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The role of rare compound heterozygous events in autism spectrum disorder.
Lin, Bochao Danae Colas, Fabrice Nijman, Isaac J Medic, Jelena Brands, William Parr, Jeremy R van Eijk, Kristel R Klauck, Sabine M Chiocchetti, Andreas G Freitag, Christine M
Lin, Bochao Danae
Colas, Fabrice
Nijman, Isaac J
Medic, Jelena
Brands, William
Parr, Jeremy R
van Eijk, Kristel R
Klauck, Sabine M
Chiocchetti, Andreas G
Freitag, Christine M
Author
Lin, Bochao Danae
Colas, Fabrice
Nijman, Isaac J
Medic, Jelena
Brands, William
Parr, Jeremy R
van Eijk, Kristel R
Klauck, Sabine M
Chiocchetti, Andreas G
Freitag, Christine M
Maestrini, Elena
Bacchelli, Elena
Coon, Hilary
Vicente, Astrid
Oliveira, Guiomar
Pagnamenta, Alistair T
Gallagher, Louise
Ennis, Sean
Anney, Richard
Bourgeron, Thomas
Luykx, Jurjen J
Vorstman, Jacob
Colas, Fabrice
Nijman, Isaac J
Medic, Jelena
Brands, William
Parr, Jeremy R
van Eijk, Kristel R
Klauck, Sabine M
Chiocchetti, Andreas G
Freitag, Christine M
Maestrini, Elena
Bacchelli, Elena
Coon, Hilary
Vicente, Astrid
Oliveira, Guiomar
Pagnamenta, Alistair T
Gallagher, Louise
Ennis, Sean
Anney, Richard
Bourgeron, Thomas
Luykx, Jurjen J
Vorstman, Jacob
Advisors
Editors
Other Contributors
Departments
Date
2020-06-22
Date Submitted
Keywords
AUTISM SPECTRUM DISORDER
GENETIC FACTORS
GENETIC FACTORS
Other Subjects
Subject Mesh
Planned Date
Start Date
Collaborators
Principal Investigators
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s41398-020-00866-7.pdf
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Abstract
The identification of genetic variants underlying autism spectrum disorders (ASDs) may contribute to a better understanding of their underlying biology. To examine the possible role of a specific type of compound heterozygosity in ASD, namely, the occurrence of a deletion together with a functional nucleotide variant on the remaining allele, we sequenced 550 genes in 149 individuals with ASD and their deletion-transmitting parents. This approach allowed us to identify additional sequence variants occurring in the remaining allele of the deletion. Our main goal was to compare the rate of sequence variants in remaining alleles of deleted regions between probands and the deletion-transmitting parents. We also examined the predicted functional effect of the identified variants using Combined Annotation-Dependent Depletion (CADD) scores. The single nucleotide variant-deletion co-occurrence was observed in 13.4% of probands, compared with 8.1% of parents. The cumulative burden of sequence variants (n = 68) in pooled proband sequences was higher than the burden in pooled sequences from the deletion-transmitting parents (n = 41, X2 = 6.69, p = 0.0097). After filtering for those variants predicted to be most deleterious, we observed 21 of such variants in probands versus 8 in their deletion-transmitting parents (X2 = 5.82, p = 0.016). Finally, cumulative CADD scores conferred by these variants were significantly higher in probands than in deletion-transmitting parents (burden test, β = 0.13; p = 1.0 × 10-5). Our findings suggest that the compound heterozygosity described in the current study may be one of several mechanisms explaining variable penetrance of CNVs with known pathogenicity for ASD.
Language
en
Citation
ISSN
eISSN
2158-3188
ISBN
DOI
10.1038/s41398-020-00866-7
PMID
32572023