Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy

Gai McMichael, Matthew Bainbridge, Eric Haan, Mark Corbett, Alison Gardner, Suzanna Thompson, Bregje Van Bon, Clare Van Eyk, Jessica Broadbent, C Reynolds, Michael O'Callaghan, Lam Nguyen, David Adelson, Remo Russo, Shalini Jhangiani, Harshavardhan Doddapaneni, Donna Muzny, Richard Gibbs, Jozef Gecz, Alastair MacLennan

Research output: Contribution to journalArticlepeer-review

100 Citations (Scopus)


Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ∼2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks - the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten de novo mutations in three previously identified disease genes (TUBA1A (n=2), SCN8A (n=1) and KDM5C (n=1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes, L1CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.

Original languageEnglish
Pages (from-to)176-182
Number of pages7
Issue number2
Publication statusPublished - 2015


Dive into the research topics of 'Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy'. Together they form a unique fingerprint.

Cite this