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Five years after the identification of Zika virus as a human teratogen, we reviewed the early clinical manifestations, collectively called congenital Zika syndrome (CZS). Children with CZS have a very poor prognosis with extremely low performance in motor, cognitive, and language development domains, and practically all feature severe forms of cerebral palsy. However, these manifestations are the tip of the iceberg, with some children presenting milder forms of deficits. Additionally, neurodevelopment can be in the normal range in the majority of the non-microcephalic children born without brain or eye abnormalities. Vertical transmission and the resulting disruption in development of the brain are much less frequent when maternal infection occurs in the second half of the pregnancy. Experimental studies have alerted to the possibility of other behavioral outcomes both in prenatally infected children and in postnatal and adult infections. Cofactors play a vital role in the development of CZS and involve genetic, environmental, nutritional, and social determinants leading to the asymmetric distribution of cases. Some of these social variables also limit access to multidisciplinary professional treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schuler-Faccini, del Campo, García-Alix, Ventura, Boquett, van der Linden, Pessoa, van der Linden Júnior, Ventura, Leal, Kowalski, Rodrigues Gerzson, Skilhan de Almeida, Santi, Beys-da-Silva, Quincozes-Santos, Guimarães, Garcez, Gomes, Vianna, Anjos da Silva, Fraga, Vieira Sanseverino, Muotri, Lopes da Rosa, Abeche, Marcolongo-Pereira and Souza.)

Recurrent pregnancy loss (RPL) is the most common reproductive failure, reaching 1-5% of women throughout their lives, and having unknown etiology in 50% of the cases. In humans, EGF-CFC1 ( E pidermal G rowth F actors & C ripto/ F RL-1/ C ryptic) gene family is composed by TDGF1 and CFC1 , two developmental genes. The aim of this study was to investigate the role of EGF-CFC on RPL. To this, multiple approaches were performed; we conducted an expression analysis of TDGF1 and CFC1 using publicly available data from Gene Omnibus Expression (GEO), systems biology analyses and functional prediction; and a molecular analysis carried out in a case-control study. Our GEO analysis showed a decrease in TDGF1 expression in the endometrium (p=0.049) and CFC1 expression in placenta (p=0.015) of women with RPL. Network analysis, gene ontology and literature pointed to a strong connection between EGF-CFC1 gene family to pathways that play key roles during pregnancy, including TGF-β, c-Src/MAPK/AKT, Notch, TNFα, IFNγ and IL-6. A pathogenicity score developed for this gene family showed that the c.-14+1429T>C (rs3806702) variant in the TDGF1 and the p.Arg47Gln (rs201431919) variant in CFC1 gene would be the ones with the highest deleterious effect for RPL. In the case-control study, which involved 149 women with RPL and 159 controls, no statistical difference was observed in the allele and genotype distributions of the variants studied in the two groups. In this study, we performed extensive bioinformatics analysis for biomarker prioritization followed by experimental validation of proposed selected markers. Although there is no statistical difference in the frequencies of these variants between RPL and controls, the expression analysis results suggest that TDGF1 and CFC1 genes might play a role in RPL. In addition, systems biology analyzes raise the hypothesis that genes in other signaling pathways that may be related to RPL as good candidates for future studies. Abbreviations RPL: recurrent pregnancy loss; EGF-CFC1 : E pidermal G rowth F actors - C ripto/ F RL-1; GEO: Gene Omnibus Expression; KEGG: Kyoto Encyclopedia of Genes and Genomes.

The Zika virus (ZIKV) was identified in 1947 in the Zika forest in Uganda, but recently it has emerged as a public health threat. The first evidence of human infection occurred in 1952, but only in April 2007 was the first outbreak in humans recognized. In the Americas, a ZIKV outbreak began in Brazil in 2015, and from the second half of 2015 onward, a substantial number of newborns with severe microcephaly began to be reported to health authorities. In February 2016, the World Health Organization (WHO) declared that the clusters of microcephaly cases in areas affected by ZIKV constituted a Public Health Emergency of International Concern. Seldom has there been such a resultingly vast production of scientific literature in record time. In this report we discuss the impact of ZIKV infection during pregnancy, the diagnosis and surveillance of microcephaly, the recognition of a clinical phenotype of ZIKV congenital infection, and opportunities for public health action. We consider this to be a unique opportunity for countries in the Region of the Americas to develop, strengthen, and improve surveillance systems for congenital anomalies and teratogen information services. Creating health needs assessment tools for low- and middle-income countries may help them to develop effective policies to ensure primary, secondary, and tertiary prevention measures for congenital anomalies. Such initiatives will be useful for ZIKV congenital syndrome control and also for having a much wider impact on a significant proportion of preventable and manageable congenital conditions ., Competing Interests: Conflicts of Interest. None declared.