Large mosaic copy number variations confer autism risk.

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Genomic Instability

Background:

• Germline de novo copy number variants (CNVs) are established genetic causes of autism spectrum disorder (ASD).
• The role of mosaic copy number variants (mCNVs), arising during early development, in ASD etiology remains largely unexplored.

Purpose of the Study:

• To investigate the contribution of mCNVs to the genetic risk of ASD.
• To determine if mCNVs are associated with ASD diagnosis and symptom severity.

Main Methods:

• Analysis of genotype array intensity data from a large cohort of 12,077 ASD probands and 5,500 unaffected siblings.
• Detection and characterization of mCNVs, including their size and cellularity.
• Experimental validation of identified mCNVs in postmortem brain tissue.

Main Results:

• A significant burden of large (>4-Mb) mCNVs was observed in ASD probands compared to siblings (OR=11.4, P=7.4×10⁻⁴).
• mCNV size positively correlated with the severity of ASD symptoms (P=0.016).
• Mosaic analogues of previously identified short de novo CNVs associated with ASD were not detected.

Conclusions:

• mCNVs represent a significant, previously unaccounted-for genetic risk factor in ASD.
• The findings highlight the importance of considering mosaic events in the genetic architecture of ASD.
• Further research into mCNVs may uncover novel therapeutic targets for ASD.