Targeted resequencing identifies genes with recurrent variation in cerebral palsy
C L van Eyk1,2, M A Corbett1,2, M S B Frank1,2
11Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA Australia.
Cerebral palsy (CP) has a complex genetic cause. This study identified six key genes contributing to CP burden and highlighted novel genetic factors, reinforcing CP as a heterogeneous neurodevelopmental disorder.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Cerebral palsy (CP) exhibits significant genetic heterogeneity.
- Previous studies suggest a substantial genetic contribution to CP etiology.
- Identifying specific genes is crucial for understanding CP's diverse causes.
Purpose of the Study:
- To identify frequently occurring genes associated with cerebral palsy.
- To investigate the genetic architecture of CP in a large cohort.
- To discover novel genetic determinants contributing to CP.
Main Methods:
- Designed a custom gene panel of 112 candidate genes for CP.
- Utilized next-generation sequencing on 366 clinically unselected singleton CP cases.
- Performed Significance of Rare Variants (SORVA) burden analysis and functional assessment in a zebrafish model.
Main Results:
- Identified clinical significance variants in 5.2% of novel CP cases and variants in candidate genes in 4.8% of cases.
- Six recurrently implicated genes (COL4A1, TUBA1A, AGAP1, L1CAM, MAOB, KIF1A) account for at least 4% of CP disease burden.
- SORVA analysis revealed genome-wide significant variant burden in AGAP1, ERLIN1, ZDHHC9, and PROC.
Conclusions:
- Cerebral palsy is a genetically heterogeneous neurodevelopmental disorder.
- This study identified known and novel genetic determinants contributing to CP.
- Genomic investigations are essential for elucidating the complex etiology of CP.
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