New ocular lesions can occur at any age after birth, in untreated and some treated children. For example, previous studies suggest that genes affecting immune response, including HLA, influence clinical outcome in the child. However, since infants who have the most severe clinical signs in the brain and eye are those infected early in pregnancy when fetal immunity is least well developed, we considered whether genes that encode molecules that play a role in developmental processes could contribute to clinical phenotype observed in the child. This could provide unique insight into events in utero and post-natally that determine the clinical outcome of infection. In particular, we hypothesized that propensity for T. gondii to cause eye disease may be associated with genes previously implicated in congenital or juvenile onset ocular disease. Two genes were of specific interest, ABCA4 encoding ATP-binding cassette transporter subfamily A member 4 associated with juvenile onset retinal dystrophies including Stargardt��s disease, and COL2A1 encoding type II collagen associated with Stickler syndrome in which there is congenital abnormal vitreous and lattice retinal degeneration. Although risk of transmission of the parasite to the fetus in pregnant women with primary infection ranges from,1�C 100% depending on the time in gestation when infection is acquired, incidence rates of clinical congenital toxoplasmosis, together with the fact that it is not a reportable disease, have 20S-Notoginsenoside-R2 precluded accumulation of large cohorts for genetic studies. Nevertheless, two unique cohorts have recently become available to test this specific genetic hypothesis. These cohorts are from the European Multicentre Cohort Study on Congenital Toxoplasmosis which recruited prospectively for mothers with primary T. gondii in pregnancy, and from the National Collaborative Chicago-based Congenital Toxoplasmosis Study in North America to which infants and children with congenital infection with T. gondii are referred. Using these cohorts we show that ocular and brain disease in congenital toxoplasmosis associate with polymorphisms in ABCA4, while polymorphisms at COL2A1 encoding type II collagen associate only with ocular disease. Both loci show unusual inheritance patterns for the disease allele when comparing outcomes in heterozygous affected children with outcomes in affected children of heterozygous mothers, and modeling suggests either an effect of mother��s genotype or parent-of-origin effects. The latter is supported by experimental data showing that both ABCA4 and COL2A1 show isoform-specific epigenetic modifications consistent with imprinting. 
The European study was undertaken as an adjunct to European Multicentre Study of Congenital Toxoplasmosis, referred to as GENET-EMSCOT. Ethical approvals for GENET-EMSCOT were obtained through the local ethical review boards of participating centres across Europe, and for the study as a whole from the Research Ethics Committee for Great Ormond Street Hospital and the Institute for Child Health in London. Screening, treatment and follow up schedules have been described in detail elsewhere. For this study, mother-child pairs were eligible for inclusion if the child had congenital toxoplasmosis or, if the child was uninfected, the mother had evidence of seroconversion during pregnancy. Infected children were identified in centres that utilized universal prenatal or neonatal screening. Uninfected children were identified only in those centres that utilized prenatal screening. Families were Benzethonium Chloride invited to participate by the clinician responsible for follow up.