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PgmNr 105: Mosaic copy number variants are associated with autism spectrum disorder.

M. Sherman 1,2,3; R. Rodin 3,4; G. Genovese 3,5; C. Dias 4,6; C. Walsh 3,4; P. Park 7; P.-R. Loh 2,3

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1) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA.; 2) Department of Genetics, Brigham and Women’s Hospital, Boston, MA.; 3) Broad Institute of MIT and Harvard, Cambridge, MA.; 4) Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA; 5) Department of Genetics, Harvard Medical School, Boston, MA; 6) Division of Developmental Medicine, Boston Children's Hospital, Boston, MA; 7) Department of Biomedical Informatics, Harvard Medical School, Boston, MA

Germline copy number variants (CNVs) are a known cause of autism spectrum disorder (ASD), but whether mosaic (post-zygotic) CNVs arising during early embryogenesis also contribute to ASD risk is unknown. Here we answer this question in the affirmative using two independent genotyping datasets of individuals with ASD (probands) and their unaffected siblings and parents: the Simons Simplex Collection (SSC) (2594 probands and 2423 siblings) and SPARK collection (8875 probands and 2931 siblings). We leveraged statistical haplotype phasing together with available parental genotypes to sensitively detect mosaic duplications, deletions and copy-number neutral loss of heterozygosity (CNN-LOH). Since genotyping was performed on blood and saliva, we filtered events appearing to arise due to clonal hematopoiesis.

Mosaic CNVs were detected infrequently in both probands and unaffected siblings (0.37% of probands and 0.28% of siblings across SSC and SPARK). Nonetheless, in both cohorts, probands carried a significant burden of large (>4 Mbp) mosaic CNVs compared to siblings (p = 0.043 and p = 0.011 in SSC and SPARK, respectively; OR=10.76, CI=1.45-79.7, p=0.0012 combined). Although most CNVs were deletions and duplications, five were CNN-LOH including uniparental disomies of chromosomes 1 and 2 and two other CNN-LOH events disrupting 1p and 2q. These CNN-LOH events occurred exclusively in probands and created homozygosity for predicted loss-of-function SNVs.

We found clear links between several events and observed phenotypes. A proband with a mosaic 18q deletion lacked verbal communication, consistent with Pitt-Hopkins syndrome; and a proband with mosaic CNN-LOH of 11p had macrocephaly and clinical growth abnormalities, consistent with Beckwith-Wiedemann syndrome. Furthermore, several short CNVs in probands disrupted known autism-related genes (e.g., TRIO and USP7), suggesting even small mosaic CNVs may contribute to ASD etiology.

To confirm the presence of mosaic CNVs in neurons, we whole-genome sequenced post-mortem brain tissue from 60 Autism BrainNet samples. We identified one large mosaic duplication and validated its presence in 15% of neurons using digital-droplet PCR; breakpoint analysis revealed the event was composed of multiple inversions and duplications. Our results demonstrate a clear association between mosaic CNVs and autism spectrum disorder, suggest a link between CNN-LOH and ASD, and demonstrate that mosaic CNVs may arise as complex rearrangements.