Rare and Low Frequency Genomic Variants Impacting Neuronal Functions Modify the Dup7q11.23 Phenotype
Document Type
Article
Publication Date
12-6-2021
Publication Title
Orphanet Journal of Rare Diseases
Volume
16
Issue
1
First page number:
1
Last page number:
11
Abstract
© 2021, The Author(s). Background: 7q11.23 duplication (Dup7) is one of the most frequent recurrent copy number variants (CNVs) in individuals with autism spectrum disorder (ASD), but based on gold-standard assessments, only 19% of Dup7 carriers have ASD, suggesting that additional genetic factors are necessary to manifest the ASD phenotype. To assess the contribution of additional genetic variants to the Dup7 phenotype, we conducted whole-genome sequencing analysis of 20 Dup7 carriers: nine with ASD (Dup7-ASD) and 11 without ASD (Dup7-non-ASD). Results: We identified three rare variants of potential clinical relevance for ASD: a 1q21.1 microdeletion (Dup7-non-ASD) and two deletions which disrupted IMMP2L (one Dup7-ASD, one Dup7-non-ASD). There were no significant differences in gene-set or pathway variant burden between the Dup7-ASD and Dup7-non-ASD groups. However, overall intellectual ability negatively correlated with the number of rare loss-of-function variants present in nervous system development and membrane component pathways, and adaptive behaviour standard scores negatively correlated with the number of low-frequency likely-damaging missense variants found in genes expressed in the prenatal human brain. ASD severity positively correlated with the number of low frequency loss-of-function variants impacting genes expressed at low levels in the brain, and genes with a low level of intolerance. Conclusions: Our study suggests that in the presence of the same pathogenic Dup7 variant, rare and low frequency genetic variants act additively to contribute to components of the overall Dup7 phenotype.
Keywords
7q11.23 duplication syndrome; Autism spectrum disorder; Copy number variant; Phenotypic variability; Single nucleotide variant; Whole genome sequencing
Disciplines
Genomics | Molecular and Cellular Neuroscience
File Format
File Size
1716 KB
Language
English
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Repository Citation
Qaiser, F.,
Yin, Y.,
Mervis, C.,
Morris, C.,
Klein-Tasman, B.,
Tam, E.,
Osborne, L.,
Yuen, R.
(2021).
Rare and Low Frequency Genomic Variants Impacting Neuronal Functions Modify the Dup7q11.23 Phenotype.
Orphanet Journal of Rare Diseases, 16(1),
1-11.
http://dx.doi.org/10.1186/s13023-020-01648-6