Family-based exome sequencing and case-control analysis implicate CEP41 as an ASD gene

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Bioinformatics

Background:

• Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with a significant genetic basis.
• While next-generation sequencing (NGS) has identified genes for de novo ASD, familial ASD genetics remain less understood.
• Rare variants in familial ASD require further investigation.

Purpose of the Study:

• To investigate the genetic architecture of familial ASD using NGS.
• To identify genes harboring rare, disruptive, or missense variants of interest (VOIs) in families with ASD.
• To explore the functional impact of identified variants on neurodevelopmental pathways.

Main Methods:

• Employed NGS exome sequencing in 26 families with distantly related individuals affected by ASD.
• Identified private gene-disrupting and missense variants of interest (VOIs).
• Utilized targeted NGS and gene-based variant burden analysis for association testing; employed a zebrafish model to study CEP41 variant mechanisms.

Main Results:

• Genes with VOIs were enriched in pathways for cell projection organization and neuron development.
• Significantly associated ASD risk with missense variants in the CEP41 gene (p=6.185e-05).
• CEP41 variants in a zebrafish model impacted axonal tract development, neural crest cell migration, and social behavior.

Conclusions:

• Heterozygous missense variants in CEP41 are implicated in familial ASD.
• The findings support the neurodevelopmental hypothesis of ASD.
• CEP41 plays a role in neuronal development and is a potential genetic factor in ASD.