Publications by authors named "Lavínia Schuler-Faccini"

150 Publications

Knowledge and actions for the control of the vector Aedes aegypti in a municipality in the Legal Amazon.

Rev Inst Med Trop Sao Paulo 2021 16;63:e64. Epub 2021 Aug 16.

Universidade Federal de Mato Grosso, Programa de Pós-Graduação em Saúde Coletiva, Cuiabá, Mato Grosso, Brazil.

Infections caused by arboviruses that have mostly impacted the Brazilian morbidity and mortality are caused by the same vector, Aedes aegypti. Preventive actions related to the vector are the most effective strategies in the prevention and control of these diseases. This study aimed to associate the knowledge on the vector that transmits dengue, Zika and chikungunya with the sociodemographic and behavioral preventive practices towards Aedes aegypti in the municipality of Tangara da Serra, Mato Grosso State, in the Brazilian Legal Amazon. A probabilistic urban population sampling was obtained by clusters: census sectors and households. The sample size calculation considered 10% of loss and a 1.5 design effect. This is a cross-sectional research carried out through a household survey in February and March 2018. There were 583 participants. The study variables were knowledge on the vector, sociodemographic characteristics and preventive practices related to the vector. The statistical analysis was based on a bivariate analysis and Poisson multiple regressions. Inadequate or insufficient knowledge on the vector Aedes aegypti remained associated with education in the categories illiterate (p<0.001) and 8 years of study or less (p<0.001), in addition to not adopting practices of capping and cleaning the water tank (p=0.002) and not using insecticides at home (p=0.007). It is concluded that there is a need for health communication actions that consider characteristics the population, especially the level of education and previous knowledge on the vector, allowing a dialogical approach and enabling the community participation in preventive practices and control of the vector Aedes aegypti .
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http://dx.doi.org/10.1590/S1678-9946202163064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376272PMC
August 2021

Evolutionary analysis of the anti-viral STAT2 gene of primates and rodents: Signature of different stages of an arms race.

Infect Genet Evol 2021 Aug 9;95:105030. Epub 2021 Aug 9.

Laboratório de Evolução Humana e Molecular, Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address:

STAT2 plays a strategic role in defending viral infection through the signaling cascade involving the immune system initiated after type I interferon release. Many flaviviruses target the inactivation or degradation of STAT2 as a strategy to impair this host's line of defense. Primates are natural reservoirs for a range of disease-causing flaviviruses (e.g., Zika, Dengue, and Yellow Fever virus), while rodents appear less susceptible. We analyzed the STAT2 coding sequence of 28 Rodentia species and 49 Primates species. Original data from 19 Platyrrhini species were sequenced for the SH2 domain of STAT2 and included in the analysis. STAT2 has many sites whose variation can be explained by positive selection, measurement by two methods (PALM indicated 12, MEME 61). Both evolutionary tests significantly marked sites 127, 731, 739, 766, and 780. SH2 is under evolutionary constraint but presents episodic positive selection events within Rodentia: in one of them, a moderately radical change (serine > arginine) at position 638 is found in Peromyscus species, and can be implicated in the difference in susceptibility to flaviviruses within Rodentia. Some other positively selected sites are functional such as 5, 95, 203, 251, 782, and 829. Sites 251 and 287 regulate the signaling mediated by the JAK-STAT2 pathway, while 782 and 829 create a stable tertiary structure of STAT2, facilitating its connection with transcriptional co-activators. Only three positively selected sites, 5, 95, and 203, are recognized members who act on the interface between STAT2 and flaviviruses NS5 protein. We suggested that due to the higher evolutionary rate, rodents are, at this moment, taking some advantage in the battle against infections for some well-known Flaviviridae, in particular when compared to primates. Our results point to dynamics that fit with a molecular evolutionary scenario shaped by a thought-provoking virus-host arms race.
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http://dx.doi.org/10.1016/j.meegid.2021.105030DOI Listing
August 2021

Functional Polymorphisms in the p53 Pathway Genes on the Genetic Susceptibility to Zika Virus Teratogenesis.

Front Cell Infect Microbiol 2021 7;11:641413. Epub 2021 Jul 7.

Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

Congenital Zika Syndrome (CZS) occurs in up to 42% of individuals exposed to ZIKV prenatally. Deregulation in gene expression and protein levels of components of the p53 signaling pathway, such as p53 and MDM2, due to ZIKV infection has been reported. Here, we evaluate functional polymorphisms in genes of the p53 signaling pathway as risk factors to CZS. Forty children born with CZS and forty-eight children exposed to ZIKV, but born without congenital anomalies were included in this study. Gestational and sociodemographic information as well as the genotypic and allelic frequencies of functional polymorphisms in and genes were compared between the two groups. We found children with CZS exposed predominantly in the first trimester and controls in the third trimester (p<0.001). Moreover, children with CZS were predominantly from families with a lower socioeconomic level (p=0.008). We did not find a statistically significant association between the investigated polymorphisms and development of CZS; however, by comparing individuals with CZS and lissencephaly or without lissencephaly, we found a significative difference in the allelic frequencies of the rs1042522, which is associated with a more potent p53-induced apoptosis (p=0.007). Our findings suggest that the rs1042522 polymorphism should be better investigate as a genetic risk factor for the development of lissencephaly in children with CZS.
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http://dx.doi.org/10.3389/fcimb.2021.641413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294037PMC
July 2021

Comparative Genomics Identifies Putative Interspecies Mechanisms Underlying Crbn-Sall4-Linked Thalidomide Embryopathy.

Front Genet 2021 23;12:680217. Epub 2021 Jun 23.

Post-Graduation Program in Genetics and Molecular Biology, PPGBM, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre, Brazil.

The identification of thalidomide-Cereblon-induced SALL4 degradation has brought new understanding for thalidomide embryopathy (TE) differences across species. Some questions, however, regarding species variability, still remain. The aim of this study was to detect sequence divergences between species, affected or not by TE, and to evaluate the regulated gene co-expression in a murine model. Here, we performed a comparative analysis of proteins experimentally established as affected by thalidomide exposure, evaluating 14 species. The comparative analysis, regarding synteny, neighborhood, and protein conservation, was performed in 42 selected genes. Differential co-expression analysis was performed, using a publicly available assay, GSE61306, which evaluated mouse embryonic stem cells (mESC) exposed to thalidomide. The comparative analyses evidenced 20 genes in the upstream neighborhood of , which are different between the species who develop, or not, the classic TE phenotype. Considering protein sequence alignments, RECQL4, SALL4, CDH5, KDR, and NOS2 proteins had the biggest number of variants reported in unaffected species. In co-expression analysis, was a gene identified as a driver of the co-expression of other genes implicated in genetic, non-teratogenic, limb reduction defects (LRD), such as , , , and ; and were shown to have a moderate co-expression correlation, which is affected after thalidomide exposure. Hence, even though the classic TE phenotype is not identified in mice, a deregulatory Crbn-induced mechanism is suggested in this animal. Functional studies are necessary, especially evaluating the genes responsible for LRD syndromes and their interaction with thalidomide-Cereblon.
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http://dx.doi.org/10.3389/fgene.2021.680217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262662PMC
June 2021

Maternal outcomes and risk factors for COVID-19 severity among pregnant women.

Sci Rep 2021 07 6;11(1):13898. Epub 2021 Jul 6.

Department of Obstetrics & Gynecology, University of Campinas, Campinas, Brazil.

Pregnant women may be at higher risk of severe complications associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may lead to obstetrical complications. We performed a case control study comparing pregnant women with severe coronavirus disease 19 (cases) to pregnant women with a milder form (controls) enrolled in the COVI-Preg international registry cohort between March 24 and July 26, 2020. Risk factors for severity, obstetrical and immediate neonatal outcomes were assessed. A total of 926 pregnant women with a positive test for SARS-CoV-2 were included, among which 92 (9.9%) presented with severe COVID-19 disease. Risk factors for severe maternal outcomes were pulmonary comorbidities [aOR 4.3, 95% CI 1.9-9.5], hypertensive disorders [aOR 2.7, 95% CI 1.0-7.0] and diabetes [aOR2.2, 95% CI 1.1-4.5]. Pregnant women with severe maternal outcomes were at higher risk of caesarean section [70.7% (n = 53/75)], preterm delivery [62.7% (n = 32/51)] and newborns requiring admission to the neonatal intensive care unit [41.3% (n = 31/75)]. In this study, several risk factors for developing severe complications of SARS-CoV-2 infection among pregnant women were identified including pulmonary comorbidities, hypertensive disorders and diabetes. Obstetrical and neonatal outcomes appear to be influenced by the severity of maternal disease.
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http://dx.doi.org/10.1038/s41598-021-92357-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260739PMC
July 2021

Zika Virus Infection Associated with Autism Spectrum Disorder: A Case Report.

Neuroimmunomodulation 2021 Jun 3:1-4. Epub 2021 Jun 3.

Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Introduction: The aim of this case was to investigate the association of the Zika virus infection in utero with the autism spectrum disorder (ASD) as clinical outcome that presented no congenital anomalies.

Methods: ASD was diagnosed in the second year of life by different child neurologists and confirmed by DSM-5 and ASQ. After that, an extensive clinical, epidemiological, and genetic evaluations were performed, with main known ASD causes ruled out.

Results: An extensive laboratorial search was done, with normal findings. SNP array identified no pathogenic variants. Normal neuroimaging and EEG findings were also obtained. ZIKV (Zika virus) IgG was positive, while IgM was negative. Other congenital infections were negative. The exome sequencing did not reveal any pathogenic variant in genes related to ASD.

Conclusion: Accordingly, this report firstly associates ZIKV exposure to ASD.
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http://dx.doi.org/10.1159/000516560DOI Listing
June 2021

Molecular mechanisms of Zika virus teratogenesis from animal studies: a systematic review protocol.

Syst Rev 2021 05 29;10(1):160. Epub 2021 May 29.

Teratology Information Service, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, 90035-903, Brazil.

Background: Due to the diversity of studies in animal models reporting that molecular mechanisms are involved in the teratogenic effect of the Zika virus (ZIKV), the objective of the present study is to evaluate the methodological quality of these studies, as well as to demonstrate which genes and which molecular pathways are affected by ZIKV in different animal models.

Methods: This search will be performed in four databases: PubMed/MEDLINE, EMBASE, Web of Science, and Scopus, as well as in the grey literature. The studies selection process will be reported through the PRISMA Statement diagram model. All studies describing the molecular mechanisms possibly involved in the development of malformations caused by embryonic/fetal ZIKV exposure in animal models with an appropriate control group and methodology will be included (including, for instance, randomized and non-randomized studies). All animals used as experimental models for ZIKV teratogenesis may be included as long as exposure to the virus occurred during the embryonic/fetal period. From the selected studies, data will be extracted using a previously prepared standard form. Bias risk evaluation will be conducted following the SYRCLE's Risk of Bias tool. All data obtained will be tabulated and organized by outcomes (morphological and molecular).

Discussion: With the proposed systematic review, we expect to present results about the methodological quality of the published studies with animal models that investigated the molecular mechanisms involved in the teratogenic effect of ZIKV, as well as to show the studies with greater reliability.

Systematic Review Registration: PROSPERO CRD42019157316.
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http://dx.doi.org/10.1186/s13643-021-01713-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164069PMC
May 2021

Prevalence and antimicrobial resistance profile of Staphylococcus aureus in inherited epidermolysis bullosa: a cross-sectional multicenter study in Brazil.

Int J Dermatol 2021 Sep 28;60(9):1126-1130. Epub 2021 May 28.

Service of Dermatology, Irmandade Santa Casa de Misericórdia de Porto Alegre/Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil.

Background: Infection is an important complication of epidermolysis bullosa (EB), and Staphylococcus aureus has been pointed out as the most common pathogen among this population. The objective of this study was to investigate the prevalence and antimicrobial resistance profile of S. aureus colonizing EB patients in Brazil.

Methods: This cross-sectional multicenter study was conducted between December 2015 and December 2017. We included a total of 89 individuals with EB from medical centers across Brazil. Data were obtained through clinical and bacteriological investigation. S. aureus were identified by biochemical tests. The nuc and mecA genes were confirmed by PCR assay. Antimicrobial susceptibility was investigated by disk diffusion method.

Results: The overall prevalence of S. aureus was 51.7% (46/89). Methicillin-resistant S. aureus (MRSA) was detected in 24.7% (19/77) of all S. aureus isolates, colonizing 15.7% (14/89) of all patients. Community-associated (CA)-MRSA strains were resistant against sulfamethoxazole/trimethoprim and levofloxacin (P < 0.05%). S. aureus colonization of the nares and belly button represented a 3.4 times higher risk of simultaneous skin lesion colonization (P < 0.05%).

Conclusions: The high frequency of MRSA colonizing patients with EB is alarming considering its association with life-threatening complications and poorer outcomes. EB patients are at increased risk of colonization and infection by Staphylococcus aureus and CA-MRSA. Getting to know S. aureus carriage sites and its antimicrobial susceptibility profile is key when planning new individualized and more effective prophylactic and therapeutic measures.
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http://dx.doi.org/10.1111/ijd.15634DOI Listing
September 2021

Machine learning model on heart rate variability metrics identifies asymptomatic toddlers exposed to zika virus during pregnancy.

Physiol Meas 2021 06 17;42(5). Epub 2021 Jun 17.

Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, United States of America.

. Although the Zika virus (ZIKV) seems to be prominently neurotropic, there are some reports of involvement of other organs, particularly the heart. Of special concern are those children exposed prenatally to ZIKV and born without microcephaly or other congenital anomalies. Electrocardiogram (ECG)-derived heart rate variability (HRV) metrics represent an attractive, low-cost, widely deployable tool for early identification of developmental functional alterations in exposed children born without such overt clinical symptoms. We hypothesized that HRV in such children would yield a biomarker of fetal ZIKV exposure. Our objective was to test this hypothesis in young children exposed to ZIKV during pregnancy.. We investigated the HRV properties of 21 children aged 4-25 months from Brazil. The infants were divided into two groups, the ZIKV-exposed ( = 13) and controls ( = 8). Single-channel ECG was recorded in each child at ∼15 months of age and HRV was analyzed in 5 min segments to provide a comprehensive characterization of the degree of variability and complexity of the heart rate.Using a cubic support vector machine classifier we identified babies as Zika cases or controls with a negative predictive value of 92% and a positive predictive value of 86%. Our results show that a machine learning model derived from HRV metrics can help differentiate between ZIKV-affected, yet asymptomatic, and non-ZIKV-exposed babies. We identified the box count as the best HRV metric in this study allowing such differentiation, regardless of the presence of microcephaly.We show that it is feasible to measure HRV in infants and toddlers using a small non-invasive portable ECG device and that such an approach may uncover the memory ofexposure to ZIKV. We discuss putative mechanisms. This approach may be useful for future studies and low-cost screening tools involving this challenging to examine population.
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http://dx.doi.org/10.1088/1361-6579/ac010eDOI Listing
June 2021

Genetic Susceptibility to Drug Teratogenicity: A Systematic Literature Review.

Front Genet 2021 27;12:645555. Epub 2021 Apr 27.

Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.

Since the 1960s, drugs have been known to cause teratogenic effects in humans. Such teratogenicity has been postulated to be influenced by genetics. The aim of this review was to provide an overview of the current knowledge on genetic susceptibility to drug teratogenicity in humans and reflect on future directions within the field of genetic teratology. We focused on 12 drugs and drug classes with evidence of teratogenic action, as well as 29 drugs and drug classes with conflicting evidence of fetal safety in humans. An extensive literature search was performed in the PubMed and EMBASE databases using terms related to the drugs of interest, congenital anomalies and fetal development abnormalities, and genetic variation and susceptibility. A total of 29 studies were included in the final data extraction. The eligible studies were published between 1999 and 2020 in 10 different countries, and comprised 28 candidate gene and 1 whole-exome sequencing studies. The sample sizes ranged from 20 to 9,774 individuals. Several drugs were investigated, including antidepressants (nine studies), thalidomide (seven studies), antiepileptic drugs (five studies), glucocorticoids (four studies), acetaminophen (two studies), and sex hormones (estrogens, one study; 17-alpha hydroxyprogesterone caproate, one study). The main neonatal phenotypic outcomes included perinatal complications, cardiovascular congenital anomalies, and neurodevelopmental outcomes. The review demonstrated that studies on genetic teratology are generally small, heterogeneous, and exhibit inconsistent results. The most convincing findings were genetic variants in , and , which were associated with drug teratogenicity by antidepressants, antiepileptics, and glucocorticoids, respectively. Notably, this review demonstrated the large knowledge gap regarding genetic susceptibility to drug teratogenicity, emphasizing the need for further efforts in the field. Future studies may be improved by increasing the sample size and applying genome-wide approaches to promote the interpretation of results. Such studies could support the clinical implementation of genetic screening to provide safer drug use in pregnant women in need of drugs.
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http://dx.doi.org/10.3389/fgene.2021.645555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107476PMC
April 2021

Dynamic mapping of the probability of infestation by urban arbovirus vectors in the municipalities of Rio Grande do Sul state, Brazil, 2016-2017.

Epidemiol Serv Saude 2021 28;30(2):e2020154. Epub 2021 Apr 28.

Universidade Federal do Rio Grande do Sul, Departamento de Ecologia, Porto Alegre, RS, Brasil.

Objective: To compare official mapping with probabilistic mapping of infestation by Aedes spp. in the municipalities of Rio Grande do Sul state, Brazil.

Methods: This was an ecological study using data from samples of mosquito breeding sites collected in 2016-2017; official classification was obtained from epidemiological reports, and infestation per municipality and week was estimated by fitting a dynamic site-occupancy model to data from municipal epidemiological surveillance.

Results: 187,245 samples collected in 473 municipalities returned 10,648 detections of Aedes aegypti, and 8,414 detections of Aedes albopictus; official mapping agrees with probabilistic mapping in municipalities in the northwestern and western regions of the state. The mappings are not in agreement in the eastern, central, northeastern and southern regions, revealing municipalities officially not infested but with high probability of infestation and notification of arbovirus infection.

Conclusion: While official classification identified critically infested municipalities in the state's northwestern and western regions, it did not identify infestation in municipalities with possible false zero errors and where infestation varies over time.
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http://dx.doi.org/10.1590/S1679-49742021000200006DOI Listing
April 2021

Zika Brazilian Cohorts (ZBC) Consortium: Protocol for an Individual Participant Data Meta-Analysis of Congenital Zika Syndrome after Maternal Exposure during Pregnancy.

Viruses 2021 04 16;13(4). Epub 2021 Apr 16.

Faculdade de Ciências Médicas, Universidade de Pernambuco, Recife 50100-130, Brazil.

Despite great advances in our knowledge of the consequences of Zika virus to human health, many questions remain unanswered, and results are often inconsistent. The small sample size of individual studies has limited inference about the spectrum of congenital Zika manifestations and the prognosis of affected children. The Brazilian Zika Cohorts Consortium addresses these limitations by bringing together and harmonizing epidemiological data from a series of prospective cohort studies of pregnant women with rash and of children with microcephaly and/or other manifestations of congenital Zika. The objective is to estimate the absolute risk of congenital Zika manifestations and to characterize the full spectrum and natural history of the manifestations of congenital Zika in children with and without microcephaly. This protocol describes the assembly of the Consortium and protocol for the Individual Participant Data Meta-analyses (IPD Meta-analyses). The findings will address knowledge gaps and inform public policies related to Zika virus. The large harmonized dataset and joint analyses will facilitate more precise estimates of the absolute risk of congenital Zika manifestations among Zika virus-infected pregnancies and more complete descriptions of its full spectrum, including rare manifestations. It will enable sensitivity analyses using different definitions of exposure and outcomes, and the investigation of the sources of heterogeneity between studies and regions.
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http://dx.doi.org/10.3390/v13040687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072625PMC
April 2021

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

Am J Orthod Dentofacial Orthop 2021 Jul 24;160(1):66-76. Epub 2021 Apr 24.

Division of Dermatology, Department of Medical Clinic, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.

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.
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http://dx.doi.org/10.1016/j.ajodo.2020.03.033DOI Listing
July 2021

List of priority congenital anomalies for surveillance under the Brazilian Live Birth Information System.

Epidemiol Serv Saude 2021 16;30(1):e2020835. Epub 2021 Apr 16.

Ministério da Saúde, Secretaria de Vigilância em Saúde, Brasília, DF, Brasil.

Objective: To define the list of priority congenital anomalies for improving their recording on the Brazilian Live Birth Information System (Sinasc).

Methods: Based on the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), international protocols and meetings with specialists, the list of priority anomalies was built considering two main criteria: being diagnosable at birth and having intervention available at different levels. The list was submitted for consideration by the Brazilian Medical Genetics and Genomics Society.

Results: The list comprised eight groups of congenital anomalies distributed according to the type of related anomaly, as well as the affected part of the body and its corresponding code in ICD-10 Chapter XVII.

Conclusion: The list of priority congenital anomalies for notification provides a basis for improving case recording on Sinasc.
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http://dx.doi.org/10.1590/S1679-49742021000100030DOI Listing
April 2021

Prevalence of congenital anomalies at birth among live births in the state of Maranhão from 2001 to 2016: temporal and spatial analysis.

Rev Bras Epidemiol 2021 16;24(suppl 1):e210020. Epub 2021 Apr 16.

Postgraduate Program in Genetics and Molecular Biology, Department of Genetics, Universidade Federal do Rio Grande do Sul - Porto Alegre (RS), Brazil.

Objectives: To analyze the prevalence at birth and the spatial and temporal distribution of congenital anomalies (CAs) among live births in the state of Maranhão in 2001 to 2016. To describe demographic, gestational and neonatal variables of interest.

Methods: Ecological, population-based study, using secondary data from the Live Birth Information System (SINASC). Annual prevalence of total and per-group CAs was calculated. Spatial analyzes were based on the Local Indicators of Spatial Association (LISA) and the Moran I Index, and interactive maps were generated. Demographic, gestational and neonatal variables of interest available from SINASC were described in the group of newborns with CAs.

Results: 1,831,830 live births, 6,110 with CAs (33.4/10,000) were included. Higher frequencies occurred in more recent years. Spatial clusters have been observed in specific years. The prevalence of newborns with CAs was different between categories of variables considered as risk factors for this outcome.

Conclusion: The prevalence at birth of total CAs was lower than expected for major human defects (3%). The temporal peak of records in 2015/2016 is probably related to the increase in CAs caused by gestational infection by the Zika virus. The spatial clusters were probably due to variations at random due to the small number of births as they are not repeated in other years. Studies like this are the basis for the establishment of CA surveillance programs.
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http://dx.doi.org/10.1590/1980-549720210020.supl.1DOI Listing
April 2021

Aprosopia/holoprosencephaly in a stillborn puppy: when the face predicts the brain.

Int J Vet Sci Med 2021 Mar 26;9(1):7-10. Epub 2021 Mar 26.

Departamento de Genética, Serviço deGenética Médica Populacional (INAGEMP), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.

In a litter of three puppies, one was stillborn and had facial and brain defects. Fusion of the maxilla and mandible and absence of the face were observed. The forebrain (telencephalon and the diencephalon) was reduced in size and fused, and the telencephalic longitudinal fissure, olfactory bulbs, and optic nerves were absent (Figures 6 and 7). Lissencephaly was observed in the telencephalon and cerebellum. A diagnosis of aprosopia/holoprosencephaly was made.
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http://dx.doi.org/10.1080/23144599.2021.1897740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008928PMC
March 2021

Prediction of eye, hair and skin colour in Latin Americans.

Forensic Sci Int Genet 2021 07 6;53:102517. Epub 2021 Apr 6.

Department of Genetics, Evolution and Environment, and UCL Genetics Institute, University College London, London WC1E 6BT, UK; Melbourne Integrative Genomics, Schools of BioSciences and Mathematics & Statistics, University of Melbourne, Melbourne, VIC 3010, Australia.

Here we evaluate the accuracy of prediction for eye, hair and skin pigmentation in a dataset of > 6500 individuals from Mexico, Colombia, Peru, Chile and Brazil (including genome-wide SNP data and quantitative/categorical pigmentation phenotypes - the CANDELA dataset CAN). We evaluated accuracy in relation to different analytical methods and various phenotypic predictors. As expected from statistical principles, we observe that quantitative traits are more sensitive to changes in the prediction models than categorical traits. We find that Random Forest or Linear Regression are generally the best performing methods. We also compare the prediction accuracy of SNP sets defined in the CAN dataset (including 56, 101 and 120 SNPs for eye, hair and skin colour prediction, respectively) to the well-established HIrisPlex-S SNP set (including 6, 22 and 36 SNPs for eye, hair and skin colour prediction respectively). When training prediction models on the CAN data, we observe remarkably similar performances for HIrisPlex-S and the larger CAN SNP sets for the prediction of hair (categorical) and eye (both categorical and quantitative), while the CAN sets outperform HIrisPlex-S for quantitative, but not for categorical skin pigmentation prediction. The performance of HIrisPlex-S, when models are trained in a world-wide sample (although consisting of 80% Europeans, https://hirisplex.erasmusmc.nl), is lower relative to training in the CAN data (particularly for hair and skin colour). Altogether, our observations are consistent with common variation of eye and hair colour having a relatively simple genetic architecture, which is well captured by HIrisPlex-S, even in admixed Latin Americans (with partial European ancestry). By contrast, since skin pigmentation is a more polygenic trait, accuracy is more sensitive to prediction SNP set size, although here this effect was only apparent for a quantitative measure of skin pigmentation. Our results support the use of HIrisPlex-S in the prediction of categorical pigmentation traits for forensic purposes in Latin America, while illustrating the impact of training datasets on its accuracy.
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http://dx.doi.org/10.1016/j.fsigen.2021.102517DOI Listing
July 2021

Classification algorithm for congenital Zika Syndrome: characterizations, diagnosis and validation.

Sci Rep 2021 03 24;11(1):6770. Epub 2021 Mar 24.

Fundação Oswaldo Cruz, Porto Velho, Rondônia, Brazil.

Zika virus was responsible for the microcephaly epidemic in Brazil which began in October 2015 and brought great challenges to the scientific community and health professionals in terms of diagnosis and classification. Due to the difficulties in correctly identifying Zika cases, it is necessary to develop an automatic procedure to classify the probability of a CZS case from the clinical data. This work presents a machine learning algorithm capable of achieving this from structured and unstructured available data. The proposed algorithm reached 83% accuracy with textual information in medical records and image reports and 76% accuracy in classifying data without textual information. Therefore, the proposed algorithm has the potential to classify CZS cases in order to clarify the real effects of this epidemic, as well as to contribute to health surveillance in monitoring possible future epidemics.
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http://dx.doi.org/10.1038/s41598-021-86361-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990918PMC
March 2021

COVID-19 during pregnancy and adverse outcomes: Concerns and recommendations from The Brazilian Teratology Information Service.

Genet Mol Biol 2021 10;44(1 Suppl 1):e20200224. Epub 2021 Mar 10.

Universidade Federal do Rio Grande do Sul, Departamento de Genética, Programa de Pós-Graduação em Genética e Biologia Molecular, Porto Alegre, RS, Brazil.

SARS-CoV-2 virus was first identified in the beginning of 2020 and has spread all over the world, causing the Coronavirus Disease 2019 (COVID-19) pandemic. The virus is a member of the Coronavirus family, which includes viruses that cause common cold, Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). MERS and SARS are known by causing adverse events in pregnancy. Considering that SARS-CoV-2 is a new infection agent, little is known about the risk of its infection to human embryo/fetal development. However, SARS and MERS were associated with negative outcomes, such as miscarriage, preterm birth, intrauterine growth restriction and perinatal death. Here, we raise concerns and possibilities related the harmful potential of SARS-CoV-2 and COVID-19 to pregnancy, discussing symptoms, immunological changes during pregnancy, SARS-CoV-2 mutation rate (and the risks related to it). Finally, we point out recommendations to be performed by the scientific community and health care workers in order to identify and to manage potential risks to pregnant women and their babies.
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http://dx.doi.org/10.1590/1678-4685-GMB-2020-0224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953204PMC
March 2021

Association between Genetic Variants in and Genes with Congenital Zika Syndrome and Severe Microcephaly.

Viruses 2021 02 20;13(2). Epub 2021 Feb 20.

Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Departamento de Genética, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 91501-970, Brazil.

Zika virus (ZIKV) causes Congenital Zika Syndrome (CZS) in individuals exposed prenatally. Here, we investigated polymorphisms in , and genes as risk factors to CZS. Forty children with CZS and forty-eight children who were in utero exposed to ZIKV infection, but born without congenital anomalies, were evaluated. Children with CZS were predominantly infected by ZIKV in the first trimester ( < 0.001) and had mothers with lower educational level ( < 0.001) and family income ( < 0.001). We found higher risk of CZS due the allele rs2297518[A] of (OR = 2.28, CI 95% 1.17-4.50, = 0.015). T allele and TT/CT genotypes of the rs1799724 and haplotypes associated with higher expression of were more prevalent in children with CZS and severe microcephaly ( = 0.029, = 0.041 and = 0.030, respectively). Our findings showed higher risk of CZS due ZIKV infection in the first trimester and suggested that polymorphisms in and genes affect the risk of CZS and severe microcephaly.
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http://dx.doi.org/10.3390/v13020325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924177PMC
February 2021

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

An Bras Dermatol 2021 Mar-Apr;96(2):155-162. Epub 2021 Feb 2.

Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Instituto Nacional de Ciência e Tecnologia de Genética Médica Populacional (INaGeMP), Porto Alegre, RS, Brazil. Electronic address:

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.
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http://dx.doi.org/10.1016/j.abd.2020.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007490PMC
March 2021

A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation.

Sci Adv 2021 Feb 5;7(6). Epub 2021 Feb 5.

Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15260, USA.

To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.
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http://dx.doi.org/10.1126/sciadv.abc6160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864580PMC
February 2021

Congenital anomalies from the health surveillance perspective: compilation of a list based on ICD-10.

Epidemiol Serv Saude 2020 4;29(5):e2020164. Epub 2020 Dec 4.

Ministério da Saúde, Secretaria de Vigilância em Saúde, Brasília, DF, Brasil.

Objective: To propose a list of congenital anomalies having corresponding codes in the International Statistical Classification of Diseases and Related Health Problems, 10thRevision (ICD-10), with the aim of applying it in health surveillance.

Methods: In December 2019, the following data sources were searched: ICD-10; ICD-11; anomalies monitored by three surveillance programs; and a database of rare diseases (Orphanet). Anomalies were retrieved from these data sources, processed to check for correspondence with ICD-10 and reviewed manually to compile the list.

Results: 898 codes were identified, of which 619 (68.9%) were contained in ICD-10 Chapter XVII. Of the 279 codes contained in other chapters, 19 were exclusive to the ICD-11 search, 72 to the surveillance programs, 79 to Orphanet and 36 to the search for terms in ICD-10.

Conclusion: The codes contained in ICD-10 Chapter XVII do not capture the totality of congenital anomalies, indicating the need to adopt an expanded list.
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http://dx.doi.org/10.1590/S1679-49742020000500015DOI Listing
September 2021

Zika virus-induced brain malformations in chicken embryos.

Birth Defects Res 2021 01 3;113(1):22-31. Epub 2020 Oct 3.

Teratogen Information Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

Background: Zika virus (ZIKV) was confirmed to be related to microcephaly in 2016. However, there is still a need for understanding the embryonic morphological changes induced by ZIKV and when they occur. Here, chicken embryos were chosen as experimental model of ZIKV to evaluate virus-associated morphological alterations that might take place during embryonic development.

Methods: A screening with different viral doses was conducted in embryos at HH Stage 10-12 (E1.5) as well as a follow up of the first 5 days postinfection (dpi) was performed to observe the main morphologic changes post ZIKV infection.

Results: ZIKV exposed embryos presented a higher prevalence of mortality and defects such as brain malformation when compared to controls. Moreover, we observed that the phenotypes become more evident at 4dpi, when the viral load quantification reaches a peak.

Conclusions: We found that ZIKV exposed embryos presented a high prevalence of mortality and central nervous system (CNS) abnormalities in a dose-dependent manner. The phenotype was more evident 4 days postinfection, when the viral load quantification reached a peak.
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http://dx.doi.org/10.1002/bdr2.1813DOI Listing
January 2021

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

An Bras Dermatol 2020 Sep - Oct;95(5):551-569. Epub 2020 Jul 8.

Dermatology Service, Santa Casa de Misericórdia de Porto Alegre/Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil; Department of Clinical Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil; Pediatric Dermatology Unit, Santa Casa de Misericórdia de Porto Alegre/Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil. Electronic address:

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.
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http://dx.doi.org/10.1016/j.abd.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563003PMC
November 2020

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

Clin Genet 2021 01 29;99(1):29-41. Epub 2020 Jun 29.

Section of Dermatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.

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 α6β4 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.
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http://dx.doi.org/10.1111/cge.13792DOI Listing
January 2021

Evolutionary analysis of the Musashi family: What can it tell us about Zika?

Infect Genet Evol 2020 10 15;84:104364. Epub 2020 May 15.

Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Postal code 15053, 91501-970 Porto Alegre, RS, Brazil. Electronic address:

Despite worldwide research efforts since 2015, Zika virus infection and its consequences are not fully understood yet. Nowadays, it is known that microcephaly is only one of the possible outcomes of being infected by ZIKV during the early stages of life. Musashi 1 (MSI1) is an RNA-binding protein that is involved in neurodevelopmental processes. Also, ZIKV genome (a single-stranded positive-sense RNA) uses MSI1 for its replication. Here we perform an evolutionary analysis of MSI1 coding sequence and their orthologs in vertebrate species. We added original sequencing data from selected regions of interest (RNA-binding domains-RBDs of MSI1) of sixteen Platyrrhini (or New World monkeys), known to have high evolutionary rates. The Musashi family (MF) includes MSI2, TARDBP, DAZAP1, HNRNPD, HNRNPDL, and HNRNPAB, which do not interact with the virus but are critical RNA-binding proteins that act on many regulatory processes ubiquitously. We found that all sixteen primate species have the RBD1 of MSI1 conserved. While the general code sequences of MF genes are under purifying selection, the evolution of regulatory mechanisms, especially alternative splicing, seems to be a frequent phenomenon in these genes. Different isoforms differ in the N-terminal region and it affects protein size. Existing MSI1 isoforms probably diverge in their binding affinity, the kinetics of interaction, and other aspects when in the MSI1-ZIKV complex. It is a signal that some RBD-containing MSI1 isoforms can be incompatible to ZIKV binding and replication. Consequently, the chance of ZIKV successfully infecting host cells could also be associated with alternative splicing and expression of ZIKV-compatible MSI1 isoforms in both inter and intraspecific levels.
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http://dx.doi.org/10.1016/j.meegid.2020.104364DOI Listing
October 2020

Site Occupancy by in a Subtropical City is Most Sensitive to Control during Autumn and Winter Months.

Am J Trop Med Hyg 2020 07 7;103(1):445-454. Epub 2020 May 7.

Programa de Pós-Graduação em Ecologia, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

The mosquito inhabits most tropical and subtropical regions of the globe, where it transmits arboviral diseases of substantial public health relevance, such as dengue fever. In subtropical regions, often presents an annual abundance cycle driven by weather conditions. Because different population states may show varying responses to control, we are interested in studying what time of the year is most appropriate for control. To do so, we developed two dynamic site-occupancy models based on more than 200 weeks of mosquito trapping data from nearly 900 sites in a subtropical Brazilian city. Our phenomenological, Markovian models, fitted to data in a Bayesian framework, accounted for failure to detect mosquitoes in two alternative ways and for temporal variation in dynamic rates of local extinction and colonization of new sites. Infestation varied from nearly full cover of the city area in late summer, to between 10% and 67% of sites occupied in winter depending on the model. Sensitivity analysis reveals that changes in dynamic rates should have the greatest impact on site occupancy during autumn and early winter months, when the mosquito population is declining. We discuss the implications of this finding to the timing of mosquito control.
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http://dx.doi.org/10.4269/ajtmh.19-0366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356486PMC
July 2020

Epidermolysis bullosa with congenital absence of skin: Clinical and genetic characterization of a 23-case series.

Clin Genet 2020 07 7;98(1):99-101. Epub 2020 May 7.

Section of Dermatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.

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http://dx.doi.org/10.1111/cge.13762DOI Listing
July 2020
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