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

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...

Full description

Saved in:
Bibliographic Details
Published in:Molecular psychiatry 2015-02, Vol.20 (2), p.176-182
Main Authors: McMichael, G, Bainbridge, M N, Haan, E, Corbett, M, Gardner, A, Thompson, S, van Bon, B W M, van Eyk, C L, Broadbent, J, Reynolds, C, O'Callaghan, M E, Nguyen, L S, Adelson, D L, Russo, R, Jhangiani, S, Doddapaneni, H, Muzny, D M, Gibbs, R A, Gecz, J, MacLennan, A H
Format: Article
Language:English
Subjects:
45
631/208
Adult
Animals
Autism
Behavioral Sciences
Biological Psychology
Causation
Cerebral palsy
Cerebral Palsy - genetics
Cohort Studies
Deoxyribonucleic acid
Depletion
DNA
Exome
Exome sequencing
Female
Gene Library
Gene mutation
Genes
Genetic aspects
Genetic Heterogeneity
Genetic Predisposition to Disease - genetics
Genetic testing
Genomes
Gestational Age
Health aspects
Heterogeneity
Hospitals
Humans
immediate-communication
Intolerance
Male
Medicine
Medicine & Public Health
Mutation
Neurosciences
Paralysis
Parents
Parents & parenting
Pediatrics
Pharmacotherapy
Posture
Psychiatry
Reproductive health
Sequence Analysis, DNA
Sodium channels (voltage-gated)
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1359-4184
1476-5578
DOI:10.1038/mp.2014.189