biostudies-literatureJin SCNICHD NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and StrokeDoris Duke Charitable FoundationNHLBI NIH HHSNHGRI NIH HHSNINDS NIH HHSU.S. Department of Health & Human Services | NIH | National Human Genome Research Institute1046-1056https://www.ebi.ac.uk/biostudies/studies/S-EPMC9148538biostudies-literatureUnknown52(10)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 Nature geneticsMutations disrupting neuritogenesis genes confer risk for cerebral palsy.PMC9148538P50 HD103538U54 HG006504-01K99 HL143036R01 NS0912995R01NS106298-02U54 HG006504R01 NS106298R00 HL143036Phillips JPKeren BBuratti JReid SMZhang JNordlie SMMacLennan SCGao CShang QMcIntyre SJCorbett MAXia LRodan LLin AEWang XWang YZhang BGuida BSXing QShetty SReddihough DSRetterer KZeng XBilguvar KMane SMWaugh JLKruer MCNovak ISheth AHFahey MCCohen JSVaughan SGecz JTikhonova IRPapavasileiou ALu QXu YLiu Jvan Eyk CLPastore SFatemi AWhalen SBerry JGFrank MSBBakhtiari SAmor DJBrunstrom-Hernandez JWebber DLSierant MCZhou CCho MWilson YAMagee HLi BHarper KMillan FZhao HJin SCBadawi NMacLennan AHElie ADoummar DFeyma TZarnescu DCZhu DPadilla-Lopez SZhu CVincent JBKnight JRCastaldi CNorton BYHeim JHaider SLopez-Giraldez FCrompton KELifton RPLewis SAfalseMutations disrupting neuritogenesis genes confer risk for cerebral palsy.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 2020-01-01T00:00:00Z2020 Oct2026-05-09T19:27:26.595Z2025-02-18T23:36:36.319ZS-EPMC91485383298932610.1038/s41588-020-0695-1