A double hit implicates DIAPH3 as an autism risk gene

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Autism spectrum disorder (ASD) is increasingly linked to de novo genomic rearrangements.
• Heritable copy number variants (CNVs) are often overlooked as potential contributors to ASD.
• This study investigates a patient with autism and unaffected parents presenting a compound heterozygous genotype.

Purpose of the Study:

• To identify and characterize novel genetic factors contributing to autism.
• To explore the role of inherited genomic rearrangements and mutations in ASD.
• To investigate the function of the DIAPH3 gene in brain development and its potential link to autism.

Main Methods:

• Whole-exome sequencing and array comparative genomic hybridization (aCGH) were used to identify genetic variants.
• Functional assays in murine fibroblasts were performed to assess the impact of the DIAPH3 variant.
• Expression analysis of Diaph3 in the developing murine cerebral cortex was conducted.

Main Results:

• A patient with autism was found to have a maternally inherited 10 Mb deletion at 13q21.2 and a paternally inherited DIAPH3 Pro614Thr mutation.
• The DIAPH3 Pro614Thr variant was absent in 328 healthy controls and reduced filopodia formation in vitro.
• Diaph3 exhibits transient expression in the developing murine cerebral cortex, suggesting a role in brain development.

Conclusions:

• The DIAPH3 gene, implicated in cell migration and neuronal development, is identified as a novel autism susceptibility gene.
• This case demonstrates the significance of inherited CNVs and compound heterozygosity ('double-hit') in autism etiology.
• Further research should consider both de novo and inherited genomic variants in understanding autism.