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Introduction: Enamel hypoplasia causes a reduction in the thickness of affected enamel and is one of the most common dental anomalies. This defect is caused by environmental and/or genetic factors that interfere with tooth formation, emphasizing the importance of investigating enamel hypoplasia on an epidemiological and genetic level. Methods: A genome-wide association of enamel hypoplasia was performed in multiple cohorts, overall comprising 7,159 individuals ranging in age from 7 to 82 years. Mixed models were used to test for genetic association while simultaneously accounting for relatedness and genetic population structure. Meta-analysis was then performed. More than 5 million single-nucleotide polymorphisms were tested in individual cohorts. Results: Analyses of the individual cohorts and meta-analysis identified association signals close to genome-wide significance (p < 5 × 10–8), and many suggestive association signals (5 × 10–8 < p < 5 × 10–6) near genes with plausible roles in tooth/enamel development. Conclusion: The strongest association signal (p = 1.57 × 10–9) was observed near BMP2K in one of the individual cohorts. Additional suggestive signals were observed near genes with plausible roles in tooth development in the meta-analysis, such as SLC4A4 which can influence enamel hypoplasia. Additional human genetic studies are needed to replicate these results and functional studies in model systems are needed to validate our findings.

We present a large, ten-generation family of 273 individuals with 84 people having preaxial polydactyly/triphalangeal thumb due to a pathogenic variant in the zone of polarizing activity regulatory sequence (ZRS) within the exon 5 of LMBR1. The causative change maps to position 396 of the ZRS, located at position c.423 + 4909C > T (chr7:156791480; hg38; LMBR1 ENST00000353442.10; rs606231153 NG_009240.2) in the intron 5 of LMBR1. The first affected individual with the disorder was traced back to mid-1700, when some settlers and workers established in Cervera de Buitrago, a small village about 82 km North to Madrid. Clinical and radiological studies of most of the affected members have been performed for 42 years (follow-up of the family by LFGA). Molecular studies have confirmed a pathogenic variant in the ZRS that segregates in this family. To the best of our knowledge, this is the largest family with preaxial polydactyly/triphalangeal thumb reported so far.

BACKGROUND The aim of this study was to determine the mediating effect of spontaneous preterm birth (PTB) main predictors that would allow to suggest etiological pathways. METHODS We carried out a case-control study, including sociodemographic characteristics, habits, health care, and obstetric data of multiparous women who gave birth at a maternity hospital from Tucuman, Argentina, between 2005 and 2010: 998 women without previous PTB who delivered at term and 562 who delivered preterm. We selected factors with the greatest predictive power using a penalized logistic regression model. A data-driven Bayesian network including the selected factors was created where we identified pathways and performed mediation analyses. RESULTS We identified three PTB pathways whose natural indirect effect was greater than zero with a 95% confidence interval: maternal age less than 20 years mediated by few prenatal visits, vaginal bleeding in the first trimester mediated by vaginal bleeding in the second trimester, and urinary tract infection mediated by vaginal bleeding in the second trimester. The effect mediated in these pathways showed greater sensitivity to confounders affecting the variables mediator-outcome and exposure-mediator in the same direction. CONCLUSION The identified pathways suggest PTB etiological lines related to social disparities and exposure to genitourinary tract infections. IMPACT Few prenatal visits (

Preterm birth (PTB) is the main condition related to perinatal morbimortality worldwide. The aim of this study was to identify associations of spontaneous PTB with genetic variants, exposures, and interactions between and within them. We carried out a retrospective case–control study including parental sociodemographic and obstetric data, and fetal genetic variants. We sequenced the coding and flanking regions of five candidate genes from the placental blood cord of 69 preterm newborns and 61 at term newborns. We identify the characteristics with the greatest predictive power of PTB using penalized regressions, in which we include exposures (E), genetic variants (G), and two-way interactions. Few prenatal visits (

Background Preterm birth (PTB) is the leading cause of perinatal morbimortality worldwide. Genetic and environmental factors could raise PTB risk. The aim of this study was to analyze the contribution of the statistical interaction between genes and vaginal-urinary tract infections (VI-UTI) to the risk of PTB by clinical subtype. Methods Twenty-four SNPs were genotyped in 18 candidate genes from 352 fetal triads and 106 maternal triads. Statistical interactions were evaluated with conditional logistic regression models based on genotypic transmission/disequilibrium test. Results In PTB-idiopathic subtype mothers exposed to UTI, fetal SNPs rs11686474 (FSHR), rs4458044 (CRHR1, allele G), rs883319 (KCNN3), and maternal SNP rs1882435 (COL4A3) showed a nominal significant increment in prematurity risk. In preterm premature rupture of membranes (PPROM), fetal SNP rs2277698 (TIMP2) showed a nominal significant risk increment. In mothers exposed to VI, fetal SNP rs5742612 (IGF1) in PTB-PPROM and maternal SNP rs4458044 (CRHR1, allele C) in spontaneous PTB showed nominal significant increment in prematurity risk. Conclusions Certain maternal and fetal genes linked to infectious/inflammatory and hormonal regulation processes increase prematurity risk according to clinical subtype when mothers are exposed to UTI or VI. These findings may help in the understanding of PTB etiology and PTB prevention. Impact Preterm birth is a major cause of perinatal morbimortality worldwide and its etiology remains unknown.This work provides evidence on the statistical interaction of six genes with gestational vaginal or urinary infections leading to the occurrence of preterm births. Statistical interactions vary according to infection type, genotype (maternal and fetal), and clinical subtype of prematurity.Certain maternal and fetal genetic variants of genes linked to infectious/inflammatory and hormonal regulation processes would increase the risk of prematurity according to clinical subtype and infection type.Our findings may help in the study of etiology of preterm birth and its prevention.

Objective: Our aim was to describe the prevalence of diseases during pregnancy and the association between fetal exposure to the most frequent maternal diseases and the risk of preterm (PTB) and/or small for gestational age (SGA) newborns in an unselected sample of women who gave birth in South American countries. Methods: We conducted a descriptive, cross-sectional study including 56,232 mothers of non-malformed infants born between 2002 and 2016, using data from the Latin American Collaborative Study of Congenital Malformations (ECLAMC). Diseases with higher- than-expected PTB/SGA frequencies were identified. Odds ratios of confounding variables for diseases and birth outcomes were calculated with a multivariable logistic regression. Results: Of the 14 most reported diseases, hypertension, genitourinary infection, epilepsy, hypothyroidism, diabetes, and HIV/AIDS showed higher PTB and/or SGA frequencies. Advanced and low maternal age, previous fetal loss, low socioeconomic level, and African-American ancestry were associated with PTB, while advanced maternal age, primigravidity, previous fetal loss, low socioeconomic level, and African-American ancestry were associated with SGA. After adjusting for the associated variables, the identified illnesses maintained their association with PTB and all, except epilepsy, with SGA. Conclusion: The description of an unselected population of mothers allowed identifying the most frequent diseases occurring during gestation and their impact on pregnancy outcomes. Six diseases were associated with PTB and two with SGA newborns. To the best of our knowledge, there are no similar reports about women not intentionally selected by specific diseases during pregnancy in South American populations.

Nonsyndromic orofacial clefts (OFCs) are among the most common craniofacial birth defects worldwide, and known to exhibit phenotypic and genetic heterogeneity. Cleft lip plus cleft palate (CLP) and cleft lip only (CL) are commonly combined together as one phenotype (CL/P), separately from cleft palate alone. In comparison, our study analyzes CL and CLP separately. A sample of 2218 CL and CLP cases, 4537 unaffected relatives of cases, and 2673 pure controls with no family history of OFC were selected from the Pittsburgh Orofacial Cleft (Pitt-OFC) multiethnic study.genome-wide association studies were run for seven specific phenotypes created based on the cleft type(s) observed within these families, as well as the combined CL/P phenotype. Five novel genome-wide significant associations, 3q29 (rs62284390), 5p13.2 (rs609659), 7q22.1 (rs6465810), 19p13.3 (rs628271), and 20q13.33 (rs2427238), and nine associations (p ≤ 1.0E−05) within previously confirmed OFC loci—PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, ARID3B, NTN1, TANC2 and the WNT9B:WNT3 gene cluster—were observed. We also found that single nucleotide polymorphisms within a subset of the associated loci, both previously known and novel, differ substantially in terms of their effects across cleft- or family-specific phenotypes, indicating not only etiologic differences between CL and CLP, but also genetic heterogeneity within each of the two OFC subtypes.

Children with orofacial clefting (OFC) present with a wide range of dental anomalies. Identifying these anomalies is vital to understand their etiology and to discern the complex phenotypic spectrum of OFC. Such anomalies are currently identified using intra-oral exams by dentists, a costly and time-consuming process. We claim that automating the process of anomaly detection using deep neural networks (DNNs) could increase efficiency and provide reliable anomaly detection while potentially increasing the speed of research discovery. This study characterizes the use of` DNNs to identify dental anomalies by training a DNN model using intraoral photographs from the largest international cohort to date of children with nonsyndromic OFC and controls (OFC1). In this project, the intraoral images were submitted to a Convolutional Neural Network (CNN) model to perform multi-label multi-class classification of 10 dental anomalies. The network predicts whether an individual exhibits any of the 10 anomalies and is able to do so significantly faster than a human rater. For every anomaly except mammalons, F1 scores suggest that our model performs competitively at anomaly detection when compared to a dentist with 8 years of clinical experience. In addition, we use saliency maps to provide a post-hoc interpretation for our model’s predictions. This enables dentists to examine and verify our model’s predictions.

Children with orofacial clefting (OFC) present with a wide range of dental anomalies. Identifying these anomalies is vital to understand their etiology and to discern the complex phenotypic spectrum of OFC. Such anomalies are currently identified using intra-oral exams by dentists, a costly and time-consuming process. We claim that automating the process of anomaly detection using deep neural networks (DNNs) could increase efficiency and provide reliable anomaly detection while potentially increasing the speed of research discovery. This study characterizes the use of` DNNs to identify dental anomalies by training a DNN model using intraoral photographs from the largest international cohort to date of children with nonsyndromic OFC and controls (OFC1). In this project, the intraoral images were submitted to a Convolutional Neural Network model to perform multi-label multi-class classification of 10 dental anomalies. The network predicts whether an individual exhibits any of the 10 anomalies and can do so significantly faster than a human rater can. For all but three anomalies, F1 scores suggest that our model performs competitively at anomaly detection when compared to a dentist with 8 years of clinical experience. In addition, we use saliency maps to provide a post-hoc interpretation for our model's predictions. This enables dentists to examine and verify our model's predictions.

OBJECTIVE To describe lethality of birth defects (BDs) in newborns categorized by gestational age and birth weight and to identify BDs associated with prematurity. STUDY DESIGN Live born infants (n = 16,452) with isolated BDs classified by severity, and 42,511 healthy controls were assigned to categories: adequate growth, preterm, or small for gestational age (SGA). Proportion of cases and BDs' lethality rates were obtained by category and compared with controls. RESULTS Overall fewer malformed than non-malformed infants were of adequate growth, while the opposite occurred in the preterm and SGA categories where gastroschisis and esophageal atresia were among the most outstanding defects. For most severe BDs, the early neonatal death rate was higher than control values in all categories; for mild defects, except cleft lip in the preterm category, they did not differ. Diaphragmatic hernia showed the highest lethality values, while those of spina bifida were among the lowest. Talipes, hypospadias, and septal heart defects were mild defects significantly associated with prematurity. CONCLUSION Although reasons, such as induced preterm delivery of fetuses with certain anomalies, could partially account for their high prematurity rates, susceptibility to preterm birth might exist through underlying mechanisms related with the defects. The identification of BDs associated with prematurity should serve to improve measures that prevent preterm birth especially of fetuses at risk. KEY POINTS · Some BDs predispose to prematurity.. · Prematurity is an additional risk factor for mortality in infants with mild defects.. · Lethality values should be adjusted by gestational age and birth weight..

Orofacial clefts (OFCs) are among the most common craniofacial birth defects and constitute a high public health burden around the world. OFCs are phenotypically heterogeneous, affecting only the lip, only the palate, or involving both the lip and palate. Cleft palate alone is demonstrably a genetically distinct abnormality from OFCs that involve the lip, therefore, it is common to study cleft lip (CL) in combination with cleft lip plus cleft palate (CLP) as a phenotypic group (i.e. cleft lip with or without cleft palate, CL/P), usually considering CLP to be a clinically more severe form of CL. However, even within CL/P, important genetic differences among subtypes may be present. The Pittsburgh Orofacial Cleft (Pitt-OFC) multiethnic study is a rich resource for the study of non-syndromic OFC, comprising a large number of families (∼12,000 individuals) from multiple populations worldwide: US and Europe (whites), Central and South America (mixed Native American, European and African), Asia, and Africa. In this study we focused on the CL/P families from this resource grouped into three non-overlapping family types: those with only CL affected members, only CLP affected members, or both CL and CLP. In all, seven total subtypes besides the combined CL/P phenotype, were defined based on the cleft type(s) that were present within pedigree members. The full sample for these analyses includes 2,218 CL and CLP cases along with 4,537 unaffected relatives, as well as 2,673 pure controls with no family history of OFC. Genome-wide association analyses were conducted within each subset, as well as the combined sample. Five novel genome-wide significant associations were observed: 3q29 (rs62284390, p=2.70E-08), 5p13.2 (rs609659, p= 4.57E-08), 7q22.1 (rs6465810, p= 1.25E-08), 19p13.3 (rs628271, p=1.90E-08) and 20q13.33 (rs2427238, p=1.51E-09). In addition, five significant and four suggestive associations confirmed regions previously published as OFC risk loci - PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, ARID3B, NTN1, TANC2 and the WNT9B:WNT3gene cluster. At each of these loci, we compared effect sizes of associated SNPs observed across subtypes and the full sample, and found that certain loci were associated with a specific cleft type, and/or specific family types. Our findings indicate that risk factors differ between cleft and family types, but each cleft type also exhibits a certain degree of genetic heterogeneity.AUTHOR SUMMARYOrofacial clefts are common birth defects. Clefts often run in families, but their genetic basis is still an active area of investigation. In this study, we use an innovative approach to identify shared and unique genetic risk factors between two types of orofacial clefts - cleft lip and cleft lip plus cleft palate, by taking the patterns of different cleft types reported in families into account. Our study provides new insights into previously known genetic risk factors, but also identifies novel genetic regions that differentially impact the risk of developing cleft lip versus cleft lip plus cleft palate. This study contributes to the growing evidence that different sets of genes impact different forms of clefting and highlights the importance of incorporating information about familial affection patterns into analyses.

Background Dental caries is one of the most common chronic diseases and is influenced by a complex interplay of genetic and environmental factors. Most previous genetic studies of caries have focused on identifying genes that contribute to dental caries in specific ethnic groups, usually of European descent. Methods The aim of this study is to conduct a genome-wide association study (GWAS) to identify associations affecting susceptibility to caries in a large multiethnic population from Argentina, the Philippines, Guatemala, Hungary, and the USA, originally recruited for studies of orofacial clefts (POFC, N = 3686). Ages of the participants ranged from 2 to 12 years for analysis of the primary dentition, and 18–60 years for analysis of the permanent dentition. For each participant, dental caries was assessed by counts of decayed and filled teeth (dft/DFT) and genetic variants (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Caries was analyzed separately for the primary and permanent dentitions, with age, gender, and presence/absence of any type of OFC treated as covariates. Efficient Mixed-Model Association eXpedited (EMMAX) was used to test genetic association, while simultaneously accounting for relatedness and stratification. Results We identified several suggestive loci (5 × 10−8 P −6) within or near genes with plausible biological roles for dental caries, including a cluster of taste receptor genes (TAS2R38, TAS2R3, TAS2R4, TASR25) on chromosome 7 for the permanent dentition analysis, and DLX3 and DLX4 on chromosome 17 for the primary dentition analysis. Genome-wide significant results were seen with SNPs in the primary dentition only; however, none of the identified genes near these variants have known roles in cariogenesis. Conclusion The results of this study warrant further investigation and may lead to a better understanding of cariogenesis in diverse populations, and help to improve dental caries prediction, prevention, and/or treatment in future.

The aim of this study was to determine the mediating effect of spontaneous preterm birth (PTB) main predictors that would allow to suggest etiological pathways.We carried out a case-control study, including sociodemographic characteristics, habits, health care, and obstetric data of multiparous women who gave birth at a maternity hospital from Tucumán, Argentina, between 2005 and 2010: 998 women without previous PTB who delivered at term and 562 who delivered preterm. We selected factors with the greatest predictive power using a penalized logistic regression model. A data-driven Bayesian network including the selected factors was created where we identified pathways and performed mediation analyses.We identified three PTB pathways whose natural indirect effect was greater than zero with a 95% confidence interval: maternal age less than 20 years mediated by few prenatal visits, vaginal bleeding in the first trimester mediated by vaginal bleeding in the second trimester, and urinary tract infection mediated by vaginal bleeding in the second trimester. The effect mediated in these pathways showed greater sensitivity to confounders affecting the variables mediator-outcome and exposure-mediator in the same direction.The identified pathways suggest PTB etiological lines related to social disparities and exposure to genitourinary tract infections.Few prenatal visits (5) and vaginal bleeding are two of the main predictors for spontaneous preterm birth in the studied population. Few prenatal visits mediates part of the risk associated with maternal age less than 20 years and vaginal bleeding in the second trimester mediates part of the risk associated with vaginal bleeding in the first trimester and with urinary tract infection. Social disparities and exposure to genitourinary tract infections would be etiological lines of spontaneous preterm birth.

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic and vary in prevalence by ethnicity. Africans have the lowest prevalence of OFCs (∼ 1/2,500), Asians have the highest prevalence (∼1/500), European and Latin Americans lie somewhere in the middle (∼1/800 and 1/900 respectively). Thus, ethnicity appears to be a major determinant of the risk of developing OFC. The Pittsburgh Orofacial Clefts Multiethnic study was designed to explore this ethnic variance, comprising a large number of families and individuals (∼12,000 individuals) from multiple populations worldwide: US and Europe, Asians, mixed Native American/Caucasians, and Africans. In this current study, we analyzed 2,915 OFC cases, 6,044 unaffected individuals related to the OFC cases, and 2,685 controls with no personal or family history of OFC. Participants were grouped by their ancestry into African, Asian, European, and Central and South American subsets, and genome-wide association run on the combined sample as well as the four ancestry-based groups. We observed 22 associations to cleft lip with or without cleft palate at 18 distinct loci with p-values < 1e-06, including 10 with genome-wide significance (< 5e-08), in the combined sample and within ancestry groups. Three loci - 2p12 (rs62164740, p=6.27e-07), 10q22.2 (rs150952246, p=3.14e-07), and 10q24.32 (rs118107597, p=8.21e-07) are novel. Nine were in or near known OFC loci - PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, NTN1, WNT3-WNT9B, TANC2, and RHPN2. The majority of the associations were observed only in the combined sample, European, and Central and South American groups. We investigated whether the observed differences in association strength were a) purely due to sample sizes, b) due to systematic allele frequency difference at the population level, or (c) due to the fact certain OFC-causing variants confer different amounts of risk depending on ancestral origin, by comparing effect sizes to observed allele frequencies of the effect allele in our ancestry-based groups. While some of the associations differ due to systematic differences in allele frequencies between groups, others show variation in effect size despite similar frequencies across ancestry groups.

Birth defects are prenatal morphological or functional anomalies. Associations among them are studied to identify their etiopathogenesis. The graph theory methods allow analyzing relationships among a complete set of anomalies. A graph consists of nodes which represent the entities (birth defects in the present work), and edges that join nodes indicating the relationships among them. The aim of the present study was to validate the graph theory methods to study birth defect associations. All birth defects monitoring records from the Estudio Colaborativo Latino Americano de Malformaciones Congénitas gathered between 1967 and 2017 were used. From around 5 million live and stillborn infants, 170,430 had one or more birth defects. Volume-adjusted Chi-Square was used to determine the association strength between two birth defects and to weight the graph edges. The complete birth defect graph showed a Log-Normal degree distribution and its characteristics differed from random, scale-free and small-world graphs. The graph comprised 118 nodes and 550 edges. Birth defects with the highest centrality values were nonspecific codes such as Other upper limb anomalies. After partition, the graph yielded 12 groups; most of them were recognizable and included conditions such as VATER and OEIS associations, and Patau syndrome. Our findings validate the graph theory methods to study birth defect associations. This method may contribute to identify underlying etiopathogeneses as well as to improve coding systems. Fil: Elias, Dario Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Campaña, Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Heisecke Peralta, Silvina Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Gili, Juan Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Ratowiecki, Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Gimenez, Lucas Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Pawluk, Mariela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Santos, María Rita. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Cosentino, Viviana Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Uranga, Rocio. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal Especializado de Agudos y Cronicos San Juan de Dios.; Argentina. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; Argentina Fil: Rittler, Monica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina. Hospital Materno Infantil Ramon Sarda ; Gobierno de la Ciudad Autonoma de Buenos Aires; Argentina Fil: López Camelo, Jorge Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina

The identification of clinical patterns of tooth agenesis in individuals born with craniofacial deformities may be a useful tool for risk determination of these defects. We hypothesize that specific craniofacial deformities are associated with third molar agenesis. Objective The aim of this study was to identify if third molar agenesis could have a relation with other craniofacial structure alterations, such as cleft lip and palate, skeletal malocclusion, or specific growth patterns in humans. Design Data were obtained from 550 individuals ascertained as part of studies aiming to identify genetic contributions to oral clefts. 831 dental records of patients aged over eight years seeking orthodontic treatment were also included. SN-GoGn angle were used to classify the growth pattern (hypo-divergent, normal and hyper-divergent), and the ANB angle was used to verify the skeletal malocclusion pattern (Class I, II and III). Panoramic radiographs were used to determine third molar agenesis. Results A high frequency of third molar agenesis among individuals born with cleft lip with or without cleft palate (55%), as well as among their relatives (93.5%) was found. Third molar agenesis was not associated to skeletal malocclusion or growth pattern. Conclusion It appears that third molar agenesis is associated with the disturbances that lead to cleft lip and palate.

Background. Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity. PTB is often classified according to clinical presentation: Idiopathic (PTB-I), preterm premature rupture of membranes (PTB-PPROM), and medically induced (PTBM). The aim of this study was to evaluate the associations between specific candidate genes and clinical subtypes of PTB. Methods. 24 SNPs were genotyped in 18 candidate genes in 709 infant triads. Of them, 243 were PTB-I, 256 PTB-PPROM, and 210 PTB-M. These data were analyzed with a Family-Based Association. Results. PTB was nominally associated with rs2272365 in PON1, rs883319 in KCNN3, rs4458044 in CRHR1, and rs610277 in F3. Regarding clinical subtypes analysis, 3 SNPs were associated with PTB-I (rs2272365 in PON1, rs10178458 in COL4A3, and rs4458044 in CRHR1), rs610277 in F3 was associated with PTBPPROM, and rs883319 in KCNN3 and rs610277 in F3 were associated with PTB-M. Conclusions. Our study identified polymorphisms potentially associated with specific clinical subtypes of PTB in this Latin American population. These results could suggest a specific role of such genes in the mechanisms involved in each clinical subtype. Further studies are required to confirm our results and to determine the role of these genes in the pathophysiology of clinical subtypes.

El objetivo fue explicar las diferencias en la frecuencia de eventos perinatales adversos entre madres adolescentes con baja y alta escolaridad. La muestra poblacional se recogió en la base de datos del Estudio Colaborativo Latinoamericano de Malformaciones Congénitas (ECLAMC). Entre 2.443.747 nacimientos ocurridos en 93 hospitales, se reclutaron 66.755 recién nacidos vivos, sin defectos congénitos, durante el período 2000-2017. Las madres adolescentes se clasificaron según su escolaridad en: baja, media y alta. Se utilizó un modelo multivariado, que incluyó efectos reproductivos, acceso a servicios de salud, variables demográficas-socioeconómicas, así como de grupo étnico. El modelo de descomposición de Fairlie se aplicó para cuantificar la contribución de variables explicativas en las frecuencias de eventos perinatales adversos. De los 66.755 recién nacidos investigados, el 21,1% (n = 14.078) fue primigrávida de madres adolescentes. La distribución por escolaridad materna fue de 24,2%, 59,8% y 16% para baja, media y alta escolaridad, respectivamente. Las mayores frecuencias de eventos perinatales adversos se observaron en madres adolescentes con baja escolaridad. La variable “acceso a servicios de salud” explicó un 35%, 37% y 23% de las disparidades en el bajo peso al nacimiento, prematuridad y retardo de crecimiento intrauterino, respectivamente, entre madres adolescentes con baja y alta escolaridad. El bajo número de consultas prenatales fue el único factor de riesgo para los dos niveles de escolaridad y la variable que mejor explica las diferencias entre las frecuencias de eventos perinatales adversos. Desde el punto de vista de la salud pública, ellos representan una intervención de bajo coste, con posibilidad de que se incrementen mediante información adecuada para la población y medidas sistemáticas en los niveles de atención primaria. The aim was to explain differences in the rates of adverse perinatal events in teenage mothers with low and high schooling. The sample was collected from the Latin American Colaborative Study of Congenital Malformations (ECLAMC) database. From a total of 2,443,747 births in 93 hospitals, 66,755 live newborns without congenital malformations were recruited from 2000 to 2017. Teenage mothers were classified according to low, medium, and high schooling. A multivariate model was used that included reproductive history, access to health services, demographic and socioeconomic variables, and ethnic group. The Fairlie decomposition model was applied to quantify the contribution of explanatory variables to the adverse perinatal event rates. Of the 66,755 newborns analyzed, 21.1% (n = 14,078) were born to teenage mothers. Distribution of maternal schooling was 24.2%, 59.8%, and 16% for low, medium, and high schooling, respectively. The highest rates of adverse perinatal events were seen in teenage mothers with low schooling. The variable “access to health services” explained 35%, 37%, and 23% of the disparities in low birthweight, prematurity, and intrauterine growth restriction, respectively, among teenage mother with low and high schooling. Low number of prenatal visits was the only risk factor for the two levels of schooling and the variable that best explained the differences between the rates of adverse perinatal events. From the public health perspective, prenatal care represents a low-cost intervention with the possibility of increased implementation through adequate information for the population and systematic measures in primary care. O objetivo foi explicar as diferenças na frequência de eventos perinatais adversos entre mães adolescentes com baixa e alta escolaridade. A amostra populacional foi coletada na base de dados do Estudo Colaborativo Latino-Americano de Malformações Congênitas (ECLAMC). Entre 2.443.747 nascimentos ocorridos em 93 hospitais, 66.755 recém-nascidos vivos sem defeitos congênitos foram recrutados no período 2000-2017. As mães adolescentes foram classificadas segundo sua escolaridade em: baixa, média e alta. Foi utilizado um modelo multivariado que incluiu efeitos reprodutivos, acesso a serviços de saúde, variáveis demográficas-socioeconômicas e de grupo étnico. O modelo de decomposição de Fairlie foi aplicado para quantificar a contribuição de variáveis explicativas nas frequências de eventos perinatais adversos. Dos 66.755 recém-nascidos pesquisados, o 21,1% (n = 14.078) foi a mãe adolescente. A distribuição por escolaridade materna foi de 24,2%, 59,8% e 16% para baixa escolaridade, média escolaridade e alta escolaridade, respectivamente. As maiores frequências de eventos perinatais adversos foram observadas em mães adolescentes com baixa escolaridade. A variável “acesso a serviços de saúde”; explicou 35%, 37% e 23% das disparidades no baixo peso ao nascer, prematuridade e retardo de crescimento intrauterino, respectivamente, entre mães adolescentes com baixa e alta escolaridades. O baixo número de consultas pré-natais foi o único fator de risco para os dois níveis de escolaridade e a variável que melhor explica as diferenças entre as frequências de eventos perinatais adversos. Do ponto de vista da saúde pública, eles representam uma intervenção de baixo custo, com possibilidade de ser incrementadas por meio de informações adequadas à população e medidas sistemáticas nos níveis de atenção primária. Fil: Ratowiecki, Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Santos, María Rita. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Heisecke Peralta, Silvina Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Elias, Dario Ezequiel. No especifíca; Fil: Gili, Juan Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Gimenez, Lucas. No especifíca; Fil: Pawluk, Mariela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Uranga, Rocio. No especifíca; Fil: Cosentino, Viviana Raquel. No especifíca; Fil: Campaña, Hebe. No especifíca; Fil: Rittler, Mónica. No especifíca; Fil: López Camelo, Jorge S.. No especifíca

Fil: Campana, Hebe. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Medicas e Investigaciones Clinicas "Norberto Quirno". CEMIC-CONICET.; Argentina

Objective To evaluate prevalence trends of hypospadias in South-America it is essential to perform multicenter and multinational studies with the same methodology. Herein we present systematic data as part of an international multicenter initiative evaluating congenital malformations in South America over a 24-year period. Materials and Methods A nested case-control study was conducted using the Latin American Collaborative Study of Congenital Malformations (ECLAMC), between January 1989 and December 2012. Cases were stratified as isolated (IH) and non-isolated hypospadias (NIH). Global prevalence was calculated and discriminated by country. Associations between birth weight and gestational age, and NIH distribution by associated abnormality and severity of hypospadias, were analyzed. Results A total of 159 hospitals from six countries participated, reporting surveillance on 4.020.384 newborns. A total of 4.537 hypospadias cases were detected, with a global prevalence of 11.3/10.000 newborns. Trend analyses showed in Chile, Brazil and Uruguay a statistically significant increase in prevalence. Analysis of severity and associated anomalies did not to find an association for distal cases, but did for proximal (RR=1.64 [95% CI=1.33-2.03]). Conclusion This is one of only a few Latin American multicenter studies reporting on the epidemiology of hypospadias in South America in the last two decades. Our data adds to evidence suggesting an increase in some countries in the region at different times. There were also variations in prevalence according to severity. This study adds to literature describing associated anomalies at a hospital-based level.

Geographical clusters are defined as the occurrence of an unusual number of cases higher than expected in a given geographical area in a certain period of time. The aim of this study was to identify potential geographical clusters of specific selected congenital anomalies (CA) in Argentina. The cases were ascertained from 703,325 births, examined in 133 maternity hospitals in the 24 provinces of Argentina. We used the spatial scan statistic to determine areas of Argentina which had statistically significant elevations of prevalence. Prenatal diagnosis followed by referral of high-risk pregnancies to high complexity hospitals in a hospital-based surveillance system can create artifactual clusters. We assessed the referral bias by evaluating the prevalence heterogeneity within each cluster. Eight clusters of selected CAs with unusually high birth prevalence were identified: anencephaly, encephalocele, spina bifida, diaphragmatic hernia, talipes equinovarus, omphalocele, Cleft lip with or without cleft palate (CL/P), and Down syndrome. The clusters of Down syndrome and CL/P observed in this study match the previously reported clusters. These findings support local targeted interventions to lower the prevalence of the CAs and/or further research on the cause of each cluster. The clusters of spina bifida, anencephaly, encephalocele, omphalocele, congenital diaphragmatic hernia, and talipes equinovarus may be influenced by prenatal diagnosis and referral to high complexity hospitals. Fil: Groisman, Boris. Ministerio de Salud de la Nación. Centro Nacional de Genética Médica. Registro Nacional de Anomalías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Gili, Juan Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Gimenez, Lucas Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina. Instituto Nacional de Genética Médica Populacional; Brasil Fil: Bidondo, Maria Paz. Ministerio de Salud de la Nación. Centro Nacional de Genética Médica. Registro Nacional de Anomalías Congénitas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina Fil: Barbero, Pablo. Ministerio de Salud de la Nación. Centro Nacional de Genética Médica. Registro Nacional de Anomalías Congénitas; Argentina Fil: Liascovich, Rosa. Ministerio de Salud de la Nación. Centro Nacional de Genética Médica. Registro Nacional de Anomalías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: López Camelo, Jorge Santiago. Instituto Nacional de Genética Médica Populacional; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina

Increased susceptibility to cleft lip, with or without cleft palate (CL±P) has been observed in South America, as related to Amerindian ancestry, using epidemiological data, uniparental markers, and blood groups. In this study, it was evaluated whether this increased risk remains when Amerindian ancestry is estimated using autosomal markers and considered in the predictive model. Ancestry was estimated through genotyping 62 insertion and deletion (INDEL) markers in sample sets of patients with CL±P, patients with cleft palate (CP), and controls, from Patagonia in southern Argentina and Belém in northern Brazil. The Amerindian ancestry in patients from Patagonia with CL±P was greater than in controls although it did not reach statistical significance. The European ancestry in patients with CL±P from Belém and in patients with CP from Belém and Patagonia was higher than in controls and statistically significant for patients with CP who were from Belém. This high contribution of European genetic ancestry among patients with CP who were from Belém has not been previously observed in American populations. Our results do not corroborate the currently accepted risks for CL±P and CP estimated by epidemiological studies in the North American populations and probably reflect the higher admixture found in South American ethnic groups when compared with the same ethnic groups from the North American populations.

Dermatoglyphic patterns on the fingers often differ in syndromes and other conditions with a developmental component, compared to the general population. Previous literature on the relationship between orofacial clefts-the most common craniofacial birth defect in humans-and dermatoglyphics is inconsistent, with some studies reporting altered pattern frequencies and/or increased asymmetry and others failing to find differences. To investigate dermatoglyphics in orofacial clefting, we obtained dermatoglyphic patterns in a large multiethnic cohort of orofacial cleft cases (N = 367), their unaffected family members (N = 836), and controls (N = 299). We categorized fingerprint pattern types from males and females who participated at five sites of the Pittsburgh Orofacial Cleft study (Hungary, United States of America (Pennsylvania, Texas), Spain, and Argentina). We also calculated a pattern dissimilarity score for each individual as a measure of left-right asymmetry. We tested for group differences in the number of arches, ulnar and radial loops, and whorls on each individual's hands, and in the pattern dissimilarity scores using ANOVA. After taking sex and site differences into account, we did not find any significant pattern count differences between cleft and non-cleft individuals. Notably, we did observe increased pattern dissimilarity in individuals with clefts, compared to both their unaffected relatives and controls. Increased dermatoglyphic pattern dissimilarity in individuals with nonsyndromic orofacial clefts may reflect a generalized developmental instability.

BACKGROUND:Despite the numerous reports on the limb body wall complex (LBWC), this association has never been adequately defined. Amniotic bands (AB) are frequently present but their role remains unclear. Since most reports were based on clinical and often subjective diagnoses, the aim of this work was to define LBWC and the role of AB, minimizing subjectivity.METHODS:Data were obtained from the ECLAMC maternity hospitals network database. A total of 450 live and stillborn infants, born during 1967-2013, with AB or the LBWC were selected. A hierarchical cluster analysis was used to classify cases into homogeneous groups (sharing similar associated defects); robustness of the classification was confirmed with a discriminant analysis. The frequency of associated defects was compared among groups; those whose frequency differed significantly were included in a logistic regression to establish their association within each group.RESULTS:The cluster analysis identified two groups: a body wall defect (BWD) predominating in one, AB in the other. These groups were further divided into: BWD (cases with only BWD), AB (with only AB), BWD + AB, and NONE (with neither). Association with caudal defects and lower limb amelia was observed for BWD, with cephalic defects and upper limb amputations for BWD + AB.CONCLUSIONS:The results, obtained with the least possible subjectivity, indicated that BWD and BWD + AB are different conditions. Since BWD specifically associates with amelia, we propose that this defect and not any limb deficiency should be considered as inclusion criterium and that it should be included in the BWD acronym as LBWC. Fil: Rittler, Monica. Universidad de Buenos Aires; Argentina Fil: Campaña, Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina. Comisión de Investigaciones Científicas, Buenos Aires; Argentina Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina. Instituto Nacional de Genética Médica Poblacional; Brasil Fil: Santos, María Rita. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Gili, Juan Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Pawluk, Mariela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Cosentino, Viviana Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Gimenez, Lucas Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: López Camelo, Jorge Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina. Instituto Nacional de Genética Médica Poblacional; Brasil

Introduction. Low birth weight (LBW) is considered a general indicator of health because it is related to complications in the life of a newborn infant and is one of the leading causes of infant mortality. It is a multifactorial indicator, and its determinants include socioeconomic factors. Objective. To assess the impact of economic inequality on the prevalence of LBW by quantifying its differential effect by maternal age, level of maternal education, and level of care. Population and methods. Epidemiological, cross-sectional study that analyzed all births occurred in Argentina between 2001 and 2013 based on data provided by the National Registry of births, corresponding to the Health Statistics and Information Department. The temporal variation in the prevalence of LBW newborn infants (< 2500 grams) and its relation to demographic and socioeconomic indicators were studied. Its association was assessed using logistic regression models. Results. A total of 9 001 960 births were included. The prevalence of LBW newborn infants during the 2001 economic crisis increased -6% in 2002 and 7% in 2003- The impact was heterogeneous and higher on public hospitals ([PR] = 1.03) and adolescent mothers (PR = 1.07), but no impact was observed on a low level of maternal education (PR= 0.99). Conclusions. The impact of socioeconomic inequality on the prevalence of LBW was significant and heterogeneous, especially on public hospitals and mothers at the extremes of maternal age. Fil: Ratowiecki, Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Gimenez, Lucas Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Gili, Juan Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Pawluk, Mariela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: López Camelo, Jorge Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene-by-sex (G x S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome-wide joint tests of the genetic (G) and G x S effects genome-wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test (p < 1.00 × 10−5) by examining the G x S effects from the same model. Out of the 133 loci with suggestive results (p < 1.00 × 10−5) for the joint test, we observed one genome-wide significant G x S effect in the 10q21 locus (rs72804706; p = 6.69 × 10−9; OR = 2.62 [1.89, 3.62]) and 16 suggestive G x S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects.

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene-by-sex (G x S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome-wide joint tests of the genetic (G) and G x S effects genome-wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test (p < 1.00 × 10(−5)) by examining the G x S effects from the same model. Out of the 133 loci with suggestive results (p < 1.00 × 10(−5)) for the joint test, we observed one genome-wide significant G x S effect in the 10q21 locus (rs72804706; p = 6.69 × 10(−9); OR = 2.62 [1.89, 3.62]) and 16 suggestive G x S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects.

The detection of high-grade intraepithelial lesions requires highly sensitive and specific methods that allow more accurate diagnoses. This contributes to a proper management of preneoplastic lesions, thus avoiding overtreatment. The purpose of this study was to analyze the value of immunostaining for p16 in the morphologic assessment of cervical intraepithelial neoplasia 2 lesions, to help differentiate between low-grade (p16-negative) and high-grade (p16-positive) squamous intraepithelial lesions. The direct medical cost of the treatment of cervical intraepithelial neoplasia 2 morphologic lesions was estimated. A retrospective observational cross-sectional study was carried out. This study analyzed 46 patients treated with excisional procedures because of cervical intraepithelial neoplasia 2 lesions, using loop electrosurgical excision procedures. Immunostaining for the biomarker was performed. For the estimation of overtreatment, percentages (%) and their 95% confidence interval were calculated. Of the 41 patients analyzed, 32 (78%) showed overexpression of p16 and 9 (22%) were negative (95% confidence interval, 11%-38%). Mean follow-up was 2.9 years, using cervical cytology testing (Pap) and colposcopy. High-risk human papillomavirus DNA tests were performed in 83% of patients. These retrospective results reveal the need for larger biopsy samples, which would allow a more accurate prediction of lesion risk. Considering the cost of p16 staining, and assuming the proper management of the low-grade lesion, an average of US$919 could be saved for each patient with a p16-negative result, which represents a global direct cost reduction of 10% Fil: Fishkel, Vanina S.. Centro de Educación Medica E Invest.clinicas; Argentina Fil: Monge, Fernando C.. Centro de Educación Medica E Invest.clinicas; Argentina Fil: von Petery, Felicitas M.. Centro de Educación Medica E Invest.clinicas; Argentina Fil: Tapper, Karen E.. Centro de Educación Medica E Invest.clinicas; Argentina Fil: Peña, Teresa M.. Centro de Educación Medica E Invest.clinicas; Argentina Fil: Torres, Florencia. Centro de Educación Medica E Invest.clinicas; Argentina Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Elgart, Jorge Federico. Universidad Nacional de La Plata; Argentina Fil: Avagnina, Alejandra. Centro de Educación Medica E Invest.clinicas; Argentina Fil: Denninghoff, Valeria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina

Background: Historically, neural tube defects (NTDs) have predominated in female infants but the reasons remain unclear. In South America, the pre-folic acid fortification (FAF) rates of NTDs were around 18/10,000 births for females and 12/10,000 births for males, with an estimated sex ratio (male/female) of 0.67. During the post-FAF period, unpublished routine reports have indicated changes in the sex ratio for these defects while some descriptive reports are controversial. To date and to our knowledge, however, no studies specifically focusing on these changes to test this hypothesis directly have been undertaken. The aim of this study was to analyze changes in the sex ratio of infants with NTDs after FAF in South American countries. Materials and methods: With a descriptive cross-sectional study design, 2,597 infants with isolated NTDs born between 1990 and 2013 in 3 countries participating in the Latin American Collaborative Study of Congenital Malformations (ECLAMC) network were included: (Chile N = 521 and Argentina N = 1,619 [with FAF policies]; Venezuela N = 457 [without FAF policies; used as control]; total births = 2,229,561). The differences-in-differences method and Poisson regressions were used to evaluate the sex ratio shift from female to male before vs. after FAF, and to assess whether these differences were related to the fortification. Results and conclusions: In Chile and Argentina the prevalence of NTDs, particularly anencephaly and cervico-tho-racic spina bifida, showed a greater reduction rate in females than in males after FAF, resulting in a change of the sex ratio of infants with NTDs. Some mechanisms possibly involved in this differential reduction are proposed which might be useful to identify the pathogenesis of NTDs as a whole and specifically of those susceptible to the protective effect of folic acid. Fil: Poletta, Fernando Adrián. Ciudad Autónoma de Buenos Aires. Hospital Materno Infantil “Ramón Sardá”; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Rittler, Monica. Ciudad Autónoma de Buenos Aires. Hospital Materno Infantil “Ramón Sardá”; Argentina Fil: Saleme, Cesar. Ciudad Autónoma de Buenos Aires. Hospital Materno Infantil “Ramón Sardá”; Argentina Fil: Campaña, Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Gili, Juan Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Pawluk, Mariela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Gimenez, Lucas Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Cosentino, Viviana Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Castilla, Eduardo Enrique. Ciudad Autónoma de Buenos Aires. Hospital Materno Infantil “Ramón Sardá”; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: López Camelo, Jorge Santiago. Ciudad Autónoma de Buenos Aires. Hospital Materno Infantil “Ramón Sardá”; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina

Background The birth prevalence rate (BPR) of congenital anomalies (CAs) is heterogeneous and exhibits geographical and sociocultural variations throughout the world. In South America (SA), high birth prevalence regions of congenital anomalies have been observed. The aim of this study was to identify, describe, and characterize geographical clusters of congenital anomalies in SA. Methods This observational descriptive study is based on clinical epidemiological data registered by the Latin-American Collaborative Study of Congenital Malformations network. Between 1995 and 2012, a total of 25,082 malformed newborns were ascertained from 2,557,424 births at 129 hospitals in SA. The spatial scan statistic was used to determine geographical regions with high BPR of CAs. The BPR was obtained with a Poisson regression model. Odds ratios were estimated for several risk factors inside the geographical clusters. Results We confirmed the existence of high BPR regions of CAs in SA. Indicators of low socioeconomic conditions, such as a low maternal education, extreme age childbearing, infectious diseases, and medicine use during pregnancy were detected as risk factors inside these regions. Native and African ancestries with high frequency of consanguineous marriages could explain partially these high BPR clusters. Conclusion The recognition of clusters could be a starting point in the identification of susceptibility genes associated with the occurrence of CA in high BPR regions. Birth Defects Research (Part A) 106:257–266, 2016. © 2016 Wiley Periodicals, Inc.

Background Although young maternal age has been identified as a risk factor for gastroschisis, its role remains undisclosed. To our knowledge, the differences between young mothers of infants with gastroschisis and young mothers of infants with other pregnancy outcomes have not been established. The aim of this work was to compare characteristics of young mothers whose newborn had gastroschisis with same aged mothers of malformed and nonmalformed control infants, diagnosed within the ECLAMC maternity hospital network. Methods Data base records of live and stillborn infants of one of three groups (with isolated gastroschisis, with 1 of 5 other isolated birth defects, and nonmalformed), and whose mothers were younger than 20 years, were selected. Secular trends were obtained for all birth defects; frequencies and odds ratios (OR) of demographic and reproductive variables were compared among the 3 groups. Significantly associated variables were adjusted with a multivariate regression. Results The association was higher with gastroschisis 1) than with other birth defects for African ancestry, smoking, adequate prenatal control and diagnosis 2) than with nonmalformed controls for maternal illnesses and alcohol 3) and than both for previous pregnancy loss and medication, mainly sex hormones. After adjustment, only previous pregnancy loss maintained its significance when compared with malformed (OR = 2.34; 1.37–3.97; P = 0.002), as well as with nonmalformed (OR = 3.43; 2.07–5.66; P

The 19q13 locus has been linked to cleft lip and palate by our group and independently by others. Here we fine mapped the region in an attempt to identify an etiological variant that can explain cleft lip and palate occurrence. A total of 2739 individuals born with cleft lip and palate, related to individuals born with cleft lip and palate, and unrelated were studied. We used linkage and association approaches to fine map the interval between D19S714 and D19S433 and genotypes were defined by the use of TaqMan chemistry. We confirmed our previous findings that markers in PVR/CD155 are associated with cleft lip and palate. We studied the mutation Ala67Thr further and calculated its penetrance. We also attempted to detect PVR/CD155 expression in human whole saliva. Our results showed that markers in PVR/CD155 are associated with cleft lip and palate and the penetrance of the Ala67Thr is very low (between 1% and 5%). We could not detect PVR/CD155 expression in adult human whole saliva and PVR/CD155 possibly interacts with maternal infection to predispose children to cleft lip only.

Orofacial clefts (OFCs) are common, complex birth defects with extremely heterogeneous phenotypic presentations. Two common subtypes—cleft lip alone (CL) and CL plus cleft palate (CLP)—are typically grouped into a single phenotype for genetic analysis (i.e., CL with or without cleft palate, CL/P). However, mounting evidence suggests there may be unique underlying pathophysiology and/or genetic modifiers influencing expression of these two phenotypes. To this end, we performed a genome-wide scan for genetic modifiers by directly comparing 450 CL cases with 1,692 CLP cases from 18 recruitment sites across 13 countries from North America, Central or South America, Asia, Europe, and Africa. We identified a region on 16q21 that is strongly associated with different cleft type (P = 5.611 × 10−8). We also identified significant evidence of gene–gene interactions between this modifier locus and two recognized CL/P risk loci: 8q21 and 9q22 (FOXE1) (P = 0.012 and 0.023, respectively). Single nucleotide polymorphism (SNPs) in the 16q21 modifier locus demonstrated significant association with CL over CLP. The marker alleles on 16q21 that increased risk for CL were found at highest frequencies among individuals with a family history of CL (P = 0.003). Our results demonstrate the existence of modifiers for which type of OFC develops and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs. Fil: Carlson, Jenna C.. University of Pittsburgh; Estados Unidos Fil: Standley, Jennifer. University of Iowa; Estados Unidos Fil: Petrin, Aline. University of Iowa; Estados Unidos Fil: Shaffer, John R.. University of Pittsburgh; Estados Unidos Fil: Butali, Azeez. University of Iowa; Estados Unidos Fil: Buxó, Carmen J.. Universidad de Puerto Rico; Puerto Rico Fil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Christensen, Kaare. University of Southern Denmark; Dinamarca Fil: Deleyiannis, Frederic W.-D.. State University of Colorado Boulder; Estados Unidos Fil: Hecht, Jacqueline T.. University of Texas; Estados Unidos Fil: Field, L. Leigh. University of British Columbia; Canadá Fil: Garidkhuu, Ariuntuul. Tohoku University; Japón. Mongolian National University Of Medical Sciences; Mongolia Fil: Moreno Uribe, Lina M.. University of Iowa; Estados Unidos Fil: Nagato, Natsume. Aichi Gakuin University; Japón Fil: Orioli, Ieda M.. Instituto Nacional de Genética Médica Populacional; Brasil. Universidade Federal do Rio de Janeiro; Brasil Fil: Padilla, Carmencita. University Of The Philippines Manila; Filipinas Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Suzuki, Satoshi. Aichi Gakuin University; Japón Fil: Vieira, Alexandre R.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos Fil: Wehby, George. University of Iowa; Estados Unidos Fil: Weinberg, Seth M.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos Fil: Beaty, Terri H.. University Johns Hopkins; Estados Unidos Fil: Feingold, Eleanor. University of Pittsburgh; Estados Unidos Fil: Murray, Jeffrey C.. University of Iowa; Estados Unidos Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos Fil: Leslie, Elizabeth J.. University of Emory; Estados Unidos

Objective To describe the prevalence and clinical spectrum of microcephaly in South America for the period 2005-14, before the start of the Zika epidemic in 2015, as a baseline for future surveillance as the Zika epidemic spreads and as other infectious causes may emerge in future.Design Prevalence and case-control study.Data sources ECLAMC (Latin American Collaborative Study of Congenital Malformations) database derived from 107 hospitals in 10 South American countries, 2005 to 2014. Data on microcephaly cases, four non-malformed controls per case, and all hospital births (all births for hospital based prevalence, resident within municipality for population based prevalence). For 2010-14, head circumference data were available and compared with Intergrowth charts.Results 552 microcephaly cases were registered, giving a hospital based prevalence of 4.4 (95% confidence interval 4.1 to 4.9) per 10 000 births and a population based prevalence of 3.0 (2.7 to 3.4) per 10 000. Prevalence varied significantly between countries and between regions and hospitals within countries. Thirty two per cent (n=175) of cases were prenatally diagnosed; 29% (n=159) were perinatal deaths. Twenty three per cent (n=128) were associated with a diagnosed genetic syndrome, 34% (n=189) polymalformed without a syndrome diagnosis, 12% (n=65) with associated neural malformations, and 26% (n=145) microcephaly only. In addition, 3.8% (n=21) had a STORCH (syphilis, toxoplasmosis, other including HIV, rubella, cytomegalovirus, and herpes simplex) infection diagnosis and 2.0% (n=11) had consanguineous parents. Head circumference measurements available for 184/235 cases in 2010-14 showed 45% (n=82) more than 3 SD below the mean, 24% (n=44) between 3 SD and 2 SD below the mean, and 32% (n=58) larger than -2 SD.Conclusion Extrapolated to the nearly 7 million annual births in South America, an estimated 2000-2500 microcephaly cases were diagnosed among births each year before the Zika epidemic began in 2015. Clinicians are using more than simple metrics to make microcephaly diagnoses. Endemic infections are important enduring causes of microcephaly. Fil: Orioli, Iêda M.. Instituto Nacional de Genética Médica Populacional; Brasil. Universidade Federal do Rio de Janeiro; Brasil Fil: Dolk, Helen. Ulster University; Reino Unido Fil: López Camelo, Jorge Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina. Instituto Nacional de Genética Médica Populacional; Brasil Fil: Mattos, Daniel. Instituto Nacional de Genética Médica Populacional; Brasil. Universidade Federal do Rio de Janeiro; Brasil Fil: Poletta, Fernando Adrián. Instituto Nacional de Genética Médica Populacional; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Dutra, Maria G.. Fundación Oswaldo Cruz; Brasil Fil: Carvalho, Flavia M.. Fundación Oswaldo Cruz; Brasil Fil: Castilla, Eduardo Enrique. Instituto Nacional de Genética Médica Populacional; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina

Objective:The aim of this study was to analyze the effects of individual low socioeconomic status (SES) and deprived geographical area (GA) on the occurrence of isolated cleft lip with or without cleft palate (CL±P) in Argentina.MethodsThis case-control study included 577 newborns with isolated CL±P and 13 344 healthy controls, born between 1992 and 2001, from a total population of 546 129 births in 39 hospitals in Argentina. Census data on unsatisfied basic needs were used to establish the degree of geographical area deprivation. An SES index for each individual was established, using maternal age, gravidity, low paternal and maternal education, and low-level paternal occupation. Logistic regression was used to assess the effects of low SES and of deprived GA on CL±P.ResultsA slightly increased risk of CL±P was observed in mothers with a low SES, while a deprived GA showed no effect. Native ancestry, acute maternal illnesses, and poor prenatal care were significant risk factors for CL±P for the mothers with low SES, after using propensity scores to adjust for the demographic characteristics in cases and controls.ConclusionsLow individual SES slightly increased the risk for CL±P, but a deprived GA did not have that effect. There was no interaction between individual SES and deprived GA. Factors related to low individual SES?including poor prenatal care, low parental education, lack of information, and lifestyle factors?should be primarily targeted as risk factors for CL±P rather than factors related to a deprived place of residence. Fil: Pawluk, Mariela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Campaña, Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Rittler, Monica. Hospital Materno Infantil Ramon Sarda ; Gobierno de la Ciudad Autonoma de Buenos Aires; Argentina Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Cosentino, Viviana Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Gili, Juan Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Gimenez, Lucas Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: López Camelo, Jorge Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina

This is a guide for fieldwork in Population Medical Genetics research projects. Data collection, handling, and analysis from large pedigrees require the use of specific tools and methods not widely familiar to human geneticists, unfortunately leading to ineffective graphic pedigrees. Initially, the objective of the pedigree must be decided, and the available information sources need to be identified and validated. Data collection and recording by the tabulated method is advocated, and the involved techniques are presented. Genealogical and personal information are the two main components of pedigree data. While the latter is unique to each investigation project, the former is solely represented by gametic links between persons. The triad of a given pedigree member and its two parents constitutes the building unit of a genealogy. Likewise, three ID numbers representing those three elements of the triad is the record field required for any pedigree analysis. Pedigree construction, as well as pedigree and population data analysis, varies according to the pre-established objectives, the existing information, and the available resources. Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Genética Médica Populacional. Estudio Colaborativo Latinoamericano de Malformaciones Congénitas; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Orioli, Ieda M.. Universidade Federal do Rio de Janeiro; Brasil Fil: Castilla, Eduardo Enrique. Instituto Nacional de Genética Médica Populacional. Estudio Colaborativo Latinoamericano de Malformaciones Congénitas; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Caries is a multifactorial disease and little is still known about the host genetic factors influencing susceptibility. Our previous genome-wide linkage scan has identified the interval 5q12.1–5q13.3 as linked to low caries susceptibility in Filipino families. Here we fine-mapped this region in order to identify genetic contributors to caries susceptibility. Four hundred and seventy-seven subjects from 72 pedigrees with similar cultural and behavioral habits and limited access to dental care living in the Philippines were studied. DMFT scores and genotype data of 75 single-nucleotide polymorphisms were evaluated in the Filipino families with the Family-Based Association Test. For replication purposes, a total 1,467 independent subjects from five different populations were analyzed in a case-control format. In the Filipino cohort, statistically significant and borderline associations were found between low caries experience and four genes spanning 13 million base pairs (PART1, ZSWIM6, CCNB1, and BTF3). We were able to replicate these results in some of the populations studied. We detected PART1 and BTF3 expression in whole saliva, and the expression of BTF3 was associated with caries experience. Our results suggest BTF3 may have a functional role in protecting against caries. Fil: Shimizu, T.. Nihon University of Dentistry; Japón Fil: Deeley, K.. University of Pittsburgh; Estados Unidos Fil: Briseño Ruiz, J.. University of Pittsburgh; Estados Unidos Fil: Faraco Junior, I. M.. University of Pittsburgh; Estados Unidos Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Brancher, J. A.. Pontifical Catholic University of Paraná; Brasil Fil: Pecharki, G. D.. Pontifical Catholic University of Paraná; Brasil Fil: Küchler, E. C.. Universidade Federal Fluminense; Brasil Fil: Tannure, P. N.. Universidade Federal do Rio de Janeiro; Brasil Fil: Lips, A.. Universidade Federal do Rio de Janeiro; Brasil Fil: Vieira, T. C. S.. Universidade Federal Fluminense; Brasil Fil: Patir, A.. Istanbul Medipol Universit; Turquía Fil: Yildirim, M.. Istanbul University; Turquía Fil: Mereb, J. C.. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina Fil: Resick, J. M.. University of Pittsburgh; Estados Unidos Fil: Brandon, C. A.. University of Pittsburgh; Estados Unidos Fil: Cooper, M. E.. University of Pittsburgh; Estados Unidos Fil: Seymen, F.. Istanbul University; Turquía Fil: Costa, M. C.. Universidade Federal do Rio de Janeiro; Brasil Fil: Granjeiro, J. M.. Universidade Federal Fluminense; Brasil Fil: Trevilatto, P. C.. Pontifical Catholic University of Paraná; Brasil Fil: Orioli, I. M.. Universidade Federal do Rio de Janeiro; Brasil. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina Fil: Castilla, Eduardo Enrique. Instituto Oswaldo Cruz; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Marazita, M. L.. University of Pittsburgh; Estados Unidos Fil: Vieira, A. R.. University of Pittsburgh; Estados Unidos

Some studies, mainly in the older literature, observed a significant association between miscarriages and birth defects (BDs) occurring in the same sibship. However, few studies examined the BD/miscarriage relationship in depth. In addition nothing has been added to the underlying mechanisms possibly linking both events. The purpose of this work was to identify specific BDs associated with maternal miscarriages. In particular, it examined whether the risk depended on the number of losses, and to suggest the existence of specific factors for each BD/miscarriage association observed.The study relied on the Latin American Collaborative Study on Congenital Malformations (ECLAMC) database registries including 26,906 live and stillborn infants with one of 19 selected isolated BDs and 93,853 normal controls. Infants born to primigravid mothers were excluded from the present study. Demographic and reproductive variables were compared between control mothers With and Without previous miscarriages. The number, frequency, and distribution of miscarriages were observed for each BD and controls. A conditional logistic regression was applied to evaluate the miscarriage risk for each BD.Control mothers with previous miscarriages were older, had had more pregnancies, and were less educated. Three risk patterns of miscarriages were observed: a very high risk of miscarriages associated with gastroschisis, omphalocele, and talipes; only one miscarriage associated with spina bifida, and two or more miscarriages associated with hypospadias.These three patterns suggest that different factors underly each BD/miscarriage association: infertility for hypospadias, vascular disruption for gastroschisis and talipes, while for spina bifida, the much debated trophoblastic cell residue theory could not be discarded. Birth Defects Research 109:254-261, 2017. © 2017 Wiley Periodicals, Inc.

Caries is a multifactorial disease, and studies aiming to unravel the factors modulating its etiology must consider all known predisposing factors. One major factor is bacterial colonization, and Streptococcus mutans is the main microorganism associated with the initiation of the disease. In our studies, we have access to DNA samples extracted from human saliva and blood. In this report, we tested a real-time PCR assay developed to detect copies of genomic DNA from Streptococcus mutans in 1,424 DNA samples from humans. Our results suggest that we can determine the presence of genomic DNA copies of Streptococcus mutans in both DNA samples from caries-free and caries-affected individuals. However, we were not able to detect the presence of genomic DNA copies of Streptococcus mutans in any DNA samples extracted from peripheral blood, which suggests the assay may not be sensitive enough for this goal. Values of the threshold cycle of the real-time PCR reaction correlate with higher levels of caries experience in children, but this correlation could not be detected for adults. Fil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unidos Fil: Deeley, Kathleen B.. University of Pittsburgh; Estados Unidos Fil: Callahan, Nicholas F.. University of Pittsburgh; Estados Unidos Fil: Noel, Jacqueline B.. University of Pittsburgh; Estados Unidos Fil: Anjomshoaa, Ida. University of Pittsburgh; Estados Unidos Fil: Carricato, Wendy M.. University of Pittsburgh; Estados Unidos Fil: Schulhof, Louise P.. University of Pittsburgh; Estados Unidos Fil: DeSensi, Rebecca S.. University of Pittsburgh; Estados Unidos Fil: Gandhi, Pooja. University of Pittsburgh; Estados Unidos Fil: Resick, Judith M.. University of Pittsburgh; Estados Unidos Fil: Brandon, Carla A.. University of Pittsburgh; Estados Unidos Fil: Rozhon, Christopher. University of Pittsburgh; Estados Unidos Fil: Patir, Asli. Istanbul Medipol University; Turquía Fil: Yildirim, Mine. Istanbul University; Turquía Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Mereb, Juan C.. Hospital de Area El Bolsón; Argentina Fil: Letra, Ariadne. University of Pittsburgh; Estados Unidos Fil: Menezes, Renato. University of Pittsburgh; Estados Unidos Fil: Wendell, Steven. University of Pittsburgh; Estados Unidos Fil: López Camelo, Jorge Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Orioli, Ieda Maria. Hospital de Area El Bolsón; Argentina Fil: Seymen, Figen. Istanbul Universit; Turquía Fil: Weyant, Robert J.. University of Pittsburgh; Estados Unidos Fil: Crout, Richard. West Virginia University; Estados Unidos Fil: McNeil, Daniel W.. West Virginia University; Estados Unidos Fil: Modesto, Adriana. University of Pittsburgh; Estados Unidos Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos

Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis. Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis.

This study was designed to characterize and compare the maternal and newborn epidemiological characteristics through analysis of environmental factors, sociodemographic characteristics and clinical characteristics between the different clinical subtypes of preterm birth (PTB): Idiopathic (PTB-I), premature rupture of the membranes (PTB-PPROM) and medically indicated (PTB-M). The two subtypes PTB-I and PTB-PPROM grouped are called spontaneous preterm births (PTB-S).A retrospective, observational study was conducted in 1.291 preterm nonmalformed singleton live-born children to nulliparous and multiparous mother's in Tucumán-Argentina between 2005 and 2010. Over 50 maternal variables and 10 newborn variables were compared between the different clinical subtypes. The comparisons were done to identify heterogeneity between subtypes of preterm birth: (PTB-S) versus (PTB-M), and within spontaneous subtype: (PTB-I) versus (PTB-PPROM). In the same way, two conditional logistic multivariate regressions were used to compare the odds ratio (OR) between PTB-S and PTB-M, as well as PTB-I and PTB-PPROM. We matched for maternal age when comparing maternal variables and gestational age when comparing infant variables.The PTB-I subtype was characterized by younger mothers of lower socio-economic status, PTB-PPROM was characterized by environmental factors resulting from inflammatory processes, and PTB-M was characterized by increased maternal or fetal risk pregnancies.The main risk factor for PTB-I and PTB-M was having had a prior preterm delivery; however, previous spontaneous abortion was not a risk factor, suggesting a reproductive selection mechanism.