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

• Published in: PLoS neglected tropical diseases 2021-06, Vol.15 (6), p.e0009507-e0009507
• Main Authors: Borda, Victor, da Silva Francisco Junior, Ronaldo, Carvalho, Joseane B, Morais, Guilherme L, Duque Rossi, Átila, Pezzuto, Paula, Azevedo, Girlene S, Schamber-Reis, Bruno L, Portari, Elyzabeth A, Melo, Adriana, Moreira, Maria Elisabeth L, Guida, Letícia C, Cunha, Daniela P, Gomes, Leonardo, Vasconcelos, Zilton F. M, Faucz, Fabio R, Tanuri, Amilcar, Stratakis, Constantine A, Aguiar, Renato S, Cardoso, Cynthia Chester, Vasconcelos, Ana Tereza Ribeiro de
• Format: Article
• Language: English
• Subjects: Amniotic fluid; Association analysis; Biology and life sciences; Care and treatment; Diagnosis; Gene expression; Genes; Genetic aspects; Genetic disorders; Genetic diversity; Genetic variance; Genetic variation; Genome-wide association studies; Genomes; Genotype & phenotype; Gestational age; Health aspects; Identification and classification; IL12Rb2 protein; Illnesses; Immunity; Infections; Interleukin 1; Medicine and Health Sciences; Methods; Microcephaly; Neonates; Nucleotides; Pathogens; Pathways; People and places; Phenotypes; Physical Sciences; Pregnancy; Principal components analysis; Research and Analysis Methods; Risk analysis; Risk factors; Sequencing; Serology; Software; Tropical diseases; Ultrasonic imaging; Vector-borne diseases; Viruses; Women; Womens health; Zika virus
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0009507

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.sup.-5). The IL12RB2 gene (p-value: 2.18x10.sup.-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.