Transcriptome meta-analysis of valproic acid exposure in human embryonic stem cells.

Valproic acid (VPA) is a widely used antiepileptic drug not recommended in pregnancy because it is teratogenic. Many assays have assessed the impact of the VPA exposure on the transcriptome of human embryonic stem-cells (hESC), but the molecular perturbations that VPA exerts in neurodevelopment are not completely understood. This study aimed to perform a transcriptome meta-analysis of VPA-exposed hESC to elucidate the main biological mechanisms altered by VPA effects on the gene expression. Publicly available microarray and RNA-seq transcriptomes were selected in the Gene Expression Omnibus (GEO) repository. Samples were processed according to the standard pipelines for each technology in the Galaxy server and R. Meta-analysis was performed using the Fisher-P method. Overrepresented genes were obtained by evaluating ontologies, pathways, and phenotypes' databases. The meta-analysis performed in seven datasets resulted in 61 perturbed genes, 54 upregulated. Ontology and pathway enrichments suggested neurodevelopment and neuroinflammatory effects; phenotype overrepresentation included epilepsy-related genes, such as SCN1A and GABRB2. The NDNF gene upregulation was also identified; this gene is involved in neuron migration and survival during development. Sub-network analysis proposed TGFß and BMP pathways activation. These results suggest VPA exerts effects in epilepsy-related genes even in embryonic cells. Neurodevelopmental genes, such as NDNF were upregulated and VPA might also disturb several development pathways. These mechanisms might help to explain the spectrum of VPA-induced congenital anomalies and the molecular effects on neurodevelopment.

Development of dentofacial characteristics related to Incontinentia Pigmenti syndrome: A repeated cross-sectional study.

INTRODUCTION: This research aimed to investigate the dentofacial characteristics of patients with Incontinentia Pigmenti (IP) (or Bloch-Sulzberger) syndrome in childhood, juvenile, and adulthood developmental stages. METHODS: Fifteen female patients with a clinical diagnosis of IP, genetically confirmed by molecular testing, were included in this study. The records of 25 nonsyndromic females with Class I occlusion and lateral cephalograms obtained at similar developmental stages were selected from the American Association of Orthodontists Foundation Legacy Collection as a control group. Dentofacial features of subjects with IP and those in the control group were compared statistically using t test and Mann-Whitney rank-sum test (significance was defined as P <0.05). RESULTS: In general, patients with IP had shorter maxillary and mandibular length, straight skeletal profile, hypodivergent growth pattern with a tendency to mandibular protrusion, shorter anterior facial height, Class III compensatory positioning of incisors, more retruded lips, and smaller maxillary incisor exposure. The degree of hypodontia severity had a significant impact on skeletal, dental, and soft-tissue features in patients with IP. CONCLUSIONS: The results of this study showed that, since childhood, the dentofacial characteristics of patients with IP were progressively distancing from those of nonsyndromic patients with Class I occlusion, presenting their own orthodontic needs.

Gene panel for the diagnosis of epidermolysis bullosa: proposal for a viable and efficient approach

Abstract Background: Epidermolysis bullosa is characterized by cutaneous fragility and blistering. Historically, diagnosis is achieved by immunofluorescence mapping or transmission electron microscopy, both involving biopsy procedures. Genetic analysis, especially through next-generation sequencing, is an important tool for the diagnosis of this disease. In Brazil, access to diagnostic methods is limited, and consequently, most patients do not have an accurate diagnosis. Diagnosis allows the indication of prognosis and genetic counselling of the patient. Objectives: To evaluate the cost-effectiveness of a gene panel compared to immunofluorescence mapping and transmission electron microscopy by analyzing its benefits, limitations, and economic aspects. Methods: The gene panel included the 11 main genes associated with epidermolysis bullosa. The techniques were compared, assessing the average cost, advantages, and limitations, through a price survey and literature review. Results: Both immunofluorescence mapping and transmission electron microscopy require skin biopsy, are dependent on the investigator's expertise, and are subject to frequent inconclusive results. The gene panel is effective for the conclusive diagnosis of epidermolysis bullosa, presents high efficiency and accuracy, is economically feasible, and excludes the need for biopsy. The gene panel allows for prognosis, prenatal genetic diagnosis, and genetic counseling. Study limitations: It was not possible to find laboratories that perform transmission electron microscopy for epidermolysis bullosa diagnosis in Brazil. Conclusion: This study supports the gene panel as the first-choice method for epidermolysis bullosa diagnosis.

Gene panel for the diagnosis of epidermolysis bullosa: proposal for a viable and efficient approach.

BACKGROUND: Epidermolysis bullosa is characterized by cutaneous fragility and blistering. Historically, diagnosis is achieved by immunofluorescence mapping or transmission electron microscopy, both involving biopsy procedures. Genetic analysis, especially through next-generation sequencing, is an important tool for the diagnosis of this disease. In Brazil, access to diagnostic methods is limited, and consequently, most patients do not have an accurate diagnosis. Diagnosis allows the indication of prognosis and genetic counselling of the patient. OBJECTIVES: To evaluate the cost-effectiveness of a gene panel compared to immunofluorescence mapping and transmission electron microscopy by analyzing its benefits, limitations, and economic aspects. METHODS: The gene panel included the 11 main genes associated with epidermolysis bullosa. The techniques were compared, assessing the average cost, advantages, and limitations, through a price survey and literature review. RESULTS: Both immunofluorescence mapping and transmission electron microscopy require skin biopsy, are dependent on the investigator's expertise, and are subject to frequent inconclusive results. The gene panel is effective for the conclusive diagnosis of epidermolysis bullosa, presents high efficiency and accuracy, is economically feasible, and excludes the need for biopsy. The gene panel allows for prognosis, prenatal genetic diagnosis, and genetic counseling. STUDY LIMITATIONS: It was not possible to find laboratories that perform transmission electron microscopy for epidermolysis bullosa diagnosis in Brazil. CONCLUSION: This study supports the gene panel as the first-choice method for epidermolysis bullosa diagnosis.

Genotype-phenotype correlations on epidermolysis bullosa with congenital absence of skin: A comprehensive review.

Congenital absence of skin (CAS) is a clinical sign associated with the main types of epidermolysis bullosa (EB). Very few studies have investigated the genetic background that may influence the occurrence of this condition. Our objective was to investigate genotype-phenotype correlations on EB with CAS through a literature revision on the pathogenic variants previously reported. A total of 171 cases (49 EB simplex, EBS; 23 junctional EB, JEB; and 99 dystrophic EB, DEB), associated with 132 pathogenic variants in eight genes, were included in the genotype-phenotype analysis. In EBS, CAS showed to be a recurrent clinical sign in EBS with pyloric atresia (PA) and EBS associated with kelch-like protein 24; CAS was also described in patients with keratins 5/14 alterations, particularly involving severe phenotypes. In JEB, this is a common clinical sign in JEB with PA associated with premature termination codon variants and/or amino acid substitutions located in the extracellular domain of integrin α6ß4 genes. In DEB with CAS, missense variants occurring close to non-collagenous interruptions of the triple-helix domain of collagen VII appear to influence this condition. This study is the largest review of patients with EB and CAS and expands the spectrum of known variants on this phenomenon.

Inherited epidermolysis bullosa: update on the clinical and genetic aspects

Abstract Inherited epidermolysis bullosa is a group of genetic diseases characterized by skin fragility and blistering on the skin and mucous membranes in response to minimal trauma. Epidermolysis bullosa is clinically and genetically very heterogeneous, being classified into four main types according to the layer of skin in which blistering occurs: epidermolysis bullosa simplex (intraepidermal), junctional epidermolysis bullosa (within the lamina lucida of the basement membrane), dystrophic epidermolysis bullosa (below the basement membrane), and Kindler epidermolysis bullosa (mixed skin cleavage pattern). Furthermore, epidermolysis bullosa is stratified into several subtypes, which consider the clinical characteristics, the distribution of the blisters, and the severity of cutaneous and extracutaneous signs. Pathogenic variants in at least 16 genes that encode proteins essential for the integrity and adhesion of skin layers have already been associated with different subtypes of epidermolysis bullosa. The marked heterogeneity of the disease, which includes phenotypes with a broad spectrum of severity and many causal genes, hinders its classification and diagnosis. For this reason, dermatologists and geneticists regularly review and update the classification criteria. This review aimed to update the state of the art on inherited epidermolysis bullosa, with a special focus on the associated clinical and genetic aspects, presenting data from the most recent reclassification consensus, published in 2020.

Inherited epidermolysis bullosa: update on the clinical and genetic aspects.

Inherited epidermolysis bullosa is a group of genetic diseases characterized by skin fragility and blistering on the skin and mucous membranes in response to minimal trauma. Epidermolysis bullosa is clinically and genetically very heterogeneous, being classified into four main types according to the layer of skin in which blistering occurs: epidermolysis bullosa simplex (intraepidermal), junctional epidermolysis bullosa (within the lamina lucida of the basement membrane), dystrophic epidermolysis bullosa (below the basement membrane), and Kindler epidermolysis bullosa (mixed skin cleavage pattern). Furthermore, epidermolysis bullosa is stratified into several subtypes, which consider the clinical characteristics, the distribution of the blisters, and the severity of cutaneous and extracutaneous signs. Pathogenic variants in at least 16 genes that encode proteins essential for the integrity and adhesion of skin layers have already been associated with different subtypes of epidermolysis bullosa. The marked heterogeneity of the disease, which includes phenotypes with a broad spectrum of severity and many causal genes, hinders its classification and diagnosis. For this reason, dermatologists and geneticists regularly review and update the classification criteria. This review aimed to update the state of the art on inherited epidermolysis bullosa, with a special focus on the associated clinical and genetic aspects, presenting data from the most recent reclassification consensus, published in 2020.

A large family with CYLD cutaneous syndrome: medical genetics at the community level.

Germline mutations in the cylindromatosis gene (CYLD) are associated with a rare autosomal dominant disease known as CYLD cutaneous syndrome (CCS). Patients present multiple neoplasms originating from skin appendages. Here, we investigated the main clinical and molecular features of a large family with CCS having lived in a small Brazilian town for 6 generations, making its prevalence significantly high. We observed a predominance of the disease among males and a wide phenotypic variation. A high frequency of basal cell carcinomas among affected people was found. The mutation c.2806C>T, p.Arg936* in the CYLD gene was detected in all patients. In this work, a geographical cluster of CCS was found, which raised some community genetics issues related not only to the high prevalence of a rare disease in a limited area but also to the strong social stigma associated with the disease.

Music genetics research: Association with musicality of a polymorphism in the AVPR1A gene

Abstract Musicality is defined as a natural tendency, sensibility, knowledge, or talent to create, perceive, and play music. Musical abilities involve a great range of social and cognitive behaviors, which are influenced by both environmental and genetic factors. Although a number of studies have yielded insights into music genetics research, genes and biological pathways related to these traits are not fully understood. Our hypothesis in the current study is that genes associated with different behaviors could also influence the musical phenotype. Our aim was to investigate whether polymorphisms in six genes (AVPR1A, SLC6A4, ITGB3, COMT, DRD2 and DRD4) related to social and cognitive traits are associated with musicality in a sample of children. Musicality was assessed through an individualized music therapy assessment profile (IMTAP) which has been validated in Brazil to measure musical ability. We show here that the RS1 microsatellite of the AVPR1A gene is nominally associated with musicality, corroborating previous results linking AVPR1A with musical activity. This study is one of the first to investigate musicality in a comprehensive way, and it contributes to better understand the genetic basis underlying musical ability.

Music genetics research: Association with musicality of a polymorphism in the AVPR1A gene.

Musicality is defined as a natural tendency, sensibility, knowledge, or talent to create, perceive, and play music. Musical abilities involve a great range of social and cognitive behaviors, which are influenced by both environmental and genetic factors. Although a number of studies have yielded insights into music genetics research, genes and biological pathways related to these traits are not fully understood. Our hypothesis in the current study is that genes associated with different behaviors could also influence the musical phenotype. Our aim was to investigate whether polymorphisms in six genes (AVPR1A, SLC6A4, ITGB3, COMT, DRD2 and DRD4) related to social and cognitive traits are associated with musicality in a sample of children. Musicality was assessed through an individualized music therapy assessment profile (IMTAP) which has been validated in Brazil to measure musical ability. We show here that the RS1 microsatellite of the AVPR1A gene is nominally associated with musicality, corroborating previous results linking AVPR1A with musical activity. This study is one of the first to investigate musicality in a comprehensive way, and it contributes to better understand the genetic basis underlying musical ability.

Dental anomalies in 14 patients with IP: clinical and radiological analysis and review.

OBJECTIVES: Current knowledge on dental anomalies in patients with incontinentia pigmenti (IP) has been obtained by examining case reports; however, an overall characterization of such alterations remains lacking. The objective of this study was to determine the frequency, type and location of dental alterations in IP using a case series. METHODS: Fourteen patients (9 children and 5 adults) with a clinical diagnosis of IP who presented dental anomalies were included in this study. All patients were administered a clinical questionnaire, dental examination and radiological investigation. RESULTS: In the present case series, agenesis of primary dentition was present in 60 % of patients and agenesis of permanent tooth was present in 92.8 % of patients. Most cases were missing at least 6 teeth. Second molar agenesis was present in 13 patients (92.8 %). Anomalies in dental crowns occurred in 71.4 % of cases, and the central incisor was most frequently affected. Two adult patients still had primary teeth. Malocclusion was found in 10 patients (71.4 %). High-arched palate was observed in 7 (50 %) patients. CONCLUSIONS: Patients with IP present alterations in both primary and permanent dentition. Because the agenesis of permanent teeth is more common, primary teeth are not always replaced. In addition, the durability of primary dentition appears to be greater in IP. CLINICAL SIGNIFICANCE: This study shows that patients with IP experience significant loss of teeth, especially in permanent dentition, and have an increased risk of high-arched palate compared to the general population. Prophylactic care of primary teeth in IP is relevant for improving functional and aesthetic outcomes until dental prostheses are implanted.