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

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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.

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We wish to thank participating CP families, Cerebral Palsy Alliance; Dr James Lupski for critical comments; Dr Jane Valentine and Peta Watts for facilitating blood collections at Princess Margaret Hospital, Western Australia; Dr James Rice and Dr Andrew Tidemann for facilitating blood collections in South Australia; Associate Professor Christopher Barnett for clinical reports; staff of the South Australian Cerebral Palsy Register; Kelly Harper for correlation of neuroimaging reports; Josh Woenig for the technical support; and Dr Kathie Friend and staff at the Department of Genetic Medicine, Women’s and Children’s Hospital, Adelaide and AGRF (Adelaide node) for the support with DNA extractions. DNA/cell lines were established by Genetic Repositories Australia, an Enabling Facility supported by the Australian National Health and Medical Research Council (Grant No. 401184). This work was funded by the Australian National Health and Medical Research Council (Grant No. 1041920 and Grant No. 1019928), JG is supported by NHMRC research fellowship 1041920, The Cerebral Palsy Foundation, The Tenix Foundation, The Robinson Institute, The University of Adelaide, Women’s & Children’s Research Foundation, MC is supported by MS McLeod research fellowship, and the Ter Meulen Fund (stipend to BWMvanB). Supported in part by the National Human Genome Research Institute U54 HG003273 (RAG).

Web Resources

The URLs for data presented herein include:

Cerebral Palsy Research Report; www.cerebralpalsy.org.au/wp-content /uploads /2013/04/ ACPR/

BCM-HGSC protocol; (https://hgsc.bcm.edu/sites/default/files/documents/Illumina _Barcoded _Paired-End _Capture_Library_Preparation.pdf).

Partek; http://www.partek.com/

1000 Genomes; http://browser.1000genomes.org/index.html

dbSNP; http://www.ncbi.nlm.nih.gov/projects/SNP/

Online Mendelian Inheritance in Man (OMIM); http://www.omim.org/

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Correspondence to J Gecz.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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