultrasound features in a case where MIRAGE syndrome was diagnosed prenatally and (2) to review the existing literature records on prenatal manifestations of MIRAGE syndrome. In our case, the fetus had severe early fetal growth restriction (FGR) with normal Doppler studies, atypical genitalia, oligohydramnios, and hyperechogenic bowel at the routine mid-gestation anomaly scan. Amniocentesis excluded infections and numeric or structural chromosomal abnormalities while whole exome sequencing (WES) of the fetal genetic material identified the specific mutation. Targeted testing in parents was negative, suggesting the "de novo" mutation in the fetus. We could not identify other specific case reports in the literature on the prenatal diagnosis of MIRAGE syndrome. In cases reported in the literature where the diagnosis of MIRAGE syndrome was achieved postnatally, there are mentions related to the marked FGR on prenatal ultrasound. Severe early-onset FGR with no other apparent cause seems to be a central prenatal feature in these babies, and WES should be offered, especially if there are other structural abnormalities. Prenatal diagnosis of MIRAGE syndrome is possible, allowing for reproductive choices, improved counseling of parents, and better preparation of neonatal care. [ABSTRACT FROM AUTHOR]

Background: The frequency of primary joint replacement surgery continues to increase worldwide. While largely considered biologically inert entities, an increasing body of evidence continues to validate a not insignificant incidence of allergic reactions to such implants. Little previous work has explored genuinely immune-mediated reactivity in this context. In the absence of a contemporary published summary on the topic, this paper explored the current state of understanding of cobalt/chromium allergy and proposes a patient management algorithm whereby such immune reactions are clinically suggested. Methods: A structured, systematic literature review was performed by following PRISMA search principles to provide an updated review of this area. Results: Thirty-six topic-related articles were identified, the majority reflecting lower tiers of scientific evidence with a lack of homogeneous quantitative data to facilitate valid cohort comparisons. Largely, the available literature represented small case series' or expert opinions. Conclusions: Despite increasing clinical awareness and acknowledgement of true allergy to joint replacement components, this review highlighted that the evidence base underpinning the diagnosis and management of such patients is limited. Both patient-reported metal allergy or skin patch testing are grossly unreliable methods and show almost no correlation with true immune reactivity. Recent studies suggested a potential role for patient-specific in vitro cellular activation testing and/or targeted genetic testing when cobalt/chromium allergy is clinically suspected. However, while likely representing the contemporary "best available" approaches both can be costly undertakings, are not yet universally available, and still require broader validation in non-research settings before wider uptake can be championed. [ABSTRACT FROM AUTHOR]

Problem definition: Through the laws of inheritance, knowing an individual's genetic status informs disease risk for family members, but current protocols for deciding whom to genetically test only consider one person at a time rather than design an optimal testing plan for the entire family. Methodology/results: We develop a Markov decision process framework for maximizing the net benefits of genetic testing that integrates a Bayesian network of genetic statuses, with a functional representation of cost-effectiveness. Our model provides a contingent sequence of family members to test one at a time, that is, a plan that dynamically incorporates new test results, revealed sequentially at random, to decide who next to test. In the general case, we show that optimal stopping follows a structure with two-sided thresholds, previously known only for individual testing. Although the optimal testing sequence, in general, is contingent on the family test results, in the special case of sibling-only tests we can identify this sequence a priori. Our numerical case study, which was conducted in a realistic BRCA1/2 testing setting, demonstrates that an optimal policy significantly improves cost-effectiveness over existing policies. Thus, our framework offers a promising and powerful new approach to genetic testing. Managerial implications: In an optimal policy, prioritizing testing family members who might otherwise not have been tested can lead to an overall improvement in familial health value, surpassing even the most cost-effective existing protocols. From a management perspective, healthcare organizations and insurance companies can potentially save costs by implementing this approach for such families. History: This paper has been accepted in the Manufacturing & Service Operations Management Frontiers in Operations Initiative. Funding: D. Adelman is grateful for financial support from Booth School of Business. Supplemental Material: The online appendix is available at https://doi.org/10.1287/msom.2023.0057. [ABSTRACT FROM AUTHOR]

Noninvasive prenatal testing (NIPT) has become widely available in recent years. While initially used to screen for trisomies 21, 18, and 13, the test has expanded to include a range of other conditions and will likely expand further. This paper addresses the ethical issues that arise from one particularly controversial potential use of NIPT: screening for adult‐onset conditions (AOCs). We report data from our quantitative survey of Australian NIPT users' views on the ethical issues raised by NIPT for AOCs. The survey ascertained support for NIPT for several traits and conditions including AOCs. Participants were then asked about their level of concern around implications of screening for AOCs for the future child and parent(s). Descriptive and comparative data analyses were conducted. In total, 109 respondents were included in data analysis. The majority of respondents expressed support for NIPT screening for preventable (70.9%) and nonpreventable AOCs (80.8%). Most respondents indicated concern around potential harmful impacts associated with NIPT for AOCs, including the psychological impact on the future child and on the parent(s). Despite this, the majority of participants thought that continuation of a pregnancy known to be predisposed to an AOC is ethically acceptable. The implications of these data are critically discussed and used to inform the normative claim that prospective parents should be given access to NIPT for AOCs. The study contributes to a body of research debating the ethical acceptability and regulation of various applications of NIPT as screening panels expand. [ABSTRACT FROM AUTHOR]

Objective: While the cognitive‐behavioral characteristics of amyotrophic lateral sclerosis (ALS) patients carrying C9orf72 pathological repeat expansion have been extensively studied, our understanding of those carrying SOD1 variants is mostly based on case reports. The aim of this paper is to extensively explore the cognitive‐behavioral characteristics of a cohort of ALS patients carrying pathogenetic variants of SOD1 gene, comparing them to patients without pathogenetic variants of 46 ALS‐related genes (wild‐type [WT]‐ALS) and healthy controls. Methods: All ALS patients seen at the Turin ALS expert center in the 2009–2021 period who underwent both cognitive/behavioral and extensive genetic testing were eligible to be included in the study. Only patients with SOD1 pathogenetic variants (n = 28) (SOD1‐ALS) and WT‐ALS (n = 829) were enrolled in the study. A series of 129 controls was also included. Results: Among the 28 SOD1‐ALS patients, 16 (57.1%) had normal cognitive function, 5 (17.9%) isolated cognitive impairment (ALSci) (17.9%), 6 (21.4%) isolated behavioral impairment (ALSbi), 1 (3.6%) cognitive and behavioral impairment (ALScbi), and no one ALS‐FTD. SOD1‐ALS performed worse than controls in all explored domains, in particular Social Cognition and Language domains. SOD1‐ALS patients had similar scores in all tests compared to WT‐ALS, except the Story‐based Empathy Task (SET), where they performed worse. Interpretation: Cognitive‐behavioral impairment is much more common in SOD1 patients than previously assumed. SOD1‐ALS are characterized by a more frequent impairment of Social Cognition and, less markedly, of Language domains. These findings have relevant implication both in the clinical and in the research setting, also considering recently approved treatment for SOD1‐ALS. ANN NEUROL 2024;96:150–158 [ABSTRACT FROM AUTHOR]

Objective: Sertoli–Leydig cell tumors (SLCTs) are rare neoplasms occurring in young women with 60% associated with DICER1 mutations. This is only the second published case series of patients with SLCTs with associated DICER1 gene alterations. DICER1 syndrome is a rare inherited tumor‐susceptibility syndrome affecting organs such as the ovaries. We use this case series to inform readers on this increasingly important condition in gynecology. Methods and Results: We present three young females presenting with secondary amenorrhoea, hirsutism, acne and in one case tonic–clonic seizures. All cases had high testosterone levels and an adnexal mass on ultrasound. Following surgical removal, pathology confirmed SLCTs and genetic testing followed. All three patients had DICER1 syndrome with two patients subsequently found to be related. Discussion: The prevalence of DICER1 syndrome in the population is estimated to be 1 in 10 000 with a spectrum of sex cord stromal tumors affecting young women. The associated pathological classifications and management. This paper describes the DICER1 gene and the associated tumor predisposition syndrome alongside a surveillance protocol for use in clinical practice. It promotes discussion over the importance of early clinical genetics involvement in sex‐cord stromal tumors and the associated difficulties in counseling in a young patient population. Genetic testing and early detection are imperative for targeted surveillance of at‐risk organs to be performed but despite this there is no international guidance. The cases highlight the psychological impact of tumors in young patients and provokes an ethical discussion over DICER1 gene's inclusion in preimplantation genetics. Conclusions: DICER1 syndrome is a rare but increasingly important condition in pediatric and adolescent gynecology with a paucity of published data and case reports. This makes international consensus on management and surveillance difficult. [ABSTRACT FROM AUTHOR]

Background and Aims: This study aimed to report nine Charcot–Marie–Tooth disease (CMT) families with six novel IGHMBP2 mutations in our CMT2 cohort and to summarize the genetic and clinical features of all AR‐CMT2S patients reported worldwide. Methods: General information, clinical and neurophysiological data of 275 axonal CMT families were collected. Genetic screening was performed by inherited peripheral neuropathy related genes panel or whole exome sequencing. The published papers reporting AR‐CMT2S from 2014 to 2023 were searched in Pubmed and Wanfang databases. Results: In our CMT2 cohort, we detected 17 AR‐CMT2S families carrying IGHMBP2 mutations and eight were published previously. Among these, c.743 T > A (p.Val248Glu), c.884A > G (p.Asp295Gly), c.1256C > A (p.Ser419*), c.2598_2599delGA (p.Lys868Sfs*16), c.1694_1696delATG (p.Asp565del) and c.2509A > T (p.Arg837*) were firstly reported. These patients prominently presented with early‐onset typical axonal neuropathy and without respiratory dysfunction. So far, 56 AR‐CMT2S patients and 57 different mutations coming from 43 families have been reported in the world. Twenty‐nine of 32 missense mutations were clustered in helicase domain and ATPase region. The age at onset ranged from 0.11to 20 years (Mean ± SD: 3.43 ± 3.88 years) and the majority was infantile‐onset (<2 years). The initial symptoms included weakness of limbs (19, 29.7%), delayed milestones (12, 18.8%), gait disturbance (11, 17.2%), feet deformity (8, 12.5%), feet drop (8, 12.5%), etc. Interpretation: AR‐CMT2S accounted for 6.2% in our CMT2 cohort. We firstly reported six novel IGHMBP2 mutations which expanded the genotypic spectrum of AR‐CMT2S. Furthermore, 17 AR‐CMT2S families could provide more resources for natural history study, drug research and development. [ABSTRACT FROM AUTHOR]

Background: Hereditary hypophosphatemia rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterised by reduced renal phosphate reabsorption leading to hypophosphataemia, rickets and bone pain. Here, we present a case of HHRH in a Chinese boy. Case presentation: We report a 11-year-old female proband, who was admitted to our hospital with bilateral genuvarum deformity and short stature. Computed Tomography (CT) showed kidney stones, blood tests showed hypophosphatemia, For a clear diagnosis, we employed high-throughput sequencing technology to screen for variants. Our gene sequencing approach encompassed whole exome sequencing, detection of exon and intron junction regions, and examination of a 20 bp region of adjacent introns. Flanking sequences are defined as ±50 bp upstream and downstream of the 5′ and 3′ ends of the coding region.The raw sequence data were compared to the known gene sequence data in publicly available sequence data bases using Burrows-Wheeler Aligner software (BWA, 0.7.12-r1039), and the pathogenic variant sites were annotated using Annovar. Subsequently, the suspected pathogenic variants were classified according to ACMG's gene variation classification system. Simultaneously, unreported or clinically ambiguous pathogenic variants were predicted and annotated based on population databases. Any suspected pathogenic variants identified through this analysis were then validated using Sanger sequencing technology. At last, the proband and her affected sister carried pathogenic homozygous variant in the geneSLC34A3(exon 13, c.1402C > T; p.R468W). Their parents were both heterozygous carriers of the variant. Genetic testing revealed that the patient has anLRP5(exon 18, c.3917C > T; p.A1306V) variant of Uncertain significance, which is a rare homozygous variant. Conclusion: This case report aims to raise awareness of the presenting characteristics of HHRH. The paper describes a unique case involving variants in both theSLC34A3andLRP5genes, which are inherited in an autosomal recessive manner. This combination of gene variants has not been previously reported in the literature. It is uncertain whether the presence of these two mutated genes in the same individual will result in more severe clinical symptoms. This report shows that an accurate diagnosis is critical, and with early diagnosis and correct treatment, patients will have a better prognosis. [ABSTRACT FROM AUTHOR]

Primary failure of eruption (PFE) is a rare non-syndromic condition involving total or partial non-eruption of posterior teeth in the absence of mechanical obstruction. This paper presents the case of a healthy girl referred at age 4 for asymmetry of the upper arch. Clinical examination confirmed a slight shift of the upper midline to the left, with no erupted teeth distal to the upper left canine and a left posterior open bite. Panoramic X-rays showed delayed intraosseous development of the lateral left upper teeth compared to the right side. Clinic and radiographic follow-up during the next 9 years showed that 26 had not erupted by almost 13 years of age, 27 had delayed development and an unusual shape, and there was an agenesis in 24 and 25. Genetic analysis using the PTH1R single-gene sequencing method did not detect any known disease-causing or rare pathogenic variants that could explain the patient's phenotype. Even when detected early, PFE raises difficult problems with regard to diagnosis and ortho-surgical treatment planning due to the impossibility of accurately predicting its evolution. Tooth agenesis on the same arch worsens the prognosis and adds challenges to planning the treatment. Close long-term follow-up and timely adjustment of the treatment plan in accordance with the evolution of the case are needed. [ABSTRACT FROM AUTHOR]

The genome of an individual from an admixed population consists of segments originated from different ancestral populations. Most existing ancestry inference approaches focus on calling these segments for the extant individual. In this paper, we present a general ancestry inference approach for inferring recent ancestors from an extant genome. Given the genome of an individual from a recently admixed population, our method can estimate the proportions of the genomes of the recent ancestors of this individual that originated from some ancestral populations. The key step of our method is the inference of ancestors (called founders) right after the formation of an admixed population. The inferred founders can then be used to infer the ancestry of recent ancestors of an extant individual. Our method is implemented in a computer program called PedMix2. To the best of our knowledge, there is no existing method that can practically infer ancestors beyond grandparents from an extant individual’s genome. Results on both simulated and real data show that PedMix2 performs well in ancestry inference. [ABSTRACT FROM AUTHOR]

Introduction: At least 60% of cases of severe hearing loss result from genetic factors. In this study genetic screening was carried out for common genetic deafness in women of childbearing age to prevent deafness and birth defects via providing genetic counseling and follow-up services for high-risk families. Material and methods: In total 60,391 pre-pregnancy/early-gestation women who received treatment in second-level or above hospitals in Weihai from February 2017 to December 2019 were selected. Venous or peripheral blood was collected to make dried blood slices on filter paper to extract genomic DNA, and high-throughput sequencing was applied to detect 20 variant sites in 4 common deafness genes (GJB2, GJB3, SLC26A4 and mitochondrial 12S rRNA) in the Chinese population. The spouses of women with deafness gene variants were sequenced. Results: In total 3,761 carriers with deafness gene variants were detected in 60,391 women of childbearing age, with a carrier rate of 6.2%. Among them, 1,739 women (2.88%) only carried GJB2 pathogenic variants. The carrying rate of c.235delC in GJB2 pathogenic variants was the highest at 2.08%. 1,553 women (2.58%) only carried SLC26A4 pathogenic variants. The carrying rate of c.919-2A>G in SLC26A4 pathogenic variants was the highest at 1.63%. 300 women (0.5%) only carried GJB3 variants, and 125 women (0.2%) carried the mitochondrial drug-sensitive gene variant. Conclusions: This screening model will greatly reduce the birth rate of children with hearing disabilities and is an effective way to prevent newborn deafness. In addition, genetic screening provided the related knowledge of hereditary deafness, especially strengthening genetic counseling and the clinical decision making from the genetic screening. [ABSTRACT FROM AUTHOR]

Introduction: The standard way of using tests for compatibility of genetic markers with the Hardy-Weinberg equilibrium (HWE) assumption as a means of quality control in genetic association studies (GAS) is to carry out this step of preliminary data analysis with the sample of non-diseased individuals only. We show that this strategy has no rational basis whenever the genotype-phenotype relation for a marker under consideration satisfies the assumption of codominance. Methods: The justification of this statement is obtained through rigorous analytical arguments. Results: The key result of the paper is that there holds the following proposition: under the codominance model, the genotype distribution of a diallelic marker is in HWE among the controls if and only if the same is true for the cases. Conclusion: The major practical consequence of that theoretical result is that under the codominance model, testing for HWE should be done both for cases and controls aiming to establish the combined (intersection) hypothesis of compatibility of both underlying genotype distributions with the HWE assumption. A particularly useful procedure serving this purpose is obtained through applying the confidence-interval inclusion rule derived by Wellek, Goddard, and Ziegler (Biom J. 2010; 52:253–270) to both samples separately and combining these two tests by means of the intersection-union principle. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Yüzüncü Yıl University, Faculty of Education is the property of Yuzuncu Yil University, Faculty of Education and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

With technological applications, especially in genetic testing, new diseases have been discovered and new disease concepts have been proposed in recent years; however, the pathogenesis and treatment of these rare diseases are not as well established as those of common diseases. To demonstrate the importance of rare disease research, in this paper we focus on our research topic, Perry disease (Perry syndrome). Perry disease is a rare autosomal dominant neurodegenerative disorder clinically characterized by parkinsonism, depression/apathy, weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. The pathological classification of Perry disease falls under TAR DNA-binding protein 43 (TDP-43) proteinopathies. Patients with Perry disease exhibit DCTN1 mutations, which is the causative gene for the disease; they also show relatively uniform pathological and clinical features. This review summarizes recent findings regarding Perry disease from both basic and clinical perspectives. In addition, we describe technological innovations and outline future challenges and treatment prospects. We discuss the expansion of research from rare diseases to common diseases and the importance of collaboration between clinicians and researchers. Here, we highlight the importance of researching rare diseases as it contributes to a deeper understanding of more common diseases, thereby opening up new avenues for scientific exploration. [ABSTRACT FROM AUTHOR]

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly diagnosed condition. Although wild-type transthyretin amyloidosis (ATTRwt) is the most common ATTR-CM, hereditary transthyretin amyloidosis (ATTRv) may also occur. Currently, genetic testing for transthyretin pathogenic variants is recommended for patients with a confirmed clinical diagnosis of ATTR-CM. In fact, confirmation of this autosomal dominant pathogenic variant prompts genetic counselling and allows early identification of affected relatives. Additionally, in the presence of an ATTR-CM-associated polyneuropathy, specific drugs targeting transthyretin can be used. In this paper, we review the utility of genetic testing for the detection of pathogenic variants among patients harboring ATTR-CM and its impact on the natural history of the disease. [ABSTRACT FROM AUTHOR]

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Genetic research's growing importance in understanding pulmonary arterial hypertension (PAH) and developing effective treatments prompted the RAPID‐PAH study. This study sought feedback from stakeholders who participated in two genomic studies to enhance genetic study delivery and clinical integration. Stakeholders from nine UK PH centres, representing various roles, ages, genders, and mutation statuses, took part in 53 semi‐structured interviews and focus groups. Transcripts were thematically coded using inductive analysis. Clustering analysis was conducted to identify patient groups that shared attitudes. In this paper, we focus on patients', carers', and relatives' perspectives. The key interview themes revealed insights into participants' attitudes toward genetic research and testing more generally, expertise and knowledge of the disease itself, motivations and barriers to participating in genetic research, awareness of and interest in consent procedures and the use of personal and genetic data, as well as the process of communicating individual genetic results. Factors influencing genetic research participation included altruistic motives, personal diagnostic experiences, and family‐related hopes. Clustering analysis produced distinct clusters based on the presence of barriers and motivators for research participation; however, hardly any patients shared identical sets of attitudes, emphasising the need for personalised approaches to recruitment. Most patients reported poor engagement with study‐related materials. Patients who received individual genetic results expressed satisfaction with the process, whereas those who did not were disappointed with the lack of feedback. Reflecting on patient perspectives, we offer recommendations to improve the genetic study delivery process. Enhancing genetic research integration into clinical practice requires tailored engagement, clear communication, and support from healthcare stakeholders. [ABSTRACT FROM AUTHOR]

Background: Pre‐implantation genetic testing for monogenic disorders (PGT‐M) is an effective approach to reducing the incidence of birth defects by preventing the transmission of inherited diseases to offspring. However, there are still controversies regarding the detection methods and transplantation of embryos. This paper aims to evaluate the effectiveness of different detection technologies applied to PGT‐M through a retrospective analysis of clinical detection data. Methods: The carrier status of pathogenic mutations and chromosomal copy number variants (CNVs) in 892 embryos was characterized using next‐generation sequencing (NGS), single‐nucleotide polymorphism (SNP) array, and PCR‐based detection technologies. Clinical data from PGT‐M cases were retrospectively analyzed to assess the effectiveness of these detection methods in identifying genetic abnormalities in embryos. Results: A total of 829 embryos were analyzed, with 63 being unsuccessful. Our study revealed that the success rate of detecting deletional mutations using Gap‐PCR 84.9%, which is lower than that of SNP array (98.7%) and NGS (92.5%). However, no significant difference was observed when detecting point mutations using any of the methods. These findings suggest that, when detecting deletional mutations, SNP array and NGS are more suitable choices compared to Gap‐PCR. While SNP array may have a lower resolution and success rate (80.5%) in analyzing CNVs compared to NGS (95.5%), it may still be useful for revealing certain abnormal types. Conclusion: In conclusion, this study found that SNP analysis is advantageous for identifying polygenic and deletional mutations, whereas NGS is more cost‐efficient for detecting common monogenic diseases. Additionally, SNP‐based haplotyping and PCR‐based direct detection of mutations can be used together to enhance the accuracy and success rates of PGT‐M. Our findings offer valuable insights for PGT technicians in choosing suitable detection methods for patients. [ABSTRACT FROM AUTHOR]