First report case with negative genetic study (array CGH, exome sequencing) in patients with vertical transmission of Zika virus infection and associated brain abnormalities

Estephania Candelo,1,2 Gabriela Caicedo,1 Fernando Rosso,3 Adriana Ballesteros,4 Jaime Orrego,4 Luis Escobar,5 Pablo Lapunzina,6,7 Julían Nevado,6,7 Harry Pachajoa1,81Center for Research on Congenital Anomalies and Rare Diseases (CIACER), Department of Basic Medical Sciences, Universidad Icesi, Cali, Colombia; 2MSc Biomaterials and Tissues Engineering and Genetics of Human Diseases, University College London, London, UK; 3Infectology Department, Fundación Valle del Lili, Cali, Colombia; 4Neonatal Department, Fundacion Valle del Lili, Cali, Colombia; 5Pathology Department, Fundacion Valle del Lili, Cali, Colombia; 6Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario La Paz, Madrid, 28046, Spain; 7CIBER de Enfermedades Raras (CIBERER), Madrid, ISCIII, Spain; 8Genetics Department, Fundacion Valle del Lili, Cali, ColombiaIntroduction: Zika virus (ZIKV) is a little-known emerging mosquito-borne flavivirus. The perinatal ZIKV infection was associated with birth defects during the Brazilian outbreak. There was an increased risk of intrauterine transmission of the virus and a marked increase in the number of newborns with microcephaly. We report on two such cases.Case Report: The first case was a 25-year-old pregnant woman from Colombia who became acutely ill with general symptoms during the tenth week of gestation, followed by severe generalized itching and maculopapular rash for approximately five days. This case was reported during the epidemic stage of the ZIKV infection in Colombia. At 23.3 gestational weeks, ultrasonography showed abnormal intracranial anatomy with cerebral ventriculomegaly, microcephaly, and parenchymal calcification. Given the grave prognosis, the patient elected to terminate the pregnancy at 25 gestational weeks. The second case was a 24-year-old pregnant woman who became acutely ill during the 17th week of gestation, which corresponded with the ZIKV epidemic in Colombia. At 30.5 gestational weeks, ultrasonography showed isolated fetal cerebral ventriculomegaly. We detected ZIKV in the amniotic fluid; however, the virus was not detected in the urine or serum of the mother or fetus. Tests for dengue virus, chikungunya virus, Toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex virus, HIV, hepatitis B and C, and parvovirus B19 were all negative. Different samples obtained from the placenta, amniotic liquid, and cerebrospinal fluid were positive for viral isolation of ZIKV RNA using TaqMan RT-PCR. Additionally, the parents and fetuses were tested for genetic diseases using whole exome sequencing and array CGH to rule out possible genetic syndromes that produce these congenital abnormalities.Conclusion: These were the first cases in Colombia to show early vertical transmission of ZIKV and the first cases associated with congenital cerebral abnormalities in which molecular, infectious, and genomic tests were performed.Keywords: Colombia, microcephaly, whole exome sequencing, Zika virus infection, vertical transmission, brain abnormalities