Brazilian Database on Craniofacial Anomalies in health care : genetic-clinical characterization and proposal for management of individuals with typical oral cleft

Orientadores: Vera Lúcia Gil da Silva Lopes, Isabella Lopes MonlleóDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: As fendas orais típicas (FOT) têm prevalência global de 1:700 nascidos vivos. A forma mais comum tem apresentação clínica isolada e etiologia multifatorial (fendas orais típicas não sindrômicas-FOTNS). Existe, ainda, uma proporção significativa de casos onde mecanismos etiológicos diversos tornam o fenótipo mais complexo, sendo associado a outros defeitos congênitos (fendas orais típicas sindrômicas-FOTS). Nestas o fenótipo pode ser sutil e evolutivo, dificultando a suspeição diagnóstica no recém-nascido. Não existem diretrizes que orientem a investigação diagnóstica precoce. O Projeto Crânio-Face Brasil (PCFB) é uma iniciativa multicêntrica sediada na FCM/Unicamp. Entre suas atividades, desenvolveu a Base Brasileira de Anomalias Craniofaciais (Cranflow®/BBAC), que permite registro padronizado e seguimento evolutivo de anomalias craniofaciais. Nesta, há um módulo específico para fendas orofaciais, o Cranflow®/BBAC-Fendas Orofaciais (CranFlow®-BBAC/FO). Objetivo: Elaborar fluxograma de apoio à investigação clínica para detecção de FOTS, a partir da caracterização genético-clínica de indivíduos com FOT na CranFlow®-BBAC/FO, revisão de bases de apoio diagnóstico on line e identificação de sinais dismórficos de alerta para diagnóstico de FOTS. Métodos: Estudo transversal e descritivo, realizado a partir de dados primários de 1129 indivíduos com fenda oral registrados no CranFlow®-BBAC/FO. Adicionalmente, foram identificados os principais sinais clínicos associados às FOTS em duas bases de dados costumeiramente utilizadas para apoio diagnóstico: OMIM (Online Mendelian Inheritance in Man) e HPO (Human Phenotype Ontology). Resultados: Dos 1129 casos, 901 preencheram critérios de inclusão no estudo. A distribuição entre FOTNS (72,81%) e FOTS (27,19%) foi semelhante à da literatura e, portanto, a amostra pode ser considerada representativa para análise dismorfológica. Dos fatores de risco estudados, observou-se que na região Nordeste (NE) a frequência de mães sem instrução (p=0,008184), o consumo de álcool durante a gestação (p=0,009952133) e a consanguinidade parental (p=0,004570) foram significativamente maiores quando comparadas às regiões Sul (S) e Sudeste (SE). A combinação das informações da CranFlow®-BBAC/FO e HPO/OMIM permitiu considerar quais os sinais de alerta associados à FOTS. Estes, em sua maioria, têm seu diagnóstico realizado com exame físico detalhado e são microcefalia, hipertelorismo ocular e micrognatia; os sinais de alerta que necessitam de propedêutica armada são, principalmente, alterações no sistema cardiovascular (defeitos de septo), e no SNC (hipoplasia/aplasia do corpo caloso). A análise desses dados permitiu a elaboração de um fluxograma de investigação diagnóstica de FOT visando à identificação precoce de formas sindrômicas. Conclusão: Este estudo traz de maneira inédita e importância universal a caracterização de sinais dismórficos que poderiam favorecer o diagnóstico precoce de FOTS. Ainda, a partir de avaliação padronizada em diferentes regiões do país, favorece a adoção de estratégias regionalizadas de educação em saúde para minimizar fatores de riscoAbstract: Typical oral clefts (TOC) are one of the most common human malformations with overall prevalence of 1:700 live births. Usually they have isolated clinical presentation and multifactorial etiology. However, in a considerable proportion of cases, there is an association with other congenital defects with various etiological mechanisms (syndromic typical oral clefts-STOC). These phenotypes can be subtle and evolving, making it difficult to elaborate a presumptive diagnosis in the newborn. There is no guidelines leading to early diagnostic investigation. The Brazil¿s CranioFacial Project (BCFP) is a multicenter initiative developed at FCM/Unicamp. One of its initiative is the Brazilian Database on Craniofacial Anomalies (Cranflow®/BDAC), which allows standardized registration and follow-up of craniofacial anomalies. BDCA has a specific module for orofacial clefts, the Cranflow®/BDAC-Orofacial Clefts (CranFlow®-BDAC/OC). Objective: To build a flowchart supporting clinical investigation to detect STOC based on genetic-clinical characterization of individuals with TOC in CranFlow®-BBAC / OC and review of diagnostic support online databases and identification of warning dysmorphic signs for diagnostic STOC, as well. Methods: Cross-sectional and descriptive study from primary data of 1129 individuals with oral cleft recorded in CranFlow®-BBAC/OC. Additionally, the main clinical signs associated with STOC were identified in two databases routinely used for diagnostic support: OMIM (Online Mendelian Inheritance in Man) and HPO (Human Phenotype Ontology). Results: Of the 1129 cases, 901 met inclusion criteria and were included in the study. The distribution between NSTOC (72.81%) and STOC (27.19%) was similar to the literature and therefore the sample were considered representative for analysis. Among the risk factors studied, it was observed that in the Northeast (NE), the frequency of mothers with no education (p=0.008184), the consumption of alcohol during pregnancy (p=0.009952133) and parental consanguinity (p=0.004570) were significantly higher. The combination of information and signs associated with TSOC in CranFlow®-BBAC/OC and HPO/OMIM allowed considering as warning signs for STOC with minor differences according to the topography of the TOC. Most of them are observed during a detailed physical examination are them microcephaly, ocular hypertelorism and micrognathia; complementary investigation are needed for cardiovascular system (septal defect) and CNS (hypoplasia/aplasia of the corpus callosum). The analysis of these data allowed the elaboration of a flowchart of TOC diagnostic investigation aimed early identification of syndromic forms. Conclusion: The characterization of dysmorphic signs that could favor the early diagnosis of STOC during clinical evaluation. In addition, this study, from standardized assessment in different regions of the country, promotes the adoption of health education regionalized strategies to minimize risk factorsMestradoGenetica MedicaMestra em Ciências Médicas2012/517996FAPESPCNP

Molecular investigation in individuals with orofacial clefts and microphthalmia-anophthalmia-coloboma spectrum

This study describes genomic findings among individuals with both orofacial clefts (OC) and microphthalmia/anophthalmia/coloboma (MAC) recorded in the Brazilian Database on Craniofacial Anomalies (BDCA). Chromosomal microarray analysis (CMA) and Whole Exome Sequencing (WES) were performed in 17 individuals with OC-MAC. Clinical interpretation of molecular findings was based on data available at the BDCA and on re-examination. No copy number variants (CNVs) classified as likely pathogenic or pathogenic were detected by CMA. WES allowed a conclusive diagnosis in six individuals (35.29%), two of them with variants in the CHD7 gene, and the others with variants in the TFAP2A, POMT1, PTPN11, and TP63 genes with the following syndromes: CHARGE, CHD7-spectrum, Branchiooculofacial, POMT1-spectrum, LEOPARD, and ADULT. Variants of uncertain significance (VUS) possibly associated to the phenotypes were found in six other individuals. Among the individuals with VUSes, three individuals presented variants in genes associated to defects of cilia structure and/or function, including DYNC2H1, KIAA0586, WDR34, INTU, RPGRIP1L, KIF7, and LMNA. These results show that WES was the most effective molecular approach for OC-MAC in this cohort. This study also reinforces the genetic heterogeneity of OC-MAC, and the importance of genes related to ciliopathies in this phenotype

Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome

Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin-catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants

NEOTROPICAL XENARTHRANS: a data set of occurrence of xenarthran species in the Neotropics

Xenarthrans—anteaters, sloths, and armadillos—have essential functions for ecosystem maintenance, such as insect control and nutrient cycling, playing key roles as ecosystem engineers. Because of habitat loss and fragmentation, hunting pressure, and conflicts with domestic dogs, these species have been threatened locally, regionally, or even across their full distribution ranges. The Neotropics harbor 21 species of armadillos, 10 anteaters, and 6 sloths. Our data set includes the families Chlamyphoridae (13), Dasypodidae (7), Myrmecophagidae (3), Bradypodidae (4), and Megalonychidae (2). We have no occurrence data on Dasypus pilosus (Dasypodidae). Regarding Cyclopedidae, until recently, only one species was recognized, but new genetic studies have revealed that the group is represented by seven species. In this data paper, we compiled a total of 42,528 records of 31 species, represented by occurrence and quantitative data, totaling 24,847 unique georeferenced records. The geographic range is from the southern United States, Mexico, and Caribbean countries at the northern portion of the Neotropics, to the austral distribution in Argentina, Paraguay, Chile, and Uruguay. Regarding anteaters, Myrmecophaga tridactyla has the most records (n = 5,941), and Cyclopes sp. have the fewest (n = 240). The armadillo species with the most data is Dasypus novemcinctus (n = 11,588), and the fewest data are recorded for Calyptophractus retusus (n = 33). With regard to sloth species, Bradypus variegatus has the most records (n = 962), and Bradypus pygmaeus has the fewest (n = 12). Our main objective with Neotropical Xenarthrans is to make occurrence and quantitative data available to facilitate more ecological research, particularly if we integrate the xenarthran data with other data sets of Neotropical Series that will become available very soon (i.e., Neotropical Carnivores, Neotropical Invasive Mammals, and Neotropical Hunters and Dogs). Therefore, studies on trophic cascades, hunting pressure, habitat loss, fragmentation effects, species invasion, and climate change effects will be possible with the Neotropical Xenarthrans data set. Please cite this data paper when using its data in publications. We also request that researchers and teachers inform us of how they are using these data

NEOTROPICAL ALIEN MAMMALS: a data set of occurrence and abundance of alien mammals in the Neotropics

Biological invasion is one of the main threats to native biodiversity. For a species to become invasive, it must be voluntarily or involuntarily introduced by humans into a nonnative habitat. Mammals were among first taxa to be introduced worldwide for game, meat, and labor, yet the number of species introduced in the Neotropics remains unknown. In this data set, we make available occurrence and abundance data on mammal species that (1) transposed a geographical barrier and (2) were voluntarily or involuntarily introduced by humans into the Neotropics. Our data set is composed of 73,738 historical and current georeferenced records on alien mammal species of which around 96% correspond to occurrence data on 77 species belonging to eight orders and 26 families. Data cover 26 continental countries in the Neotropics, ranging from Mexico and its frontier regions (southern Florida and coastal-central Florida in the southeast United States) to Argentina, Paraguay, Chile, and Uruguay, and the 13 countries of Caribbean islands. Our data set also includes neotropical species (e.g., Callithrix sp., Myocastor coypus, Nasua nasua) considered alien in particular areas of Neotropics. The most numerous species in terms of records are from Bos sp. (n = 37,782), Sus scrofa (n = 6,730), and Canis familiaris (n = 10,084); 17 species were represented by only one record (e.g., Syncerus caffer, Cervus timorensis, Cervus unicolor, Canis latrans). Primates have the highest number of species in the data set (n = 20 species), partly because of uncertainties regarding taxonomic identification of the genera Callithrix, which includes the species Callithrix aurita, Callithrix flaviceps, Callithrix geoffroyi, Callithrix jacchus, Callithrix kuhlii, Callithrix penicillata, and their hybrids. This unique data set will be a valuable source of information on invasion risk assessments, biodiversity redistribution and conservation-related research. There are no copyright restrictions. Please cite this data paper when using the data in publications. We also request that researchers and teachers inform us on how they are using the data