Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome

Congenital Zika Syndrome (CZS) is a critical illness with a wide range of severity caused by Zika virus (ZIKV) infection during pregnancy. Life-threatening neurodevelopmental dysfunctions are among the most common phenotypes observed in affected newborns. Risk factors that contribute to susceptibility and response to ZIKV infection may be related to the virus itself, the environment, and maternal genetic background. Nevertheless, the newborn's genetic contribution to the critical illness is still not elucidated. Here, we aimed to identify possible genetic variants as well as relevant biological pathways that might be associated with CZS phenotypes. For this purpose, we performed a whole-exome sequencing in 40 children born to women with confirmed exposure to ZIKV during pregnancy. We investigated the occurrence of rare harmful single-nucleotide variants (SNVs) possibly associated with inborn errors in genes ontologically related to CZS phenotypes. Moreover, an exome-wide association analysis was also performed using a case-control design (29 CZS cases and 11 controls), for both common and rare variants. Five out of the 29 CZS patients harbored known pathogenic variants likely to contribute to mild to severe manifestations observed. Approximately, 30% of affected individuals carried at least one pathogenic or likely pathogenic SNV in genes candidates to play a role in CZS. Our common variant association analysis detected a suggestive protective effect of the rs2076469 in DISP3 gene (p-value: 1.39 x 10(-5)). The IL12RB2 gene (p-value: 2.18x10(-11)) also showed an unusual distribution of nonsynonymous rare SNVs in control samples. Finally, genes harboring harmful variants are involved in processes related to CZS phenotypes such as neurological development and immunity. Therefore, both rare and common variations may be likely to contribute as the underlying genetic cause of CZS susceptibility. The variations and pathways identified in this study may also have implications for the development of therapeutic strategies in the future. Author summary Since the beginning of Zika virus outbreak in Brazil, five years ago, we still don't understand the genetic factors associated with the small number of babies born with Congenital Zika Syndrome (CZS). Here, we focused on the host genetic susceptibility by studying the whole-exome of the CZS affected (n = 29) and healthy (n = 11) neonates, both born to ZIKV infected women from Brazil. We applied two strategies: 1) Determine whether cases individuals have pathogenic or harmful variants that explain the CZS outcomes (i.e. microcephaly) independently of ZIKV infection or not, 2) Exploring the common and rare variants association with CZS. We found that common and rare variants in genes like DISP3 and IL12RB2 could explain some level of the susceptibility to CZS. Moreover, by considering these and other candidate genes, we observed an over-representation of Gene Ontology terms related to neurological system, metabolism and microtubule-cytoskeleton organization.