Journal article

Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

Sheng Chih Jin, Sara A Lewis, Somayeh Bakhtiari, Xue Zeng, Michael C Sierant, Sheetal Shetty, Sandra M Nordlie, Aureliane Elie, Mark A Corbett, Bethany Y Norton, Clare L van Eyk, Shozeb Haider, Brandon S Guida, Helen Magee, James Liu, Stephen Pastore, John B Vincent, Janice Brunstrom-Hernandez, Antigone Papavasileiou, Michael C Fahey Show all

Nature Genetics | NATURE RESEARCH | Published : 2020

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, ex..

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Grants

Awarded by Yale-NIH Center for Mendelian Genomics


Awarded by Doris Duke Charitable Foundation


Awarded by NHMRC


Awarded by NHMRC Senior Principal Research Fellowship


Awarded by National Natural Science Foundation of China


Awarded by Henan Key Research Program of China


Awarded by VINNOVA


Awarded by American Heart Association Postdoctoral Fellowship


Awarded by NIH K99/R00 Pathway to Independence Award


Awarded by NIH


Funding Acknowledgements

We gratefully acknowledge the support of the patients and families who have graciously and patiently supported this work from its inception. Without their partnership, these studies would not have been possible. We acknowledge the support of the clinicians who generously provided their expertise in support of this study, including M.-C. Waugh, M. Axt and V. Roberts of the Children's Hospital Westmead; K. Lowe of Sydney Children's Hospital; R. Russo, J. Rice and A. Tidemann of the Women's and Children's Hospital, Adelaide; T. Carroll and L. Copeland of the Lady Cilento Children's Hospital, Brisbane; and J. Valentine of Perth Children's Hospital. We appreciate the collaboration of S. Knoblach and E. Hoffman (Children's National Medical Center). This work was supported in part by the Cerebral Palsy Alliance Research Foundation (M.C.K.), the Yale-NIH Center for Mendelian Genomics (U54 HG006504-01), Doris Duke Charitable Foundation CSDA 2014112 (M.C.K.), the Scott Family Foundation (M.C.K.), Cure CP (M.C.K.), NHMRC grant 1099163 (A.H.M., C.L.v.E., J.G. and M.A.C.), NHMRC Senior Principal Research Fellowship 1155224 (J.G.), Channel 7 Children's Research Foundation (J.G.), a Cerebral Palsy Alliance Research Foundation Career Development Award (M.A.C.), the Tenix Foundation (A.H.M., J.G., C.L.v.E. and M.A.C.), the National Natural Science Foundation of China (U1604165, X.W.), Henan Key Research Program of China (171100310200, C. Zhu), VINNOVA (2015-04780, C. Zhu), the James Hudson Brown-Alexander Brown Coxe Postdoctoral Fellowship at the Yale University School of Medicine (S.C.J.), an American Heart Association Postdoctoral Fellowship (18POST34060008 to S.C.J.), the NIH K99/R00 Pathway to Independence Award (R00HL143036-02 to S.C.J.) and NIH grants R01NS091299 (D.C.Z.) and NIH R01NS106298 (M.C.K.).