Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

Abstract

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.

Variant recurrence confirms the existence of a FBXO31‐related spastic‐dystonic cerebral palsy syndrome

“…Additional consistent features included profound abnormalities of speech and muscle tone. The latter comprised spasticity (as seen in all three patients), predominantly affecting the lower limbs and leading to a diagnosis of CP in each subject, 5 as well as dystonia (observed in the herein reported case). Other neurological and non‐neurological manifestations such as congenital malformations, behavioral issues, minor dysmorphia, and neuroanatomical alterations occurred in two or only one of the subjects.…”

“…The location of the patient‐specific recurrent missense variant at amino acid position 334 is indicated. * the previously described cases are labeled as in Jin et al 5 (B) Three‐dimensional model of the FBXO31‐SKP1‐cyclin D1 complex (PDB: 5VZU). The spatial proximity of the mutated Asp334 residue (stick‐and‐ball representation) to FBXO31`s substrate cyclin D1 (stick representation) is illustrated.…”

“…A clinical overview of the proband presented here and the individuals reported by Jin et al 5 is given in Table 1. The three cases shared a presentation of motor and/or speech delay, and all had ID that varied from mild to moderate.…”

Cerebral palsy with autism and ADHD: time to pay attention

“…There are wearable exoskeletons for both overground walking and for walking on a treadmill. 3 A key difference between end-effectors and exoskeletons is located at the level of the legs: while end-effectors only act on the feet, lower limb exoskeletons act on the hip, knee, and sometimes the ankle joints.…”

“…Apart from observing a moderate association with the presence of intellectual disability, Påhlman et al 2 did not go as far as to speculate on possible common pathogenesis of CP with ASD and/or ADHD. Altered neural migration and synaptogenesis are posited to be important in the aetiology of at least genetic CP 3 as they are also important in ASD 4 . Possible overlap of neurodevelopmental origins of CP and ASD was also flagged by gene expression analysis of cells from unselected CP cases 5 .…”