TY - JOUR
T1 - Targeted resequencing identifies genes with recurrent variation in cerebral palsy
AU - van Eyk, C. L.
AU - Corbett, M. A.
AU - Frank, M. S.B.
AU - Webber, D. L.
AU - Newman, M.
AU - Berry, J. G.
AU - Harper, K.
AU - Haines, B. P.
AU - McMichael, G.
AU - Woenig, J. A.
AU - MacLennan, A. H.
AU - Gecz, J.
N1 - Funding Information:
The authors would like to thank the families reported in this study for their contributions to this research. We thank Stanley Tan, Hannah McDonald and Marie Shaw for technical assistance, A/Prof Michael Lardelli and members of the Alzheimer’s Disease Genetics Laboratory at the University of Adelaide for technical assistance and use of the zebrafish facility, Myungchull Rhee for use of the pcGlobin vector, and the School of Biological Science at the University of Adelaide for their support towards maintenance of the Adelaide Zebrafish Facility. We would also like to thank the Australian CP registers and A/Professor Ray Russo, Dr. James Rice, Dr. Andrew Tidemann, Dr. Mary-Clare Waugh, Dr. Matthias Axt, Dr. Kevin Lowe, Dr. Michael Stening and Dr. Lisa Copeland for assistance in recruitment of participants and clinical data review. M.N. wishes to thank the family of Lindsay Carthew for financial support. This work was supported by a Cerebral Palsy Alliance Research Foundation Innovative Research Grant (IRG3113), Australian National Health and Medical Research Council Project Grants (1019928 and 1099163), Australian National Health and Medical Research Council Fellowship (1041920) to J.G., and Infrastructure funding from the Tenix Foundation and the Robinson Research Institute, University of Adelaide.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85074326727&partnerID=8YFLogxK
U2 - 10.1038/s41525-019-0101-z
DO - 10.1038/s41525-019-0101-z
M3 - Article
AN - SCOPUS:85074326727
VL - 4
JO - npj Genomic Medicine
JF - npj Genomic Medicine
SN - 2056-7944
IS - 1
M1 - 27
ER -