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De novo indels within introns contribute to ASD incidence

Adriana Munoz, Boris Yamrom, Yoon-ha Lee, Peter Andrews, Steven Marks, Kuan-Ting Lin, Zihua Wang, Adrian R. Krainer, Robert B. Darnell, Michael Wigler, Ivan Iossifov
doi: https://doi.org/10.1101/137471
Adriana Munoz
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
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Boris Yamrom
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
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Yoon-ha Lee
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
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Peter Andrews
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
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Steven Marks
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
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Kuan-Ting Lin
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
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Zihua Wang
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
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Adrian R. Krainer
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
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Robert B. Darnell
2Laboratory of Molecular Neuro-oncology, Rockefeller University, New York, NY
3Howard Hughes Medical Institute, Rockefeller University, New York, NY
4New York Genome Center, New York, NY
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Michael Wigler
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
4New York Genome Center, New York, NY
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Ivan Iossifov
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
4New York Genome Center, New York, NY
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  • For correspondence: iossifov@cshl.edu
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Abstract

Copy number profiling and whole-exome sequencing has allowed us to make remarkable progress in our understanding of the genetics of autism over the past ten years, but there are major aspects of the genetics that are unresolved. Through whole-genome sequencing, additional types of genetic variants can be observed. These variants are abundant and to know which are functional is challenging. We have analyzed whole-genome sequencing data from 510 of the Simons Simplex Collections quad families and focused our attention on intronic variants. Within the introns of 546 high-quality autism target genes, we identified 63 de novo indels in the affected and only 37 in the unaffected siblings. The difference of 26 events is significantly larger than expected (p-val = 0.01) and using reasonable extrapolation shows that de novo intronic indels can contribute to at least 10% of simplex autism. The significance increases if we restrict to the half of the autism targets that are intolerant to damaging variants in the normal human population, which half we expect to be even more enriched for autism genes. For these 273 targets we observe 43 and 20 events in affected and unaffected siblings, respectively (p-value of 0.005). There was no significant signal in the number of de novo intronic indels in any of the control sets of genes analyzed. We see no signal from de novo substitutions in the introns of target genes.

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Posted May 24, 2017.
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De novo indels within introns contribute to ASD incidence
Adriana Munoz, Boris Yamrom, Yoon-ha Lee, Peter Andrews, Steven Marks, Kuan-Ting Lin, Zihua Wang, Adrian R. Krainer, Robert B. Darnell, Michael Wigler, Ivan Iossifov
bioRxiv 137471; doi: https://doi.org/10.1101/137471
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De novo indels within introns contribute to ASD incidence
Adriana Munoz, Boris Yamrom, Yoon-ha Lee, Peter Andrews, Steven Marks, Kuan-Ting Lin, Zihua Wang, Adrian R. Krainer, Robert B. Darnell, Michael Wigler, Ivan Iossifov
bioRxiv 137471; doi: https://doi.org/10.1101/137471

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