Elucidating the Genetic Landscape of Cerebral Palsy Following Perinatal Cerebrovascular Events

Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder resulting from damage to the developing brain. While perinatal ischemic and hemorrhagic cerebrovascular events are well-established causes, the potential genetic contribution to these injuries remains underexplored. This study investigated the role of genetic factors in a selected CP cohort secondary to perinatal cerebrovascular injury and explored helpful clinical characteristics that may guide genetic evaluation.

Chromosomal microarray and exome sequencing were performed in 61 individuals diagnosed with CP secondary to perinatal cerebrovascular injury, of which 37 with ischemic and 24 with hemorrhagic brain injury.

A genetic diagnosis was established in five out of 61 cases (8.2%) with a striking difference between the hemorrhagic and ischemic groups: four out of 24 cases (16.7%) with hemorrhagic injury had a confirmed genetic diagnosis compared to only one out of 37 (2.7%) in the ischemic group. Three hemorrhagic cases carried (likely) pathogenic variants in COL4A1. One additional case carried a de novo 12pter duplication, a previously unreported association with perinatal brain hemorrhage. The single diagnosis in the ischemic group was a mosaic JAG1 variant related to Alagille syndrome.

Our findings underscore the value of genetic testing in children with CP due to perinatal hemorrhagic brain injury, with a seemingly important role for COL4A1. Less diagnoses were made in the ischemic group, suggesting a potential multifactorial underlying pathophysiology. Further research in larger cohorts and by using genome-wide technologies is essential in further elucidating the genetic architecture of perinatal cerebrovascular injury.