title: Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy.
abstract: 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.
authors: Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
authors: G
authors: G
authors: McMichael
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors: M N
authors: MN
authors: Bainbridge
authors: 1] South Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), North Adelaide, SA, Australia [2] School of Pediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA, Australia.
authors: E
authors: E
authors: Haan
authors: 1] Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia [2] School of Pediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA, Australia.
authors: M
authors: M
authors: Corbett
authors: 1] Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia [2] School of Pediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA, Australia.
authors: A
authors: A
authors: Gardner
authors: 1] School of Pediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA, Australia [2] Department of Pediatric Neurology, Women's and Children's Hospital, North Adelaide, SA, Australia.
authors: S
authors: S
authors: Thompson
authors: 1] South Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), North Adelaide, SA, Australia [2] Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: B W M
authors: BW
authors: van Bon
authors: Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
authors: C L
authors: CL
authors: van Eyk
authors: Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
authors: J
authors: J
authors: Broadbent
authors: Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
authors: C
authors: C
authors: Reynolds
authors: Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
authors: M E
authors: ME
authors: O'Callaghan
authors: School of Pediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA, Australia.
authors: L S
authors: LS
authors: Nguyen
authors: School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, SA, Australia.
authors: D L
authors: DL
authors: Adelson
authors: Department of Pediatric Rehabilitation, Women's and Children's Hospital, North Adelaide, SA, Australia.
authors: R
authors: R
authors: Russo
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors: S
authors: S
authors: Jhangiani
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors: H
authors: H
authors: Doddapaneni
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors: D M
authors: DM
authors: Muzny
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors: R A
authors: RA
authors: Gibbs
authors: 1] Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia [2] School of Pediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA, Australia.
authors: J
authors: 0000000278846861
authors: J
authors: Gecz
authors: Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
authors: A H
authors: AH
authors: MacLennan
mesh_terms: D000328:Adult; D000818:Animals; D002547:Cerebral Palsy / Q000235:genetics*; D015331:Cohort Studies; D059472:Exome; D005260:Female; D015723:Gene Library; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005865:Gestational Age; D006801:Humans; D008297:Male; D009154:Mutation; D010290:Parents; D017422:Sequence Analysis, DNA