Language
English
Publication Date
11-1-2024
DOI
10.1038/s41431-024-01661-4
PMID
38965372
PMCID
PMC11577032
PubMedCentral® Posted Date
7-4-2024
PubMedCentral® Full Text Version
Post-print
Abstract
This study aimed to uncover novel genes associated with neurodevelopmental disorders (NDD) by leveraging recent large-scale de novo burden analysis studies to enhance a virtual gene panel used in a diagnostic setting. We re-analyzed historical trio-exome sequencing data from 745 individuals with NDD according to the most recent diagnostic standards, resulting in a cohort of 567 unsolved individuals. Next, we designed a virtual gene panel containing candidate genes from three large de novo burden analysis studies in NDD and prioritized candidate genes by stringent filtering for ultra-rare de novo variants with high pathogenicity scores. Our analysis revealed an increased burden of de novo variants in our selected candidate genes within the unsolved NDD cohort and identified qualifying de novo variants in seven candidate genes: RIF1, CAMK2D, RAB11FIP4, AGO3, PCBP2, LEO1, and VCP. Clinical data were collected from six new individuals with de novo or inherited LEO1 variants and three new individuals with de novo PCBP2 variants. Our findings add additional evidence for LEO1 as a risk gene for autism and intellectual disability. Furthermore, we prioritize PCBP2 as a candidate gene for NDD associated with motor and language delay. In summary, by leveraging de novo burden analysis studies, employing a stringent variant filtering pipeline, and engaging in targeted patient recruitment, our study contributes to the identification of novel genes implicated in NDDs.
Keywords
Humans, Female, Male, Child, Neurodevelopmental Disorders, Intellectual Disability, RNA-Binding Proteins, Child, Preschool, Exome Sequencing, Autistic Disorder, Cohort Studies, Genetics research, Genetic testing, Neurodevelopmental disorders
Published Open-Access
yes
Recommended Citation
Smal, Noor; Majdoub, Fatma; Janssens, Katrien; et al., "Burden Re-Analysis of Neurodevelopmental Disorder Cohorts for Prioritization of Candidate Genes" (2024). Faculty and Staff Publications. 5039.
https://digitalcommons.library.tmc.edu/baylor_docs/5039
Included in
Genetic Phenomena Commons, Genetic Processes Commons, Genetic Structures Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Medical Specialties Commons