Paediatric cerebral visual impairments (CVIs) are vision problems caused by damage to the brain rather than the eyes. Injuries to the newborn brain are by far the most common causes, including injuries associated with prematurity, hypoxia-ischemia and/or infections in the perinatal period. Many of these children have multiple neurodevelopmental impairments affecting movement, cognition and/or behaviour, and require extra educational support. There is concern that in some of these children CVIs go unnoticed or mistaken for other problems. Recent work by our group has shown that CVIs might be more prevalent than previously appreciated in the population, highlighting the need for a panel of biomarkers/predictors which can promote earlier and more accurate identification of high-risk children.
Genetic variants may affect how the newborn brain responds to perinatal stresses capable of causing brain injury. Compared to other neurodevelopmental disorders, research into the genetic contributions to CVIs is lacking, although a few genetic associations have been reported (1, 2).
This study aims at evaluating whether candidate genetic variants in the main candidate pathways involved in perinatal brain injuries (glutamate signalling and inflammation) are associated with CVIs. This hypothesis has derived partly from work carried out by two of the applicants (CW and KL) in the DRIFT study(3), in which children were assessed 10-years after a new intervention to treat brain bleeds. A high proportion of these children had CVIs and the number of CVIs correlated with the degree of structural damage to the brain that the children sustained in infancy. The genetic variants we will investigate have been identified both from the wider literature and from our own previous work (4). This includes preliminary findings within the Bristol Neonatal Gene Study, implicating candidate genetic variants in the glutamate signalling and inflammation pathways in childhood motor and cognitive outcomes. For some of these variants, us and others have explicitly shown functional effects on glutamatergic and inflammatory regulation in in vivo models relevant to brain injuries.
Associations between candidate genetic variants and vision outcomes in children from the general population will be explored within ALSPAC. By combining research from the Bristol Neonatal Gene Study with the rich database of visual function data within ALSPAC, we will be able to consider of a range of potentially important perinatal factors (e.g. prematurity, birth complications, evidence of brain injuries during the neonatal stay in the hospital) that may modify the effect of genotype on visual outcomes. We will also examine the associations between the same SNPs with (a) cognitive and (b) motor findings. From the existing literature we expect there is to be associations and we will compare the effect sizes (ES) in analyses of associations between the vision data and the SNPs of interest, with those obtained when using the motor and cognitive data. These results will be used to onform designs for future powered studies.
Additionally, we will collect new prospective data for children at risk for CVIs, enrolled by the PI at the Bristol Eye Hospital. This new clinical data will include additional more in-depth vision assessments compared to those routinely offered in the standard clinic, which will be evaluated as novel biomarkers for CVIs. Genetic profiles of these children with clinical diagnoses of CVIs will be compared to those from ALSPAC representing the general population.
This work is a collaboration between research groups in Bristol and is complementary to a proposal already approved, submitted in 2019 by SR. Some of the work proposed here is already approved as part of that proposal - however use of the vision data is unique to this proposal

References

1. Bosch DG, Boonstra FN, de Leeuw N, Pfundt R, Nillesen WM, de Ligt J, et al. Novel genetic causes for cerebral visual impairment. European journal of human genetics : EJHG. 2016;24(5):660-5.
2. Bosch DG, Boonstra FN, Reijnders MR, Pfundt R, Cremers FP, de Vries BB. Chromosomal aberrations in cerebral visual impairment. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2014;18(6):677-84.
3. Luyt K, Jary SL, Lea CL, Young GJ, Odd DE, Miller HE, et al. Drainage, irrigation and fibrinolytic therapy (DRIFT) for posthaemorrhagic ventricular dilatation: 10-year follow-up of a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2020;105(5):466-73.
4. Pregnolato S, Chakkarapani E, Isles AR, Luyt K. Glutamate Transport and Preterm Brain Injury. Front Physiol. 2019;10:417.
5. Williams C, Northstone K, Sabates R, Feinstein L, Emond A, Dutton GN. Visual perceptual difficulties and under-achievement at school in a large community-based sample of children. PLoS One. 2011;6(3):e14772.