Journal Article

Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

Corbett, Mark A., Webber, Dani L., Phillips, John P., Fatemi, Ali, Xing, Qinghe, Xu, Yiran, Reddihough, Dinah S., Liu, James, McIntyre, Sarah J., Pastore, Stephen, Zhang, Junhui, Brunstrom-Hernandez, Janice, Frank, Mahalia S. B., Doummar, Diane, Cho, Megan, Harper, Kelly, Shang, Qing, Zeng, Xue, Whalen, Sandra, Keren, Boris, Guida, Brandon S., Lin, Angela E., Lu, Qiongshi, Nordlie, Sandra M., Zhao, Hongyu, Mane, Shrikant M., Norton, Bethany Y., Berry, Jesia G., Wang, Xiaoyang, Gecz, Jozef, van Eyk, Clare L., Fahey, Michael C., Badawi, Nadia, Lewis, Sara A., Feyma, Timothy, Magee, Helen, Knight, James R., Papavasileiou, Antigone, Retterer, Kyle, Gao, Chao, Heim, Jennifer, Bakhtiari, Somayeh, Waugh, Jeff L., Elie, Aureliane, Lifton, Richard P., Wang, Yangong, Amor, David J., Novak, Iona, Vaughan, Spencer, Crompton, Kylie E., Sierant, Michael C., Xia, Lei, Tikhonova, Irina R., Cohen, Julie S., Millan, Francisca, Zhu, Dengna, Zarnescu, Daniela C., Haider, Shozeb, Shetty, Sheetal, Sheth, Amar H., Padilla-Lopez, Sergio, Jin, Sheng Chih, Zhou, Chongchen, Rodan, Lance, Vincent, John B., López-Giráldez, Francesc, Wilson, Ya

2020

Overview

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. Whole-exome sequencing of 250 parent–offspring trios identifies an enrichment of rare damaging de novo mutations in individuals with cerebral palsy and implicates genetically mediated dysregulation of early neuronal connectivity in the etiology of this disorder.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/366 / 692/308/2056 / 692/699/375/2764 / 692/699/375/366 / Agriculture / alk kinase / Animal Genetics and Genomics / Animals / Autism / Axonogenesis / beta Catenin - genetics / Binding sites / Biomedical and Life Sciences / Biomedicine / brain / Cancer Research / Cerebral palsy / Cerebral Palsy - genetics / Cerebral Palsy - pathology / congenital heart-disease / copy-number variations / Cyclin D / Cyclin D - genetics / Cytoskeleton / Cytoskeleton - genetics / de-novo / disability / Drosophila - genetics / Enrichment / Environmental factors / Etiology / Exome - genetics / Exome Sequencing / Extracellular matrix / Extracellular Matrix - genetics / F-Box Proteins - genetics / Female / Focal Adhesions - genetics / Gene Function / Genes / Genetic Predisposition to Disease / Genetics / Genetics & Heredity / Genetics and Genomics / Genetik och genomik / Genome, Human - genetics / Genomes / Human Genetics / Humans / Hypoxia / intellectual / Ischemia / Kinases / Language disorders / Magnetic resonance imaging / Male / Medical Genetics and Genomics / Medicinsk genetik och genomik / Movement disorders / Mutation / Mutation - genetics / Neural networks / Neurites - metabolism / Neurites - pathology / Neurodevelopmental disorders / Offspring / Paralysis / phosphorylation / protein / Proteins / rare / rhoB GTP-Binding Protein - genetics / Risk / Risk Factors / Sequence Analysis, DNA / Signal Transduction - genetics / truncating mutations / Tubulin - genetics / Tumor Suppressor Proteins - genetics