| Literature DB >> 32989326 |
Sheng Chih Jin1,2,3, Sara A Lewis4,5, Somayeh Bakhtiari4,5, Xue Zeng1,2, Michael C Sierant1,2, Sheetal Shetty4,5, Sandra M Nordlie4,5, Aureliane Elie4,5, Mark A Corbett6, Bethany Y Norton4,5, Clare L van Eyk6, Shozeb Haider7, Brandon S Guida4,5, Helen Magee4,5, James Liu4,5, Stephen Pastore8, John B Vincent8, Janice Brunstrom-Hernandez9, Antigone Papavasileiou10, Michael C Fahey11, Jesia G Berry6, Kelly Harper6, Chongchen Zhou12, Junhui Zhang1, Boyang Li13, Hongyu Zhao13, Jennifer Heim4, Dani L Webber6, Mahalia S B Frank6, Lei Xia14, Yiran Xu14, Dengna Zhu14, Bohao Zhang14, Amar H Sheth1, James R Knight15, Christopher Castaldi15, Irina R Tikhonova15, Francesc López-Giráldez15, Boris Keren16, Sandra Whalen17, Julien Buratti16, Diane Doummar18, Megan Cho19, Kyle Retterer19, Francisca Millan19, Yangong Wang20, Jeff L Waugh21, Lance Rodan22, Julie S Cohen23, Ali Fatemi23, Angela E Lin24, John P Phillips25, Timothy Feyma26, Suzanna C MacLennan27, Spencer Vaughan28, Kylie E Crompton29, Susan M Reid29, Dinah S Reddihough29, Qing Shang12, Chao Gao30, Iona Novak31, Nadia Badawi31, Yana A Wilson31, Sarah J McIntyre31, Shrikant M Mane15, Xiaoyang Wang14,32, David J Amor29, Daniela C Zarnescu28, Qiongshi Lu33, Qinghe Xing20, Changlian Zhu14,32, Kaya Bilguvar1,15, Sergio Padilla-Lopez4,5, Richard P Lifton1,2, Jozef Gecz6, Alastair H MacLennan6, Michael C Kruer34,35.
Abstract
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.Entities:
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Year: 2020 PMID： 32989326 PMCID： PMC9148538 DOI： 10.1038/s41588-020-0695-1
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 41.307