Mutations Disrupting Neuritogenesis Genes Confer Risk for Cerebral Palsy.

Mutations Disrupting Neuritogenesis Genes Confer Risk for Cerebral Palsy.

AUTHORS:

Sheng Chih JinSara A LewisSomayeh BakhtiariXue ZengMichael C SierantSheetal ShettySandra M NordlieAureliane ElieMark A Corbett , Bethany Y NortonClare L van EykShozeb HaiderBrandon S GuidaHelen MageeJames LiuStephen PastoreJohn B Vincent, Janice Brunstrom-HernandezAntigone PapavasileiouMichael C FaheyJesia G BerryKelly HarperChongchen ZhouJunhui ZhangBoyang LiJennifer HeimDani L WebberMahalia S B FrankLei XiaYiran XuDengna ZhuBohao ZhangAmar H ShethJames R KnightChristopher CastaldiIrina R TikhonovaFrancesc López-GiráldezBoris KerenSandra WhalenJulien BurattiDiane DoummarMegan ChoKyle RettererFrancisca MillanYangong WangJeff L WaughLance RodanJulie S CohenAli FatemiAngela E LinJohn P PhillipsTimothy FeymaSuzanna C MacLennanSpencer VaughanKylie E CromptonSusan M ReidDinah S ReddihoughQing ShangChao GaoIona NovakNadia BadawiYana A WilsonSarah J McIntyreShrikant M ManeXiaoyang WangDavid J AmorDaniela C ZarnescuQiongshi LuQinghe XingChanglian ZhuKaya BilguvarSergio Padilla-LopezRichard P LiftonJozef GeczAlastair H MacLennanMichael C Kruer

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.

FOR FULL ARTICLE:  https://www.nature.com/articles/s41588-020-0695-1