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Abstract Background Ectodermal dysplasia (ED) is a rare genetic disorder that affects structures derived from the ectodermal germ layer. Results In this study, we analyzed the genetic profiles of 27 Korean patients with ED. Whole exome sequencing (WES) was performed on 23 patients, and targeted panel sequencing was conducted on the remaining 4 patients. Among the patients in the cohort, 74.1% (20/27) tested positive for ED. Of these positive cases, EDA and EDAR mutations were found in 80% (16/20). Notably, 23.1% (3/13) of EDA-positive cases exhibited copy number variations. Among the 23 patients who underwent WES, we conducted a virtual panel analysis of eight well-known genes, resulting in diagnoses for 56.5% (13/23) of the cases. Additionally, further analysis of approximately 5,000 OMIM genes identified four more cases, increasing the overall positivity rate by approximately 17%. These findings underscore the potential of WES for improving the diagnostic yield of ED. Remarkably, 94.1% of the patients manifesting the complete triad of ED symptoms (hair/skin/dental) displayed detectable EDA/EDAR mutations. In contrast, none of the 7 patients without these three symptoms exhibited EDA/EDAR mutations. Conclusions When conducting molecular diagnostics for ED, opting for targeted sequencing of EDA/EDAR mutations is advisable for cases with classical symptoms, while WES is deemed an effective strategy for cases in which these symptoms are absent.

Abstract Introduction Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In this study, we sought to determine whether transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) defines subsets of individuals with A-T beyond mild and classic phenotypes, enabling identification of novel features for disease classification and treatment response to therapy. Methods Participants with classic A-T (n = 77), mild A-T (n = 13), and unaffected controls (n = 15) were recruited from two outpatient clinics. PBMCs were isolated and bulk RNAseq was performed. Plasma was also isolated in a subset of individuals. Affected individuals were designated mild or classic based on ATM mutations and clinical and laboratory features. Results People with classic A-T were more likely to be younger and IgA deficient and to have higher alpha-fetoprotein levels and lower % forced vital capacity compared to individuals with mild A-T. In classic A-T, the expression of genes required for V(D)J recombination was lower, and the expression of genes required for inflammatory activity was higher. We assigned inflammatory scores to study participants and found that inflammatory scores were highly variable among people with classic A-T and that higher scores were associated with lower ATM mRNA levels. Using a cell type deconvolution approach, we inferred that CD4 + T cells and CD8 + T cells were lower in number in people with classic A-T. Finally, we showed that individuals with classic A-T exhibit higher SERPINE1 (PAI-1) mRNA and plasma protein levels, irrespective of age, and higher FLT4 (VEGFR3) and IL6ST (GP130) plasma protein levels compared with mild A-T and controls. Conclusion Using a transcriptomic approach, we identified novel features and developed an inflammatory score to identify subsets of individuals with different inflammatory phenotypes in A-T. Findings from this study could be used to help direct treatment and to track treatment response to therapy.

Abstract Background TBL1XR1 encodes a F-box-like/WD40 repeat-containing protein that plays a role in transcription mediated by nuclear receptors and is a known genetic cause of neurodevelopmental disease of childhood (OMIM# 608628). Yet the developmental trajectory and progression of neurologic symptoms over time remains poorly understood. Methods We developed and distributed a survey to two closed Facebook groups devoted to families of patients with TBL1XR1-related disorder. The survey consisted of 14 subsections focused upon the developmental trajectories of cognitive, behavioral, motor, and other neurological abnormalities. Data were collected and managed using REDCap electronic data capture tools. Results Caregivers of 41 patients with a TBL1XR1-related disorder completed the cross-sectional survey. All reported variants affecting a single amino acid, including missense mutations and in-frame deletions, were found in the WD40 repeat regions of Tbl1xr1. These are domains considered important for protein–protein interactions that may plausibly underlie disease pathology. The majority of patients were diagnosed with a neurologic condition before they received their genetic diagnosis. Language appeared most significantly affected with only a minority of the cohort achieving more advanced milestones in this domain. Conclusion TBL1XR1-related disorder encompasses a spectrum of clinical presentations, marked by early developmental delay ranging in severity, with a subset of patients experiencing developmental regression in later childhood.

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited condition characterized by the growth of multiple bilateral cysts in the kidneys. We describe the case of a 35-year-old male with combined ADPKD and type 1 diabetes mellitus with a strong family history of both. At the age of 32, he developed end-stage kidney disease for which he underwent preemptive simultaneous pancreatic and kidney transplant, which in turn led to multiple perioperative complications. Evaluation of familial clustering of genetic disease is critical in genetic epidemiology and precision medicine as it enables estimation of lifetime disease risk and early assessment as well as detection of the disease among one’s siblings.

Introduction and Purpose: In last years gene modification technologies such as CRISPR/Cas9 has had a revolutionary impact on the treatment of inherited diseases. Technologies developed from bacterial defense mechanisms, has become a basic tools in scientific research and medical therapies. In our article we provided an overview of applications of gene modifications technologies, directly focusing on CRISPR/Cas9, in genetic disease treatment. State of Knowledge: New applications of CRISPR/Cas9 are still being explored. Treating inherited diseases such as cystic fibrosis, Duchenne muscular dystrophy, thalassemia, hemophilia, Huntington's disease, Crigler-Najjar syndrome, sickle cell anemia, Marfan syndrome, and phenylketonuria, is feasible with this novel technique. A comparative analysis with other gene editing methods highlights CRISPR/Cas9's efficacy, ease of use, and multiplexing capabilities. Summary: CRISPR/Cas9 is a groundbreaking technology with broad applications in genetic research and therapy. Its ease of use, cost-effectiveness, and ability to target multiple genes simultaneously position it as a preferred method. However, there are some challenges associated with precision issues and ethical considerations in human embryo gene editing. As CRISPR/Cas9 continues to evolve, responsible application and ethical considerations are important for maximizing its potential in treatment of genetic diseases.

Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here, we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (Lepob/ob). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake but is instead associated with alterations in the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that gut microbial CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have potential as anti-obesity therapeutics.

Objective·To summarize and analyze the clinical and genetic characteristics of adult cerebral adrenoleukodystrophy(ACALD ).Methods·The data of eight patients with ACALD who attended the Shanghai Sixth People′s Hospital, Shanghai Jiao Tong University School of Medicine from June 2018 to September 2022 were collected and comprehensively analyzed. Clinical data included age at onset, duration of disease, family history, present history and physical examination. Imaging examinations included magnetic resonance imaging (MRI) of the cranial, cervical spine and thoracic spine. Laboratory tests included serum very-long-chain fatty acids (VLCFA), adrenal cortical function and genetic test. Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (Moca) were used to assess patients′ cognitive function.Results·A total of 8 male patients with ACALD were included in this study. Ageat onset ranged from 23 to 40 years old with an average age of (32.75±5.80) years, and the disease duration ranged from 4 to 59 months. Patients′ first symptoms were highly variable. Three patients showed memory loss and cognitive dysfunction, two showed irritability and personality change, one showed mental and behavioral abnormalities, one showed dysarthria and ataxia, and one showed persistent dizziness, occipital numbness and insomnia. All the patients had multiple white matter demyelination lesions, and white matter demyelination in parietal occipital lobe and posterior corpus callosum was the most common. Enhancement MRI showed patchy Gd-enhancement of partial lesions in three cases. In two patients, magnetic resonance spectroscopy showed that choline (Cho) peak increased and N-acetyl-aspartate (NAA) peak decreased. Serum VLCFA levels of C26, C24/C22 and C26/C22 were elevated in six patients who underwent serum VLCFA examination. Seven patients underwent adrenal cortical function testing, of which six experienced adrenal cortical dysfunction. Six patients were cognitively impaired, four of whom had decreased MMSE and MoCA scores, and two of whom were unable to cooperate with the assessment due to severe cognitive impairment. Eight different ABCD1 gene mutations were identified, among which c.1750delC (p.H584Tfs*52) and c.160_170delACGCAGGAGGC (p.T54Lfs*137) were novel mutations.Conclusion·The initial symptoms of ACALD vary, among which memory loss and cognitive dysfunction are the most common. White matter demyelination lesions in the parietal and corpus callosum pressure are the most common, and imaging abnormalities precede neurological symptoms. The clinical features of the disease are hair thinning and skin pigmentation, and the biochemical features are elevated serum VLCFA and adrenal insufficiency. Missense mutations are more common in the ABCD1 gene, and exons 1 and 6 are the hot mutant exons in Chinese.

Abstract Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive lung disease caused by variants in the SLC34A2 gene encoding the sodium-dependent phosphate transport protein 2B, NaPi-2b. PAM is characterized by deposition of calcium phosphate crystals in the alveoli. Onset and clinical course vary considerably; some patients remain asymptomatic while others develop severe respiratory failure with a significant symptom burden and compromised survival. It is likely that PAM is under-reported due to lack of recognition, misdiagnosis, and mild clinical presentation. Most patients are genetically uncharacterized as the diagnostic confirmation of PAM has traditionally not included a genetic analysis. Genetic testing may in the future be the preferred tool for diagnostics instead of invasive methods. This systematic review aims to provide an overview of the growing knowledge of PAM genetics. Rare variants in SLC34A2 are found in almost all genetically tested patients. So far, 34 allelic variants have been identified in at least 68 patients. A majority of these are present in the homozygous state; however, a few are found in the compound heterozygous form. Most of the allelic variants involve only a single nucleotide. Half of the variants are either nonsense or frameshifts, resulting in premature termination of the protein or decay of the mRNA. There is currently no cure for PAM, and the only effective treatment is lung transplantation. Management is mainly symptomatic, but an improved understanding of the underlying pathophysiology will hopefully result in development of targeted treatment options. More standardized data on PAM patients, including a genetic diagnosis covering larger international populations, would support the design and implementation of clinical studies to the benefit of patients. Further genetic characterization and understanding of how the molecular changes influence disease phenotype will hopefully allow earlier diagnosis and treatment of the disease in the future.

Purpose: Rare diseases substantially contribute to population morbidity and mortality. Understanding rare disease health-related quality of life (HRQL) is essential for evaluating platform-based interventions that aim to tackle multiple rare diseases at a time. However, most HRQL studies focus on single or select group of rare diseases, often in a single country. Our study aimed to identify patient- and disease-specific correlates of HRQL across diverse rare diseases. Methods: We conducted an international online survey of rare disease patients and caregiver proxies affected by a systematically identified sample of rare diseases. We calculated EQ-5D scores and conducted multivariate linear regression to examine sociodemographic and disease predictors of EQ-5D-5L visual analog scale (VAS) and utility scores (United States only). Results: A total of 1053 individuals affected by 103 different rare diseases participated, including 660 patients and 393 caregiver proxies. Disability status and disease prevalence correlated with poorer HRQL across models (P < .05). Increased pain and decreased ability to perform usual activities also correlated with lower VAS for both adult patients and caregiver proxies (P < .05). Being unemployed approached significance as a correlate of both lower caregiver proxy VAS and lower patient utility scores. Conclusion: Our results suggest that across rare diseases, lower HRQL is associated with a reduced rare disease prevalence and disability status, among other predictors. Understanding the key correlates of HRQL is essential for developing interventions for improving health care delivery and quality of life for rare disease patients and families.

Abstract Background Prader–Willi syndrome (PWS) is a rare and complex genetic disease, with numerous implications on metabolic, endocrine, neuropsychomotor systems, and with behavioural and intellectual disorders. Rare disease patient registries are important scientific tools (1) to collect clinical and epidemiologic data, (2) to assess the clinical management including the diagnostic delay, (3) to improve patients’ care and (4) to foster research to identify new therapeutic solutions. The European Union has recommended the implementation and use of registries and databases. The main aims of this paper are to describe the process of setting up the Italian PWS register, and to illustrate our preliminary results. Materials and methods The Italian PWS registry was established in 2019 with the aims (1) to describe the natural history of the disease, (2) to determine clinical effectiveness of health care services, (3) to measure and monitor quality of care of patients. Information from six different variables are included and collected into this registry: demographics, diagnosis and genetics, patient status, therapy, quality of life and mortality. Results A total of 165 patients (50.3% female vs 49.7% male) were included into Italian PWS registry in 2019–2020 period. Average age at genetic diagnosis was 4.6 years; 45.4% of patients was less than 17 years old aged, while the 54.6% was in adult age (> 18 years old). Sixty-one percent of subjects had interstitial deletion of the proximal long arm of paternal chromosome 15, while 36.4% had uniparental maternal disomy for chromosome 15. Three patients presented an imprinting centre defect and one had a de novo translocation involving chromosome 15. A positive methylation test was demonstrated in the remaining 11 individuals but the underlying genetic defect was not identified. Compulsive food-seeking and hyperphagia was present in 63.6% of patients (prevalently in adults); 54.5% of patients developed morbid obesity. Altered glucose metabolism was present in 33.3% of patients. Central hypothyroidism was reported in 20% of patients; 94.7% of children and adolescents and 13.3% of adult patients is undergoing GH treatment. Conclusions The analyses of these six variables allowed to highlight important clinical aspects and natural history of PWS useful to inform future actions to be taken by national health care services and health professionals.

Background Genetic variants may potentially play a contributing factor in the development of diseases. Several genetic disease databases are used in medical research and diagnosis but the web applications used to search these databases for disease-associated variants have limitations. The application may not be able to search for large-scale genetic variants, the results of searches may be difficult to interpret and variants mapped from the latest reference genome (GRCH38/hg38) may not be supported. Methods In this study, we developed a novel R library called “DisVar” to identify disease-associated genetic variants in large-scale individual genomic data. This R library is compatible with variants from the latest reference genome version. DisVar uses five databases of disease-associated variants. Over 100 million variants can be simultaneously searched for specific associated diseases. Results The package was evaluated using 24 Variant Call Format (VCF) files (215,054 to 11,346,899 sites) from the 1000 Genomes Project. Disease-associated variants were detected in 298,227 hits across all the VCF files, taking a total of 63.58 m to complete. The package was also tested on ClinVar’s VCF file (2,120,558 variants), where 20,657 hits associated with diseases were identified with an estimated elapsed time of 45.98 s. Conclusions DisVar can overcome the limitations of existing tools and is a fast and effective diagnostic and preventive tool that identifies disease-associated variations from large-scale genetic variants against the latest reference genome.

The discovery of low-coverage (i.e. uncovered) regions containing clinically significant variants, especially when they are related to the patient’s clinical phenotype, is critical for whole-exome sequencing (WES) based clinical diagnosis. Therefore, it is essential to develop tools to identify the existence of clinically important variants in low-coverage regions. Here, we introduce a desktop application, namely DEVOUR (DEleterious Variants On Uncovered Regions), that analyzes read alignments for WES experiments, identifies genomic regions with no or low-coverage (read depth < 5) and then annotates known variants in the low-coverage regions using clinical variant annotation databases. As a proof of concept, DEVOUR was used to analyze a total of 28 samples from a publicly available Hirschsprung disease-related WES project (NCBI Bioproject: https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJEB19327), revealing the potential existence of 98 disease-associated variants in low-coverage regions. DEVOUR is available from https://github.com/projectDevour/DEVOUR under the MIT license.

Abstract Background Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating blistering genodermatosis caused by mutations in the COL7A1 gene, which encodes for type VII collagen and is necessary for dermal-epidermal adhesion and integrity. Disease manifestations include severe and debilitating wounds, aggressive squamous cell carcinomas, and premature death; however, there are currently no approved therapies. This Phase 1/2a, open-label study evaluated the long-term efficacy and safety of gene-corrected autologous keratinocyte grafts (EB-101) for chronic RDEB wounds. Methods Autologous keratinocytes were harvested from participants with severe RDEB, transduced with a retrovirus containing the full-length COL7A1 gene, and grown into 5 × 7 cm (35 cm2) sheets. Gene-corrected keratinocyte sheets were then transplanted onto chronic RDEB wounds present for ≥ 12 weeks. Results Seven adult participants with severe RDEB were grafted with six sheets each (42 total sheets) onto wounds and followed for a mean of 5.9 years (range 4–8 years). Long-term improvements in wound healing and symptoms were observed. At year five, 70% (21/30) of treated sites demonstrated ≥ 50% wound healing compared to baseline by investigator global assessment. No sites with ≥ 50% wound healing were painful or pruritic, compared to 67% (6/9) of sites with

Abstract Fibrodysplasia ossificans progressiva (FOP) is an ultrarare condition and one of the most impactful disorders associated with progressive heterotopic ossification events. It is estimated that there are 120–150 patients in Brazil; however, currently, fewer than 100 patients have been identified, and the role of a FOP advocacy group (FOP Brazil) has been instrumental for the identification and follow-up of these individuals and families. The aim of this article is to summarize the current status of FOP in Brazil and describe strategies proposed to approach this challenge in a continental size country.

Despite ground-breaking genetic studies that have identified thousands of risk variants for developmental diseases, how these variants lead to molecular and cellular phenotypes remains a gap in knowledge. Many of these variants are non-coding and occur at enhancers, which orchestrate key regulatory programs during development. The prevailing paradigm is that non-coding variants alter the activity of enhancers, impacting gene expression programs, and ultimately contributing to disease risk. A key obstacle to progress is the systematic functional characterization of non-coding variants at scale, especially since enhancer activity is highly specific to cell type and developmental stage. Here, we review the foundational studies of enhancers in developmental disease and current genomic approaches to functionally characterize developmental enhancers and their variants at scale. In the coming decade, we anticipate systematic enhancer perturbation studies to link non-coding variants to molecular mechanisms, changes in cell state, and disease phenotypes.

Resumen: Las Enfermedades Raras son un problema prioritario y creciente en salud pública. Su diagnóstico es un desafío y para su manejo es fundamental el diagnóstico de precisión.La medicina de precisión, junto con apoyar al equipo médico y la familia en concluir con la denominada odisea diagnóstica, genera una serie de cuestionamientos en relación con la equidad al acceso a las nuevas metodologías diagnósticas y terapéuticas.En el presente artículo se revisa la epidemiología de las Enfermedades Raras, la importancia del diagnóstico temprano y certero, los beneficios de la medicina de precisión y algunos de los dilemas éticos involucrados. Summary: Rare Diseases are a priority and increasing problem for public health. Their diagnosis is a challenge and for their management precision diagnosis is fundamental.Precision medicine helps the medical team and the family to end the “diagnostic odyssey”, but also generates many questions related with equity in the access of patients to new diagnostic and therapeutic methodologies.In this article we reviewed the epidemiology of Rare Diseases, the importance of a precise early diagnosis, the benefits of precision medicine and some of the ethical dilemmas involved.

Previously we showed the generation of a protein trap library made with the gene-break transposon (GBT) in zebrafish (Danio rerio) that could be used to facilitate novel functional genome annotation towards understanding molecular underpinnings of human diseases (Ichino et al, 2020). Here, we report a significant application of this library for discovering essential genes for heart rhythm disorders such as sick sinus syndrome (SSS). SSS is a group of heart rhythm disorders caused by malfunction of the sinus node, the heart’s primary pacemaker. Partially owing to its aging-associated phenotypic manifestation and low expressivity, molecular mechanisms of SSS remain difficult to decipher. From 609 GBT lines screened, we generated a collection of 35 zebrafish insertional cardiac (ZIC) mutants in which each mutant traps a gene with cardiac expression. We further employed electrocardiographic measurements to screen these 35 ZIC lines and identified three GBT mutants with SSS-like phenotypes. More detailed functional studies on one of the arrhythmogenic mutants, GBT411, in both zebrafish and mouse models unveiled Dnajb6 as a novel SSS causative gene with a unique expression pattern within the subpopulation of sinus node pacemaker cells that partially overlaps with the expression of hyperpolarization activated cyclic nucleotide gated channel 4 (HCN4), supporting heterogeneity of the cardiac pacemaker cells.

Abstract Background Thalassemia is an inherited autosomal recessive blood disorder causing abnormal formation of hemoglobin, known as a syndrome of anemia with microcytic erythrocytes. It is the most common genetic disorder worldwide, with a high prevalence among individuals of Mediterranean descent. The state of homozygosity of the beta-globin mutated gene is known as beta-thalassemia major, and these patients require regular blood transfusions and iron chelation therapy for survival. The rapid loss of red blood cells among affected individuals activates compensatory mechanisms of excessive medullary and extramedullary hematopoiesis, leading to severe skeletal bone deformity. Case presentation We present the case of a 39-year-old Bedouin male, diagnosed with beta-thalassemia major at infancy, with diagnosed homozygosity for the intervening sequence 2-1 (guanine > adenine) mutation. Since early infancy, he started receiving blood transfusions with a gradual increase in treatment frequency through adulthood due to the severe clinical progression of the disease. He was referred to the oral and maxillofacial surgery department at Galilee Medical Center to evaluate his facial deformity in the upper jaw and treat his severe periodontal disease. The patient presented maxillary overgrowth, and severe dental deformity resulted in progressive disfigurement and difficulty chewing, swallowing, and speaking. To address the challenge of surgical treatment, we utilized the advantage of three-dimensional planning and printing technology to simulate the optimal result. Resection of maxillary bone overgrowth and insertion of custom-made subperiosteal implants were followed by rehabilitation of both jaws to the patients' satisfaction at 3-year follow-up. Conclusions The ongoing implementation of state-of-the-art technologies such as virtual reality and three-dimensional printing has become a prominent component in surgical toolsets. Comprehensive case simulation and accurate planning before surgery will improve surgical results and patient satisfaction. This approach is highly advocated when approaching a case of rare maxillofacial deformity associated with either genetic or orphan diseases.

Today, the number of genetic diseases is around 10000 conditions, affecting to 6%-8% of all populations. This review shows us how the discovery of genetic variants in our genome, this facilitated to know with precision about the mechanisms physiopathological, and hence to recognize those target points susceptible to modifications, through therapeutical strategies different with palliative proposals, increase life expectancy, or improve qualities of life. These therapies are diverse, using drugs for polygenic diseases, nutritional therapy, special formulas, enzyme replacement therapies, hematopoietic stem cell transplant, substrate reduction, oligonucleotides, and gene therapy. These genetic diseases are heterogeneous clinically with a very low frequency; nevertheless, open to the possibility of research in new strategies for more genetic disease, that today, furthermore, are orphans.

Abstract The COVID-19 pandemic is adding an unanticipated concern for those affected by genetic diseases. Most of the new treatment achievements for these patients are made possible as a result of advances in viral-based products. Among them, adenoviruses (AdV) and especially adeno-associated viruses (AAV) are important players. The concerns and the conversation around this issue have increased as COVID-19 vaccines approach the market. What if the viral vectors become the mainstream strategy for vaccine development? Will the immune response elicited against the vector compromise the efficacy of future gene therapies? Patients with genetic diseases and patient advocacy groups are requesting information to the medical community about the potential impact of these vaccines in future gene therapy treatments, and physicians and scientists are not able to provide satisfactory answer yet. Importantly, the frequency of cross-reactivity among different AAV serotypes can be as high as 50%. This would have potential implications for patients with genetic disorders who could benefit from gene therapies, often coming in the form of AAV-based gene therapies. As in many other aspects, this pandemic is challenging our capacity to coordinate, plan ahead and align different medical objectives. In this case, having such conversation early on might allow us to make the right choices while we are still on time.

Abstract Introduction Rare diseases affect approximately 350 million people worldwide. Delayed diagnosis is frequent due to lack of knowledge of most clinicians and a small number of expert centers. Consequently, computerized diagnosis support systems have been developed to address these issues, with many relying on rare disease expertise and taking advantage of the increasing volume of generated and accessible health-related data. Our objective is to perform a review of all initiatives aiming to support the diagnosis of rare diseases. Methods A scoping review was conducted based on methods proposed by Arksey and O’Malley. A charting form for relevant study analysis was developed and used to categorize data. Results Sixty-eight studies were retained at the end of the charting process. Diagnosis targets varied from 1 rare disease to all rare diseases. Material used for diagnosis support consisted mostly of phenotype concepts, images or fluids. Fifty-seven percent of the studies used expert knowledge. Two-thirds of the studies relied on machine learning algorithms, and one-third used simple similarities. Manual algorithms were encountered as well. Most of the studies presented satisfying performance of evaluation by comparison with references or with external validation. Fourteen studies provided online tools, most of which aimed to support the diagnosis of all rare diseases by considering queries based on phenotype concepts. Conclusion Numerous solutions relying on different materials and use of various methodologies are emerging with satisfying preliminary results. However, the variability of approaches and evaluation processes complicates the comparison of results. Efforts should be made to adequately validate these tools and guarantee reproducibility and explicability.

Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here, we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (Lepob/ob). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake but is instead associated with alterations in the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that gut microbial CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have potential as anti-obesity therapeutics.

Genetic diseases are often progressive in nature, and without proper treatment may result in disability or death. Difficulties with diagnosis of genetic diseases and lack of effective treatment are global public health challenges. Medical care for patients with genetic diseases is often confined to symptomatic and palliative care. Starting from the 2000s, great hopes have been placed on cell-based medicinal products (which are referred to as biomedical cell products in the Russian legislation) and gene therapy products. The aim of the study was to review current trends in the development of biomedical cell products for the treatment of genetic diseases. The paper focuses on cell-based products for the treatment of monogenic genetic diseases, such as severe combined immunodeficiency (SCID), recessive dystrophic epidermolysis bullosa (RDEB), beta-haemoglobinopathies, alpha-1-antitrypsin deficiency, haemophilia A, and Duchenne muscular dystrophy. Such drugs are being developed in many countries and are now entering preclinical and different stages of clinical trials. Products based on various types of viable cells, including differentiated cells, stem cells, induced pluripotent cells, as well as cells genetically modified ex vivo, may be developed for the treatment of one and the same disease. The main priority is the creation of such products that will obviate the need for replacement therapy or palliative care, and that will significantly increase life expectancy and quality of life.

In this case report, we review a male child who presented with severe bilateral hearing loss. Preoperative high-resolution computed tomography (HRCT) evaluation facilitated the initial diagnosis of the disease, which revealed typical findings of cochlear incomplete partition type III anomaly (IP-III), surgical planning, and cochlear implant selection to avoid possible complications. The child underwent cochlear implantation, which resulted in gushing and misplacement of the electrodes into the internal auditory canal (IAC) as postoperative complications. Postoperative imaging was used to determine the position of the implant and to assess the complications. The child’s postoperative X-ray revealed misplacement of the cochlear implant, the extent of which was further assessed by a HRCT scan for preplanning the revision surgery and electrode selection. Following the revision surgery, a further HRCT scan confirmed proper implantation and ruled out any further complications.

Abstract Background Individuals diagnosed with a rare genetic disease that affects skeletal development often have physical limitations and orofacial problems that exert an impact on oral health. The aim of the present study was to analyze the possible vulnerability to dental caries in individuals with rare genetic diseases that affect skeletal development. Methods A paired cross-sectional study was carried out with a sample of 140 individuals [70 with rare genetic diseases affecting skeletal development: mucopolysaccharidosis (MPS) (n = 29) and osteogenesis imperfecta (OI) (n = 41) and 70 without rare diseases] and their parents/caregivers. The participants in the first group were recruited from two reference hospitals specialized in rare genetic diseases in the city of Belo Horizonte, Brazil. All participants were examined for the evaluation of breathing type, malocclusion, dental anomalies, oral hygiene and dental caries. The parents/caregivers answered a structured questionnaire addressing the individual/behavioral characteristics and medical/dental history of the participants. Statistical analysis involved the chi-square test and multiple logistic regression analysis for the dependent variable (dental caries) (α = 5%). This study received approval from the Human Research Ethics Committee of the Universidade Federal de Minas Gerais. Results The mean age of the individuals was 10.34 ± 6.55 years (median: 9.50 years). Individuals with inadequate oral hygiene were 4.70–fold more likely to have dental caries (95% CI: 2.13–10.40) and those with the rare genetic diseases (MPS/OI) were 2.92-fold more likely to have dental caries (95% CI: 1.38–6.17). Conclusion Individuals with inadequate oral hygiene and those with MPS and OI had a greater chance of belonging to the group with dental caries. Based on the present findings, individuals with the rare genetic diseases may be considered vulnerable to caries.

INTRODUCTION: Genetic diseases and congenital anomalies place a significant burden on the health of new-borns and their mothers. Despite the availability of a variety of prenatal screening tests, mothers´ knowledge has been documented to determine uptake. This study aims to assess the knowledge of pregnant women about birth defects and the associated correlates with regard to willingness to do prenatal screening. METHODS: a cross-sectional descriptive study was conducted among 422 antenatal mothers, recruited sequentially as they attended antenatal clinic at the Lagos University Teaching Hospital. An interviewer-administered questionnaire was used to determine their knowledge of congenital birth defects and willingness to do prenatal testing. RESULTS: majority of the participants (92.2%) had at least secondary education. The mean total knowledge score of the respondents was 63%. Age and knowledge scores were not significantly correlated (r=-0.071, p=0.14). Being employed predicted higher knowledge scores (95% CI: 0.09, 2.09, p=0.03). Respondents who had primary school education and those who replied "I don´t know" to willingness to test had significantly lower knowledge scores (95% CI:-15.01, -1.19, p=0.02 and 95% CI:-4.52, -0.68, p=0.01 respectively). Majority (79.1%) of the respondents were willing to undergo testing. Respondents´ level of education was significantly associated with willingness to test (p=0.03). CONCLUSION: the observed knowledge gaps were considerable. There is need for improvement in education, the empowerment of women and access to quality healthcare including prenatal screening.

Noonan syndrome is an autosomal dominant inherited disorder with variable phenotypic expression. It belongs to the group of diseases known as RASopathies, which are characterized by mutations in the RAS genes. Patients develop symptoms such as facial dysmorphism, short stature, congenital heart disease, musculoskeletal disorders and mental retardation. In this article, we report a case of Noonan syndrome in a 14-year-old patient, diagnosed in a primary health center in Ecuador. The syndrome was identified through clinical diagnosis, after which the patient was referred to the secondary and tertiary levels for specialized care.

Background: Phenylketonuria, commonly known as PKU, is an inherited disorder in which there is an abnormally elevated blood level of the amino acid phenylalanine leading to several pathologies affecting multiple organs including the central nervous system and resulting in debilitating intellectual disability and other neuropsychiatric disorders. Phenylalanine is a building block of several critical proteins within the biological systems. Aims and Objective: To assess the digital epidemiology and geographic mapping of Phenylketonuria. Materials and Methods: This study is a retrospective analytic (2013‑2017) of a very large database existing on the surface web known as Google Trends. it aims to extrapolate a statistical inference concerning the digital epidemiology and the geographic mapping of phenylketonuria. The trends database will be explored via thematic keywords specific to the condition of phenylketonuria including “Phenylketonuria [PKU]”, “Phenylalanine”, “Inborn errors of metabolism”, “Tetrahydrobiopterin”, and “Chromosome 12 (human)”. Results: The digital epidemiology is densely clustered in countries from the developed world, eastern Europe, and Latin America. Surface web users from China appears to possess the highest interest in phenylketonuria. The contribution of the Middle Eastern and Arabic countries to the geographic mapping did not exceed 10.51% at its best. Significant changes existed for year-to-year variations of trends. Statistical outliers were also found, the strongest of which was observed during April 2016 for which there’s no plausible explanation. Conclusion: Trends databases operating on the surface web represent potent tools of big data that can be exploited to assess the digital epidemiology and geographic mapping of countless phenomenon including rare genetic diseases and inborn errors of metabolism. There are also enormous potentials for real-time and predictive analytics of these databases when investing the application of automation in data collection and principles of machine learning.

Class A G-protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third of all marketed drugs target members of this family. GPCR activation is an allosteric process that couples agonist binding to G-protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue level changes of this movement remain less well understood. Here, we report a framework to quantify conformational changes. By analyzing the conformational changes in 234 structures from 45 class A GPCRs, we discovered a common GPCR activation pathway comprising of 34 residue pairs and 35 residues. The pathway unifies previous findings into a common activation mechanism and strings together the scattered key motifs such as CWxP, DRY, Na+ pocket, NPxxY and PIF, thereby directly linking the bottom of ligand-binding pocket with G-protein coupling region. Site-directed mutagenesis experiments support this proposition and reveal that rational mutations of residues in this pathway can be used to obtain receptors that are constitutively active or inactive. The common activation pathway provides the mechanistic interpretation of constitutively activating, inactivating and disease mutations. As a module responsible for activation, the common pathway allows for decoupling of the evolution of the ligand binding site and G-protein-binding region. Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature.

Background and purpose: Neurofibromatosis type 1 (NF1) is a dominant genetic disorder of the skin and the nervous system that is seen in equal proportions in both sexes. The incidence of NF1 is about one in every 3,000. Chronic skin diseases have a significant impact on the individual's mental image and also affect mental health and quality of life. The aim of this study was to investigate the quality of life in a group of Iranian patients with NF1 suffering from skin problems. Materials and methods: A cross-sectional, descriptive-analytical study was conducted in 2015-2017 in 193 patients with NF1 attending the Iranian Neurofibromatosis Society, using convenient sampling. Data were collected by Skindex-16 quality of life measure which is composed of 16 questions in three dimensions (emotions, symptoms, and performance). Data were analyzed using SPSS applying Pearson Correlation and ANOVA. Results: Of 193 patients with NF1, 69.5% (n=132) were females. The mean age of patients was 31.58±9.21. The mean score for quality of life was 44.88±22.06. In the domains of symptoms, emotions, and performance the mean scores were 6.57±4.99, 24.76±11.64, and 13.64±8.86, respectively. Quality of life was not statistically correlated with age and sex, but the relationship between the domain of symptoms with age was found to be significant (P=0.01). Conclusion: The results showed that patients with neurofibromatosis have moderate quality of life and lower quality in terms of emotions and performance. These findings can be used to provide better health care for this group of patients and improve their quality of life.

Abstract Advances in Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated system (CRISPR/Cas9) has dramatically reshaped our ability to edit genomes. The scientific community is using CRISPR/Cas9 for various biotechnological and medical purposes. One of its most important uses is developing potential therapeutic strategies against diseases. CRISPR/Cas9 based approaches have been increasingly applied to the treatment of human diseases like cancer, genetic, immunological and neurological disorders and viral diseases. These strategies using CRISPR/Cas9 are not only therapy oriented but can also be used for disease modeling as well, which in turn can lead to the improved understanding of mechanisms of various infectious and genetic diseases. In addition, CRISPR/Cas9 system can also be used as programmable antibiotics to kill the bacteria sequence specifically and therefore can bypass multidrug resistance. Furthermore, CRISPR/Cas9 based gene drive may also hold the potential to limit the spread of vector borne diseases. This bacterial and archaeal adaptive immune system might be a therapeutic answer to previous incurable diseases, of course rigorous testing is required to corroborate these claims. In this review, we provide an insight about the recent developments using CRISPR/Cas9 against various diseases with respect to disease modeling and treatment, and what future perspectives should be noted while using this technology.

Jeune syndrome is a low frequency, autosomal recessive and potentially life-threatening skeletal dysplasia. From a clinical perspective, it has a wide variety of manifestations; however, it is commonly characterized by a narrow thorax; secondary pulmonary hypoplasia; brachymelia; and pelvic, cardiac and renal abnormalities. Lung involvement is variable and may be lethal. The diagnosis may be suspected prenatally through an ultrasonography, by measuring the thoracic and rib cage circumference, and studying the relation between them and with the abdominal circumference. This article describes the clinical case of a 3-month-old female patient with a mild disease presentation and postnatal diagnosis.

Abstract Background Advances in next generation sequencing technologies have revolutionized our ability to discover the causes of rare genetic diseases. However, developing treatments for these diseases remains challenging. In fact, when we systematically analyze the US FDA orphan drug list, we find that only 8% of rare diseases have an FDA-designated drug. Our approach leverages three primary insights: first, diseases with gain-of-function mutations and late onset are more likely to have drug options; second, drugs are more often inhibitors than activators; and third, some disease-causing proteins can be rescued by allosteric activators in diseases due to loss-of-function mutations. Results We have developed a pipeline that combines natural language processing and human curation to mine promising targets for drug development from the Online Mendelian Inheritance in Man (OMIM) database. This pipeline targets diseases caused by well-characterized gain-of-function mutations or loss-of-function proteins with known allosteric activators. Applying this pipeline across thousands of rare genetic diseases, we discover 34 rare genetic diseases that are promising candidates for drug development. Conclusion Our analysis has revealed uneven coverage of rare diseases in the current US FDA orphan drug space. Diseases with gain-of-function mutations or loss-of-function mutations and known allosteric activators should be prioritized for drug treatments.

Inflammatory bowel disease (IBD) affects 1.5–3.0 million people in the United States. IBD is genetically determined and many common risk alleles have been identified. Yet, a large proportion of genetic predisposition remains unexplained. In this study, we report the identification of an ultra rare missense variant (NM_006998.3:c.230G > A;p.Arg77His) in the SCGN gene causing Mendelian early-onset ulcerative colitis. SCGN encodes a calcium sensor that is exclusively expressed in neuroendocrine lineages, including enteroendocrine cells and gut neurons. SCGN interacts with the SNARE complex, which is required for vesicle fusion with the plasma membrane. We show that the SCGN mutation identified impacted the localization of the SNARE complex partner, SNAP25, leading to impaired hormone release. Finally, we show that mouse models of Scgn deficiency recapitulate impaired hormone release and susceptibility to DSS-induced colitis. Altogether, these studies demonstrate that functional deficiency in SCGN can result in intestinal inflammation and implicates the neuroendocrine cellular compartment in IBD.

Major histocompatibility complex (MHC) class II deficiency is a rare primary immunodeficiency disorder (PID) with less than 200 cases worldwide. Here, we report an 8 month–old girl with MHC class II deficiency with a novel homozygous mutation in RFXANK gene (NM_001278728: exon 5: c.495G>A: p.Trp165*) and normal CD4+ T cell counts, diagnosed by whole exome sequencing (WES) and negative HLA–DR proteins on peripheral blood mononuclear cell (PBMC) in flow cytometry. She was referred with pneumonia, prolonged fever, resistance to antibiotics (ceftriaxone, clindamycin, and vancomycin), and low serum immunoglobulin (IG) levels, while natural killer (NK), B, and T cells were normal. She received intra-venous immune-globulin (IVIG) replacement, broad spectrum antibiotics, and anti-fungal treatments. The presented case report is interesting not only because of the rarity of the PID but also due to normal CD4+ T cell counts. According to our experience, we suggest that physicians consider MHC class II deficiency in families with consanguineous marriages, even with normal CD4+ T cell counts. At the first, the diagnosis of the disease could be successfully perform using WES, and finally, treatment with hematopoietic stem cell transplantation can save the patients’ lives.

Background: A better understanding of sickle cell anemia (SCA) and improvements in drug therapy and health policy have contributed to the emergence of a large population of adults living with this disease. The mechanisms by which SCA produces adverse effects on the respiratory system of these patients are largely unknown. Fractional-order (FrOr) models have a high potential to improve pulmonary clinical science and could be useful for diagnostic purposes, offering accurate models with an improved ability to mimic nature. Part 2 of this two-part study examines the changes in respiratory mechanics in patients with SCA using the new perspective of the FrOr models. These results are compared with those obtained in traditional forced oscillation (FOT) parameters, investigated in Part 1 of the present study, complementing this first analysis. Methodology/Principal findings: The data consisted of three categories of subjects: controls (n = 23), patients with a normal spirometric exam (n = 21) and those presenting restriction (n = 24). The diagnostic accuracy was evaluated by investigating the area under the receiver operating characteristic curve (AUC). Initially, it was observed that biomechanical changes in SCA included increased values of fractional inertance, as well as damping and hysteresivity (p<0.001). The correlation analysis showed that FrOr parameters are associated with functional exercise capacity (R = -0.57), pulmonary diffusion (R = -0.71), respiratory muscle performance (R = 0.50), pulmonary flows (R = -0.62) and airway obstruction (R = 0.60). Fractional-order modeling showed high diagnostic accuracy in the detection of early respiratory abnormalities (AUC = 0.93), outperforming spirometry (p<0.03) and standard FOT analysis (p<0.01) used in Part 1 of this study. A combination of machine learning methods with fractional-order modeling further improved diagnostic accuracy (AUC = 0.97). Conclusions: FrOr modeling improved our knowledge about the biomechanical abnormalities in adults with SCA. Changes in FrOr parameters are associated with functional exercise capacity decline, abnormal pulmonary mechanics and diffusion. FrOr modeling outperformed spirometric and traditional forced oscillation analyses, showing a high diagnostic accuracy in the diagnosis of early respiratory abnormalities that was further improved by an automatic clinical decision support system. This finding suggested the potential utility of this combination to help identify early respiratory changes in patients with SCA. [ABSTRACT FROM AUTHOR]

The Galliera Genetic Bank is part of the Laboratory of Human Genetics of Galliera Hospital in Genoa and has collected samples from patients affected by genetic diseases since 1983. Presently, it stores 10,259 biospecimens and associated data from about 200 genetic disorders. The most representative disorders are chromosome disorders (Down s., Ring chromosome 14 s., Cri du chat s. and Isodicentric 15 chromosome), neurological diseases (Fragile X s., Mowat Wilson s. and Dravet s.), rare bone diseases (Crouzon s., Achondroplasia, Grieg s. and Thanathophoric dwarfism), overgrowth syndromes (Sotos s.), familial hypertrophic cardiomyopathy and other rare disease such as IPEX and Aarskog s. The biobank has been supported by Italian Telethon grants since 1993 and since 2008 is partner of the Telethon Network of Genetic Biobanks. It operates according to Italian and international regulations. Since 2008 the biobank is certified ISO 9001, and in 2010 it was officially authorized by the Liguria Region to operate as a facility in support of diagnosis and research on genetic diseases. Since its inception, the biobank has offered the following services to the biomedical community: (i) access to sample and data collection; (ii) sample processing (e.g., cell lines establishment, DNA/RNA extraction, etc); (iii) preservation of biological specimens and related data (repository service), garnering more than 110 acknowledgements in scientific articles.