Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.

TitleMutations disrupting neuritogenesis genes confer risk for cerebral palsy.
Publication TypeJournal Article
Year of Publication2020
AuthorsJin, SChih, Lewis, SA, Bakhtiari, S, Zeng, X, Sierant, MC, Shetty, S, Nordlie, SM, Elie, A, Corbett, MA, Norton, BY, van Eyk, CL, Haider, S, Guida, BS, Magee, H, Liu, J, Pastore, S, Vincent, JB, Brunstrom-Hernandez, J, Papavasileiou, A, Fahey, MC, Berry, JG, Harper, K, Zhou, C, Zhang, J, Li, B, Zhao, H, Heim, J, Webber, DL, Frank, MAHSB, Xia, L, Xu, Y, Zhu, D, Zhang, B, Sheth, AH, Knight, JR, Castaldi, C, Tikhonova, IR, López-Giráldez, F, Keren, B, Whalen, S, Buratti, J, Doummar, D, Cho, M, Retterer, K, Millan, F, Wang, Y, Waugh, JL, Rodan, L, Cohen, JS, Fatemi, A, Lin, AE, Phillips, JP, Feyma, T, MacLennan, SC, Vaughan, S, Crompton, KE, Reid, SM, Reddihough, DS, Shang, Q, Gao, C, Novak, I, Badawi, N, Wilson, YA, McIntyre, SJ, Mane, SM, Wang, X, Amor, DJ, Zarnescu, DC, Lu, Q, Xing, Q, Zhu, C, Bilguvar, K, Padilla-Lopez, S, Lifton, RP, Gecz, J, MacLennan, AH, Kruer, MC
JournalNat Genet
Date Published2020 10
KeywordsAnimals, beta Catenin, Cerebral Palsy, Cyclin D, Cytoskeleton, Drosophila, Exome, Extracellular Matrix, F-Box Proteins, Female, Focal Adhesions, Genetic Predisposition to Disease, Genome, Human, Humans, Male, Mutation, Neurites, rhoB GTP-Binding Protein, Risk Factors, Sequence Analysis, DNA, Signal Transduction, Tubulin, Tumor Suppressor Proteins, Whole Exome Sequencing

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

Alternate JournalNat Genet
PubMed ID32989326
Grant ListU54 HG006504 / HG / NHGRI NIH HHS / United States
P50 HD103538 / HD / NICHD NIH HHS / United States
R01 NS106298 / NS / NINDS NIH HHS / United States
K99 HL143036 / HL / NHLBI NIH HHS / United States
R01 NS091299 / NS / NINDS NIH HHS / United States