An Intronic Variant of CHD7 Identified in Autism Patients Interferes with Neuronal Differentiation and Development

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Genetic variations, particularly intronic variants, are implicated in autism spectrum disorder (ASD) pathogenesis.
• The functional significance of intronic variants in ASD remains challenging to elucidate.
• The CHD7 gene, associated with developmental disorders and ASD, harbors intronic variants relevant to East Asian populations.

Purpose of the Study:

• To investigate the impact of a recurrent inherited intronic variant in the CHD7 gene on neural development in the context of ASD.
• To explore the functional consequences of this variant on CHD7 expression and neuronal maturation.
• To identify potential molecular mechanisms, including interactions with other ASD-associated genes like TBR1, underlying the observed defects.

Main Methods:

• Established human embryonic stem cells with the specific CHD7 intronic variant using CRISPR/Cas9 gene editing.
• Differentiated these cells into forebrain neuronal lineages to assess neural development.
• Analyzed CHD7 mRNA levels, neuronal morphology, maturity, and the expression of TBR1.
• Performed knockdown experiments of TBR1 to evaluate its role in the observed defects.
• Assessed the functional impact of alternatively spliced transcripts generated by the variant.

Main Results:

• The CHD7 intronic variant led to a significant decrease in CHD7 mRNA levels.
• Neurons with the variant exhibited developmental delays and maturity defects.
• TBR1 expression was significantly increased in variant neurons, and its knockdown rescued morphological defects.
• Three aberrant transcripts resulting from alternative splicing showed loss-of-function.

Conclusions:

• The identified intronic variant in CHD7 is a potential autism susceptibility factor.
• This variant disrupts neural development through decreased CHD7 expression and altered splicing, potentially involving TBR1.
• The study highlights the importance of investigating intronic variants in ASD genetic research.