Targeted resequencing identifies genes with recurrent variation in cerebral palsy

C L van Eyk; M A Corbett; M S B Frank; D L Webber; M Newman; J G Berry; K Harper; B P Haines; G McMichael; J A Woenig; A H MacLennan; J Gecz

doi:10.1038/s41525-019-0101-z

Targeted resequencing identifies genes with recurrent variation in cerebral palsy

NPJ Genom Med. 2019 Nov 4:4:27. doi: 10.1038/s41525-019-0101-z. eCollection 2019.

Authors

C L van Eyk^{1

2}, M A Corbett^{1

2}, M S B Frank^{1

2}, D L Webber^{1

2}, M Newman³, J G Berry^{1

2}, K Harper^{1

2}, B P Haines^{1

2}, G McMichael^{1

2}, J A Woenig^{1

2}, A H MacLennan^{1

2}, J Gecz^{1

2

4}

Affiliations

¹ 1Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA Australia.
² 2Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA Australia.
³ 3Alzheimer's Disease Genetics Laboratory, Centre for Molecular Pathology, School of Biological Sciences, University of Adelaide, Adelaide, SA Australia.
⁴ 4South Australian Health and Medical Research Institute, Adelaide, SA Australia.

Abstract

A growing body of evidence points to a considerable and heterogeneous genetic aetiology of cerebral palsy (CP). To identify recurrently variant CP genes, we designed a custom gene panel of 112 candidate genes. We tested 366 clinically unselected singleton cases with CP, including 271 cases not previously examined using next-generation sequencing technologies. Overall, 5.2% of the naïve cases (14/271) harboured a genetic variant of clinical significance in a known disease gene, with a further 4.8% of individuals (13/271) having a variant in a candidate gene classified as intolerant to variation. In the aggregate cohort of individuals from this study and our previous genomic investigations, six recurrently hit genes contributed at least 4% of disease burden to CP: COL4A1, TUBA1A, AGAP1, L1CAM, MAOB and KIF1A. Significance of Rare VAriants (SORVA) burden analysis identified four genes with a genome-wide significant burden of variants, AGAP1, ERLIN1, ZDHHC9 and PROC, of which we functionally assessed AGAP1 using a zebrafish model. Our investigations reinforce that CP is a heterogeneous neurodevelopmental disorder with known as well as novel genetic determinants.

Keywords: Genetic testing; Molecular medicine; Neurodevelopmental disorders; Paediatric neurological disorders.