Cerebral palsy (CP), a neurodevelopmental disorder characterized by irreversible, nonprogressive central motor dysfunction, is commonly associated with prematurity or perinatal brain injury. However, accumulating evidence suggests deleterious genomic variants may contribute to CP in addition to environmental insults. To identify genes contributing to risk for CP, we performed whole-exome sequencing on 250 parent-offspring CP trios. We identified a significant contribution of damaging de novo mutations (DNMs), especially in genes that are intolerant to loss of function mutations. Eight genes had multiple, independently-arising damaging DNMs, including two novel CP-associated genes, FBXO31 and RHOB, and four genes previously implicated in cerebral palsy phenotypes, TUBA1A, CTNNB1, SPAST, and ATL1. Functional experiments, including molecular and biochemical assays and patient fibroblast studies indicate that the recurrent RHOB mutation identified in patients enhances Rho effector binding in the active state and that the FBXO31 mutation leads to elevated levels of cyclin D. Analysis of candidate CP risk genes highlighted genetic overlap with hereditary spastic paraplegia as well as intellectual disability, autism, and epilepsy, converging with epidemiologic findings. Computational network analysis of risk genes identified significant enrichment of Rho GTPase, extracellular matrix, focal adhesions, cytoskeleton, and cell projection pathways. CP risk genes in Rho GTPase, cytoskeleton and cell projection pathways were found to play an important role in neuromotor development via a Drosophila reverse genetics screen. Based on enrichment analysis, we estimate that an excess of damaging de novo and inherited recessive variants collectively account for ~14% of the cases in our cohort, whereas perinatal asphyxia is currently estimated to occur in 8-10% of CP cases. Together, these findings provide evidence for the role of genetically-mediated dysregulation of early brain connectivity in CP.

A growing body of evidence points to a considerable and heterogeneous genetic aetiology of cerebral palsy (CP). To identify recurrently variant CP genes, we designed a custom gene panel of 112 candidate genes. We tested 366 clinically unselected singleton cases with CP, including 271 cases not previously examined using next-generation sequencing technologies. Overall, 5.2% of the naïve cases (14/271) harboured a genetic variant of clinical significance in a known disease gene, with a further 4.8% of individuals (13/271) having a variant in a candidate gene classified as intolerant to variation. In the aggregate cohort of individuals from this study and our previous genomic investigations, six recurrently hit genes contributed at least 4% of disease burden to CP: COL4A1, TUBA1A, AGAP1, L1CAM, MAOB and KIF1A. Significance of Rare VAriants (SORVA) burden analysis identified four genes with a genome-wide significant burden of variants, AGAP1, ERLIN1, ZDHHC9 and PROC, of which we functionally assessed AGAP1 using a zebrafish model. Our investigations reinforce that CP is a heterogeneous neurodevelopmental disorder with known as well as novel genetic determinants.

Perinatal death, of a fetus or newborn, is a devastating event for families. Following nationwide multicentre recruitment, we assessed 'genomic autopsy' as an adjunct to standard autopsy for 200 families who experienced perinatal death, and provided a de nite or candidate genetic diagnosis in 105 families. From this understudied cohort, half of the (candidate) diagnoses were phenotype expansions or novel disease genes, revealing previously unknown in-utero presentations of existing developmental disorders, and genomic disorders that are likely incompatible with life. Among the de nite diagnoses, 43% were recessively or dominantly inherited, posing a 25% or 50% recurrence risk for future pregnancies. Ten families used their diagnosis for preimplantation or prenatal diagnosis of 12 pregnancies, facilitating the delivery of ten healthy newborns and management of two affected pregnancies. We emphasize the clinical importance of genomic investigations of perinatal death, with short turn-around times, enabling accurate counselling and options for families to prevent recurrence.

No abstract

No abstract