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Jin, S.C., Lewis, S.A., Bakhtiari, S., Zeng, X., Sierant, M.C., Shetty, S., Nordlie, S.M., Elie, A., Corbett, M.A., Norton, B.Y., van Eyk, C.L., Haider, S., Guida, B.S., Magee, H., Liu, J., Pastore, S., Vincent, J.B., Brunstrom-Hernandez, J., Papavasileiou, A., Fahey, M.C., Berry, J.G., Harper, K., Zhou, C., Zhang, J., Li, B., Heim, J., Webber, D.L., Frank, M.S.B., Xia, L., Xu, Y., Zhu, D., Zhang, B., Sheth, A.H., Knight, J.R., Castaldi, C., Tikhonova, I.R., López-Giráldez, F., Keren, B., Whalen, S., Buratti, J., Doummar, D., Cho, M., Retterer, K., Millan, F., Wang, Y., Waugh, J.L., Rodan, L., Cohen, J.S., Fatemi, A., Lin, A.E., Phillips, J.P., Feyma, T., MacLennan, S.C., Vaughan, S., Crompton, K.E., Reid, S.M., Reddihough, D.S., Shang, Q., Gao, C., Novak, I., Badawi, N., Wilson, Y.A., McIntyre, S.J., Mane, S.M., Wang, X., Amor, D.J., Zarnescu, D.C., Lu, Q., Xing, Q., Zhu, C., Bilguvar, K., Padilla-Lopez, S., Lifton, R.P., Gecz, J., MacLennan, A.H., Kruer, M.C. (2020). Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.  Nat. Genet. 52(10): 1046--1056.
FlyBase ID
FBrf0246850
Publication Type
Research paper
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.

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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Nat. Genet.
    Title
    Nature Genetics
    Publication Year
    1992-
    ISBN/ISSN
    1061-4036 1546-1718
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