Characterizing the spectrum of genomic and phenotypic variation in cerebral palsy

描述脑瘫的基因组和表型变异谱

• 批准号: 10651821
• 负责人: Andres Moreno De Luca
• 金额: $ 68.02万
• 依托单位: GEISINGER CLINIC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651821
• 关键词: Adult; Affect; Architecture; Asphyxia Neonatorum; Biological; Brain Diseases; Candidate Disease Gene; Cerebral Palsy; Childhood; Clinical; Clinical Data; Cohort Analysis; Collaborations; Common Data Element; Copy Number Polymorphism; Correlation Studies; Data; Data Set; Databases; Development; Disease; Electronic Health Record; Enrollment; Etiology; Evaluation; Fostering; Frequencies; Gene Family; Generations; Genes; Genome; Genomics; Genotype; Guidelines; Healthcare; Heritability; Human; Impairment; Individual; Intellectual functioning disability; Investigation; Knowledge; Laboratories; Link; Medical; Medical Genetics; Molecular; Motor; National Institute of Neurological Disorders and Stroke; Ontology; Outcome Study; Participant; Pathogenicity; Pathway interactions; Patients; Pediatric cohort; Phenotype; Prevalence; Publishing; Research; Risk Factors; Role; SNP genotyping; Site; Source; Standardization; Subgroup; Testing; Variant; autism spectrum disorder; bioinformatics tool; brain abnormalities; candidate identification; clinical care; cohort; comorbidity; cost effective; exome sequencing; genetic variant; genome wide association study; genomic data; neuroimaging; novel; novel strategies; phenotypic data; population based; rare variant; recruit; success; targeted treatment; transmission process

PROJECT SUMMARY/ABSTRACT Cerebral palsy (CP) is a common (prevalence 1 in 500), nonprogressive developmental brain disorder (DBD) characterized by neuromotor impairments often accompanied by other neurodevelopmental and medical disorders. Birth asphyxia, long considered the most frequent cause of CP, accounts for <10% of cases and a specific cause remains unknown for most individuals. A growing body of evidence suggests that a large proportion of CP is caused by rare genomic variants, as has been shown for other DBDs. Additionally, the contribution of common genomic variants to CP has not been adequately evaluated. Here, we propose to elucidate the complete genomic architecture of CP, including the contribution of rare and common genomic variants. We will capitalize on data generated from two complementary sources: 1) a pediatric CP cohort referred for exome sequencing (ES) to a clinical genetics laboratory (GeneDx) and 2) an adult CP cohort from Geisinger’s MyCode study, a large-scale genomics initiative with paired electronic health record (EHR), ES, and SNP genotype data. As with other DBDs, clinical variability is common in CP and detailed genotype-phenotype correlation studies are required to characterize the contributors to phenotypic variance. Similarly, neuroimaging studies reveal brain abnormalities in 70-90% of individuals with CP; however, finding a neuroimaging abnormality does not establish the underlying cause for most individuals without further evaluations and there is a lack of neuroimaging studies to link genomic findings with CP. We will address these significant knowledge gaps through the following aims: 1) Extract and standardize genomics, EHR, and neuroimaging data to create a large, harmonized CP dataset for analysis. We will leverage genotype and phenotype data from 4,000 individuals with CP and harmonize their available genomic, EHR, and neuroimaging data. 2) Determine the contribution of rare genomic variants to the etiology of CP and identify new gene-disease relationships and CP-related genes; 3) Evaluate the role of common genomic variants in CP and the influence of genomic liability for DBD on CP. We will comprehensively assess the full genomic landscape of CP, including multiple classes of genomic variants. 4) Develop a genomically-informed approach to neuroimaging interpretation in CP and characterize genotype- phenotype correlations for CP-related genes. We will perform genomically-informed neuroimaging interpretation in a subgroup of participants with pathogenic variants to identify profiles of brain abnormalities related to specific genes. We will also explore the contributors to clinical variability among individuals with rare variants in the same gene. Overall, there is a very high likelihood of success that this project will lead to the identification of novel genomic variants that cause CP. An immediate outcome of this study will be the generation of required evidence to support the incorporation of clinical genomic testing into routine clinical care for individuals with CP. This project will foster future research into molecular mechanisms of disease, which will be critical to developing targeted therapies for specific genomic variants, and will inform clinical genomic testing for individuals with CP.

项目总结/文摘

项目成果

Implications of Genetic Variants in Cerebral Palsy-Reply.

遗传变异对脑瘫应答的影响。

• DOI: 10.1001/jamapediatrics.2023.1858
• 发表时间: 2023
• 期刊: JAMA pediatrics
• 影响因子: 26.1
• 作者: Myers,ScottM;Martin,ChristaL;Moreno-De-Luca,Andres
• 通讯作者: Moreno-De-Luca,Andres

It's time to offer genetic testing to all individuals diagnosed with cerebral palsy.

是时候为所有被诊断患有脑瘫的人提供基因检测了。

• DOI: 10.1016/j.parkreldis.2023.105449
• 发表时间: 2023
• 期刊: Parkinsonism & related disorders
• 影响因子: 4.1
• 作者: Moreno-De-Luca,Andrés

A novel SMARCC1 -mutant BAFopathy implicates epigenetic dysregulation of neural progenitors in hydrocephalus.

一种新的 SMARCC1 突变 BAF 病涉及脑积水神经祖细胞的表观遗传失调。

• DOI: 10.1101/2023.03.19.23287455
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Singh,AmritaK;Viviano,Stephen;Allington,Garrett;McGee,Stephen;Kiziltug,Emre;Mekbib,KedousY;Shohfi,JohnP;Duy,PhanQ;DeSpenza,Tyrone;Furey,CharutaG;Reeves,BenjaminC;Smith,Hannah;Ma,Shaojie;Sousa,AndréMM;Cherskov,Adriana

PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic-dyskinetic encephalopathy.

• DOI: 10.1002/acn3.51634
• 发表时间: 2022-09
• 期刊: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
• 影响因子: 5.3
• 作者: Dafsari, Hormos Salimi;Pemberton, Joshua G.;Ferrer, Elizabeth A.;Yammine, Tony;Farra, Chantal;Mohammadi, Mohammad Hasan;Karimiani, Ehsan Ghayoor;Hashemi, Narges;Souaid, Mirna;Sabbagh, Sandra;Torbati, Paria Najarzadeh;Khan, Suliman;Roze, Emmanuel;Moreno-De-Luca, Andres;Bertoli-Avella, Aida M.;Houlden, Henry;Balla, Tamas;Maroofian, Reza
• 通讯作者: Maroofian, Reza