We report the clinical and molecular data of a large cohort comprising 242 individuals with RASopathies, from a single Tertiary Center in Brazil, the largest study from Latin America. Noonan syndrome represented 76% of the subjects, with heterozygous variants in nine different genes, mainly PTPN11, SOS1, RAF1, LZTR1, and RIT1, detected by Sanger and next-generation sequencing. The latter was applied to 126 individuals, with a positive yield of 63% in genes of the RAS/MAPK cascade. We present evidence that there are some allelic differences in PTPN11 across distinct populations. We highlight the clinical aspects that pose more medical concerns, such as the cardiac anomalies, bleeding diathesis and proliferative lesions. The genotype-phenotype analysis between the RASopathies showed statistically significant differences in some cardinal features, such as craniofacial and cardiac anomalies, the latter also statistically significant for different genes in Noonan syndrome. We present two individuals with a Noonan syndrome phenotype, one with an atypical, structural cardiac defect, harboring variants in genes mainly associated with isolated hypertrophic cardiomyopathy and discuss the role of these variants in their phenotype.

Objective: To evaluate risk factors associated with fetal gastroschisis.Methods: As a secondary aim of a larger case-control study, pregnant women attending the Fetal Medicine Unit at the Department of Obstetrics and Gynecology at Hospital das Clinicas, Sao Paulo University Medical School between July 1, 2013, and July 31, 2015, were allocated into either the gastroschisis group, where the woman was carrying a fetus with gastroschisis, or the control group, where the fetus was normal. Patients in the control group were matched at study entry for maternal age, preconception body mass index and weeks of gestation. In-person interviews were conducted during pregnancy to obtain data on demographic, medical, and social characteristics; exposure to substances; pregnancy history; the presence of chronic disease, urinary tract infections (UTIs), influenza, and fever; and the occurrence of stress events between the month before the last menstrual period and the first trimester of pregnancy. Results:Of 171 women included in the study, 57 were allocated to the gastroschisis group and 114 to the control group. There were significant associations between gastroschisis and maternal UTI (P=0.011), tobacco use (P=0.001), alcohol consumption (P≤0.001), and illicit drug use (P=0.012). After analysis by standard logistic regression, the remaining significant factors were UTI, tobacco use, and alcohol consumption.Conclusion: UTI and exposure to tobacco or alcohol just before conception and during early pregnancy were associated with an increase in the likelihood of fetal gastroschisis.

Objective: The purpose of this study was to describe the genomic deoxyribonucleic acid (DNA) methylation profile in fetuses with gastroschisis, determine whether the profile was inherited, and investigate any possible correlations with maternal risk factors. Method: Genome-wide DNA methylation analysis of 96 blood samples was performed using the Illumina Human Methylation 850K BeadChip. The blood samples were collected as follows: 32 from the umbilical cord of fetuses with gastroschisis, 32 from their respective mothers, 16 from the umbilical cord of fetuses without malformation, and 16 from their respective mothers. Results: The differential DNA methylation analysis showed a significant difference between the groups. The enrichment analysis resulted in 12 sites related to T-cell activation (p ¼ 0.0128). The sites with different methylation status contained 10 genes, three of which were related to the beta-2-microglobulin gene. The methylation profile observed in the fetuses with gastroschisis was not inherited from the mothers. In addition, there was no association between maternal urinary tract infection, smoking, and alcohol use and different methylated sites. Conclusion: We established the methylation profile of gastroschisis fetuses, which differs from that of normal fetuses. The profile was not inherited and did not correlate with maternal risk factors. Key Points What is known about this topic? � The etiology and pathogenesis of fetal gastroschisis and its association with environmental factors are not clearly understood, and attempts to identify a biological marker have not been successful. No previous investigation into the methylation patterns in pregnant women carrying fetuses with gastroschisis has been published What does this study add? � This study provides the methylation pattern of fetuses with gastroschisis

Background To reveal the complex etiology of gastroschisis through two independent cases. Cases Case 1 involves gastroschisis recurrence in a consanguineous marriage, and Case 2 concerns a fetus with gastroschisis whose mother had undergone gastroplasty. Methylation array was carried out in both cases (two fetuses with gastroschisis, their two mothers, one father from the consanguineous marriage), and in 16 controls (fetuses and their respective mothers). Conclusion The two cases presented different noninherited methylation profiles.

A conclusão de uma tese nos faz refletir sobre todos os que contribuíram para que este projeto se concretizasse. Com isso, gostaria de expressar meu carinho e gratidão:Aos pacientes e seus familiares que possibilitaram a realização deste estudo.

Objectives To investigate the association between selected single nucleotide polymorphisms (SNPs) with cervical insufficiency and its relationship with obstetric history. Methods Twenty-eight women with cervical insufficiency (case group) and 29 non-pregnant women (control group) were included. The SNPs sequenced included rs2586490 in COL1A1, rs1882435 in COL4A3, rs2277698 in TIMP2, and rs1800468 in TGFB1. Results We found a higher frequency of the normal allele in the control group (65.5%) and the homozygous mutated genotype in the case group (64.3%) for rs2586490 in COL1A1 (p=0.023). An unplanned finding in the cervical insufficiency group was a higher gestational age of delivery (median≥38 weeks) in the mutated allele than in the wild-type genotype (median of 28.2 weeks) for rs2857396, which is also in the COL1A1 gene (p=0.011). Conclusions The findings of the present study corroborate the hypothesis that cervical insufficiency has a genetic component and probably involves genes encoding proteins in the extracellular matrix, in addition to inflammatory processes.