Rare and low frequency genomic variants impacting neuronal functions modify the Dup7q11.23 phenotype

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• 7q11.23 duplication (Dup7) is a common copy number variant (CNV) associated with autism spectrum disorder (ASD).
• Only 19% of Dup7 carriers are diagnosed with ASD, indicating that other genetic factors are required for phenotype manifestation.
• Understanding these additional genetic contributors is crucial for explaining the variable expressivity of the Dup7 phenotype.

Purpose of the Study:

• To investigate the role of additional genetic variants in individuals with 7q11.23 duplication (Dup7).
• To compare whole-genome sequencing data between Dup7 carriers with and without ASD.
• To identify genetic factors contributing to the phenotypic variability in Dup7 carriers.

Main Methods:

• Whole-genome sequencing was performed on 20 Dup7 carriers (9 with ASD, 11 without ASD).
• Analysis focused on identifying rare and low-frequency genetic variants.
• Correlations were assessed between variant burden and clinical measures including ASD severity, intellectual ability, and adaptive behavior.

Main Results:

• Three rare variants of potential clinical relevance were identified, including a 1q21.1 microdeletion and two deletions disrupting IMMP2L.
• No significant differences in gene-set or pathway variant burden were found between ASD and non-ASD groups.
• Intellectual ability correlated negatively with rare loss-of-function variants in nervous system development and membrane component pathways.
• Adaptive behavior correlated negatively with low-frequency likely-damaging missense variants in genes expressed in the prenatal brain.
• ASD severity correlated positively with low-frequency loss-of-function variants impacting genes with low expression and low intolerance in the brain.

Conclusions:

• Rare and low-frequency genetic variants act additively to influence the Dup7 phenotype.
• These additional genetic factors contribute to specific components of the overall phenotype, including ASD.
• The findings highlight the complex genetic architecture underlying neurodevelopmental disorders associated with CNVs.