Background: Cerebral Palsy (CP) is a group of neurodevelopmental disorders characterized by injury to the developing brain. CP is caused by environmental and genetic factors; however, the genetic contributions are poorly understood.
Objectives: To better understand genetic factors, The Centre For Applied Genomics conducted whole genome sequencing on DNA from CP patients and their parents and identified potential clinically relevant variants. Of these variants, I confirmed the de novo predictive loss-of-function and missense variants using Sanger Sequencing.
Here, I highlight three de novo variants in genes that have been previously linked to neurodevelopmental disorders: BCL11A (c.A200G:p.(K67R)), GATAD2B (c.T1321C:p.(C441R)) and PIK3R2 (c.G1117A:p.(G373R)). I investigated each gene’s functions, previously identified gene variants, and impacts of those variants in animal models, cell lines, and clinical studies to understand each genes’ potential link to CP.
Results: BCL11A encodes a transcription regulating protein that suppresses fetal hemoglobin after birth and promotes axonal growth and branching. GATAD2B encodes a subunit of the nucleosome remodeling and histone deacetylase complex which regulates transcription and is linked to neural development. PIK3R2 encodes a regulatory subunit of a kinase which is involved in growth signaling and transcription regulation. All genes are highly expressed in the brain, and all variants are in conserved regions of their respective gene. Other de novo missense alterations in the same exon of each gene have been identified in patients with other neurodevelopmental disorders such as intellectual disability. Knockdown studies in mice and Drosophila as well as molecular pathway analyses show evidence for pathogenicity of similar variants in all genes.
Conclusions: The validation of sequence level variants adds to the growing database of genes and variants connected to CP, including three variants, two of which are completely novel, on genes that have not previously been linked to CP. Further investigation can be done on other variants and how they impact gene function, adding to the overall understanding of potential causes of CP.
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