Exome Sequencing of Young Children with Cerebral Palsy Reveals Considerable Genetic Heterogeneity and Clinically Actionable Findings

Background: Cerebral palsy (CP) is the most common motor disability of children with substantial heritability, yet the extent of its genetic etiology is not fully appreciated.Methods: Exome sequencing (ES) with copy number variant (CNV) calling was performed on 1536 children with CP and genome sequencing (GS) was performed on 42 children with CP (mean age 24·5 months, range 5 to 216 months). Genetic variant interpretation of 2293 known neurodevelopmental disorder (NDD) genes followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines.Findings: 369 of 1578 (23·4%) children with CP had a genetic diagnosis by virtue of detection of pathogenic variants in known NDD genes. Single nucleotide variants (SNVs) alone accounted for 20·3% (321/1578), CNVs alone accounted for 2·6% (41/1578), a combination of one SNV and one CNV on the same gene accounted for 0·06% (1/1578), and in 0·4% (6/1578) cases blended diagnoses were reached with both diagnostic CNVs and SNVs on different genes. The genetic diagnostic rate in children with CP and history of perinatal asphyxia was significantly higher than in CP cases without asphyxia (28·4% vs. 21·9%, p = 0·0094). In addition, 33 out of 369 children (8·9%) with a genetic diagnosis had clinically actionable results. We identified six candidate CP genes by association analysis, including GPM6A, FOXD1, BSG, POSTN, SLC9A3R1, and STXBP5.Interpretation: A substantial proportion of CP cases in young children have a genetic cause. Early genetic testing facilitates evidence-based medical decision making and provides clinically actionable opportunities for young children with CP. At least some known epidemiological risk factors of CP like perinatal asphyxia might represent consequences of the maldevelopment of the fetus due to an inborn genetic etiology, rather than explaining CP themselvesFunding: This work was supported by the Shanghai Municipal Commission of Science and Technology Research Project (19JC1411001), the National Natural Science Foundation of China ( U21A20347, 31972880, 32170615, 31371274, 82203969), the National Key Research and Development Program from the Ministry of Science and Technology of the People's Republic of China (2021YFC2700800, 2022YFC2704800), the National Key Research and Development Plan for Stem Cell and Transformation Research (2017YFA0104202), the collaborative innovation center project construction for Shanghai women and children's health, the grant from Department of Science and Technology of Henan Province for international collaboration (GZS2023003), Swedish governmental grants to scientists working in health care (ALFGBG-965197, ALFGBG-966034), the Swedish Research Council (2018-02267, 2021-01950, 2022-01019), the Brain Foundation (FO2022-0120), the Eunice Kennedy Shriver National Institute of Child health & Human Development of the National Institutes of Health (R01HD104938).Declaration of Interest: All authors have completed the ICMJE form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work.Ethical Approval: Guardians signed informed consent and agreed with carrying out this study and publishing the results of this study. This study passed the review of Ethics Committee in Fudan University.