. 2022 Nov 10;185(23):4409-4427.e18.

doi: 10.1016/j.cell.2022.10.009.

Genomic architecture of autism from comprehensive whole-genome sequence annotation

Brett Trost¹, Bhooma Thiruvahindrapuram², Ada J S Chan¹, Worrawat Engchuan¹, Edward J Higginbotham¹, Jennifer L Howe², Livia O Loureiro¹, Miriam S Reuter³, Delnaz Roshandel⁴, Joe Whitney², Mehdi Zarrei¹, Matthew Bookman⁵, Cherith Somerville⁶, Rulan Shaath², Mona Abdi⁷, Elbay Aliyev⁸, Rohan V Patel², Thomas Nalpathamkalam², Giovanna Pellecchia², Omar Hamdan², Gaganjot Kaur², Zhuozhi Wang², Jeffrey R MacDonald², John Wei², Wilson W L Sung², Sylvia Lamoureux², Ny Hoang⁹, Thanuja Selvanayagam¹⁰, Nicole Deflaux⁵, Melissa Geng¹¹, Siavash Ghaffari¹, John Bates⁵, Edwin J Young¹², Qiliang Ding⁶, Carole Shum¹, Lia D'Abate¹, Clarrisa A Bradley¹³, Annabel Rutherford¹⁴, Vernie Aguda², Beverly Apresto², Nan Chen², Sachin Desai², Xiaoyan Du², Matthew L Y Fong², Sanjeev Pullenayegum², Kozue Samler², Ting Wang², Karen Ho², Tara Paton², Sergio L Pereira², Jo-Anne Herbrick², Richard F Wintle², Jonathan Fuerth¹⁵, Juti Noppornpitak¹⁵, Heather Ward¹⁵, Patrick Magee¹⁵, Ayman Al Baz¹⁵, Usanthan Kajendirarajah¹⁵, Sharvari Kapadia¹⁵, Jim Vlasblom¹⁵, Monica Valluri¹⁵, Joseph Green¹⁵, Vicki Seifer¹⁶, Morgan Quirbach¹⁶, Olivia Rennie², Elizabeth Kelley¹⁷, Nina Masjedi¹⁸, Catherine Lord¹⁸, Michael J Szego¹⁹, Ma'n H Zawati²⁰, Michael Lang²⁰, Lisa J Strug²¹, Christian R Marshall²², Gregory Costain²³, Kristina Calli²⁴, Alana Iaboni²⁵, Afiqah Yusuf²⁶, Patricia Ambrozewicz²⁷, Louise Gallagher²⁸, David G Amaral²⁹, Jessica Brian³⁰, Mayada Elsabbagh²⁶, Stelios Georgiades³¹, Daniel S Messinger³², Sally Ozonoff²⁹, Jonathan Sebat³³, Calvin Sjaarda³⁴, Isabel M Smith³⁵, Peter Szatmari³⁶, Lonnie Zwaigenbaum³⁷, Azadeh Kushki³⁸, Thomas W Frazier³⁹, Jacob A S Vorstman⁴⁰, Khalid A Fakhro⁴¹, Bridget A Fernandez⁴², M E Suzanne Lewis²⁴, Rosanna Weksberg⁴³, Marc Fiume¹⁵, Ryan K C Yuen¹¹, Evdokia Anagnostou³⁰, Neal Sondheimer⁴⁴, David Glazer⁵, Dean M Hartley¹⁶, Stephen W Scherer⁴⁵

Affiliations

¹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
² The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
³ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; CGEn, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁴ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁵ Verily Life Sciences, South San Francisco, CA 94080, USA.
⁶ Ted Rogers Centre for Heart Research, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁷ Department of Human Genetics, Sidra Medicine, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁸ Department of Human Genetics, Sidra Medicine, Doha, Qatar.
⁹ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Autism Research Unit, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
¹⁰ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Autism Research Unit, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
¹¹ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹² Genome Diagnostics, Department of Paediatric Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
¹³ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
¹⁴ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁵ DNAstack, Toronto, ON M5H 1T1, Canada.
¹⁶ Autism Speaks, Princeton, NJ 08540, USA.
¹⁷ Department of Psychology, Queen's University, Kingston, ON K7L 3N6, Canada; Department of Psychiatry, Queen's University, Kingston, ON K7L 7X3, Canada.
¹⁸ Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA.
¹⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Family and Community Medicine, University of Toronto, Toronto, ON M5G 1V7, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada.
²⁰ Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
²¹ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Statistical Sciences, University of Toronto, Toronto, ON M5S 3G3, Canada.
²² Genome Diagnostics, Department of Paediatric Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
²³ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
²⁴ Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.
²⁵ Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON M4G 1R8, Canada.
²⁶ Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
²⁷ Autism Research Unit, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Psychology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
²⁸ Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin 2, Ireland; Department of Psychiatry, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Child, Youth and Family Services, The Centre for Addiction and Mental Health, Toronto, ON M6J 1H4, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada.
²⁹ MIND Institute, University of California, Davis, Sacramento, CA 95817, USA; Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, CA 95817, USA.
³⁰ Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada; Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON M4G 1R8, Canada.
³¹ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON L8N 3K7, Canada.
³² Department of Psychology, University of Miami, Miami, FL 33124, USA.
³³ Department of Psychiatry and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
³⁴ Department of Psychiatry, Queen's University, Kingston, ON K7L 7X3, Canada; Queen's Genomics Lab at Ongwanada, Queen's University, Kingston, ON K7M 8A6, Canada.
³⁵ Department of Pediatrics, Dalhousie University, Halifax, NS B3H 4R2, Canada; IWK Health Centre, Halifax, NS B3K 6R8, Canada.
³⁶ Department of Psychiatry, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada; Centre for Addiction and Mental Health, Toronto, ON M6J 1H4, Canada.
³⁷ Department of Pediatrics, University of Alberta, Edmonton, AB T6G 1C9, Canada.
³⁸ Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON M4G 1R8, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
³⁹ Autism Speaks, Princeton, NJ 08540, USA; Department of Psychology, John Carroll University, Cleveland, OH 44118, USA.
⁴⁰ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada.
⁴¹ Department of Human Genetics, Sidra Medicine, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar; Department of Genetic Medicine, Weill Cornell Medical College in Qatar, Doha, Qatar.
⁴² Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA; Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90033, USA.
⁴³ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
⁴⁴ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
⁴⁵ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; McLaughlin Centre, Toronto, ON M5G 0A4, Canada. Electronic address: stephen.scherer@sickkids.ca.

PMID: 36368308
PMCID: PMC10726699
DOI: 10.1016/j.cell.2022.10.009

Genomic architecture of autism from comprehensive whole-genome sequence annotation

Brett Trost et al. Cell. 2022.

. 2022 Nov 10;185(23):4409-4427.e18.

doi: 10.1016/j.cell.2022.10.009.

Authors

Affiliations

¹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
² The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
³ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; CGEn, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁴ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁵ Verily Life Sciences, South San Francisco, CA 94080, USA.
⁶ Ted Rogers Centre for Heart Research, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁷ Department of Human Genetics, Sidra Medicine, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁸ Department of Human Genetics, Sidra Medicine, Doha, Qatar.
⁹ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Autism Research Unit, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
¹⁰ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Autism Research Unit, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
¹¹ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹² Genome Diagnostics, Department of Paediatric Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
¹³ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
¹⁴ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁵ DNAstack, Toronto, ON M5H 1T1, Canada.
¹⁶ Autism Speaks, Princeton, NJ 08540, USA.
¹⁷ Department of Psychology, Queen's University, Kingston, ON K7L 3N6, Canada; Department of Psychiatry, Queen's University, Kingston, ON K7L 7X3, Canada.
¹⁸ Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA.
¹⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Family and Community Medicine, University of Toronto, Toronto, ON M5G 1V7, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada.
²⁰ Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
²¹ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Statistical Sciences, University of Toronto, Toronto, ON M5S 3G3, Canada.
²² Genome Diagnostics, Department of Paediatric Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
²³ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
²⁴ Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.
²⁵ Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON M4G 1R8, Canada.
²⁶ Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
²⁷ Autism Research Unit, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Psychology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
²⁸ Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin 2, Ireland; Department of Psychiatry, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Child, Youth and Family Services, The Centre for Addiction and Mental Health, Toronto, ON M6J 1H4, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada.
²⁹ MIND Institute, University of California, Davis, Sacramento, CA 95817, USA; Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, CA 95817, USA.
³⁰ Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada; Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON M4G 1R8, Canada.
³¹ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON L8N 3K7, Canada.
³² Department of Psychology, University of Miami, Miami, FL 33124, USA.
³³ Department of Psychiatry and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
³⁴ Department of Psychiatry, Queen's University, Kingston, ON K7L 7X3, Canada; Queen's Genomics Lab at Ongwanada, Queen's University, Kingston, ON K7M 8A6, Canada.
³⁵ Department of Pediatrics, Dalhousie University, Halifax, NS B3H 4R2, Canada; IWK Health Centre, Halifax, NS B3K 6R8, Canada.
³⁶ Department of Psychiatry, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada; Centre for Addiction and Mental Health, Toronto, ON M6J 1H4, Canada.
³⁷ Department of Pediatrics, University of Alberta, Edmonton, AB T6G 1C9, Canada.
³⁸ Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON M4G 1R8, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
³⁹ Autism Speaks, Princeton, NJ 08540, USA; Department of Psychology, John Carroll University, Cleveland, OH 44118, USA.
⁴⁰ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada.
⁴¹ Department of Human Genetics, Sidra Medicine, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar; Department of Genetic Medicine, Weill Cornell Medical College in Qatar, Doha, Qatar.
⁴² Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA; Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90033, USA.
⁴³ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
⁴⁴ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
⁴⁵ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; McLaughlin Centre, Toronto, ON M5G 0A4, Canada. Electronic address: stephen.scherer@sickkids.ca.

PMID: 36368308
PMCID: PMC10726699
DOI: 10.1016/j.cell.2022.10.009

Abstract

Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.

Keywords: autism spectrum disorder; copy-number variation; neurodevelopmental disorders; phenotype measures; polygenic risk scores; rare variants; structural variation; whole-genome sequencing.

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Conflict of interest statement

Declaration of interests E. Anagnostou has received consultation fees from Roche, Quadrant, and Oron; grant funding from Roche; in-kind supports from AMO Pharma and CRR; editorial honoraria from Wiley; and book royalties from APPI and Springer. She co-holds a patent for the device Anxiety Meter (patent # US20160000365A1). S.W.S. is on the Scientific Advisory Committee of Population Bio and serves as a Highly Cited Academic Advisor for King Abdulaziz University, and intellectual property from aspects of his research held at The Hospital for Sick Children are licensed to Athena Diagnostics and Population Bio. These relationships did not influence data interpretation or presentation during this study but are disclosed for potential future considerations.

Figures

**Figure 1.. Data Processing and Analysis Workflow.**
The Genetic Variant Data section applies to all samples except 1,738 sequenced by Complete Genomics, which used proprietary software. Although CNVs and TREs are types of SVs, they are shown separately because different methods were used for their detection. CNVs include deletions and duplications ≥1 kb, while SVs include deletions, duplications, insertions, and inversions ≥50 bp.

**Figure 2.. Identification of ASD-Associated Genes Using TADA+.**
(A) Exonic *de novo* variants per individual in ASC, MSSNG, and SPARK. (B) ASD-associated genes discovered only in the previous TADA+ analysis (“ASC”), only in the current analysis (“ASC+MSSNG+SPARK”), or both. (C) Distribution of SFARI Gene scores for the newly discovered genes. (D) FDRs for the 134 ASD-associated genes. Blue dots: genes also identified in the previous TADA+ analysis; green dots: new genes. Genes with FDR calculated as zero were assigned a value of 10⁻¹⁷. The blue line represents FDR=0.1. (E) Evidence supporting the new ASD-associated genes. “Case-control difference” represents PTVs in cases minus controls. The y-axis is truncated at −3; the value for MIB1 is −9. (F) pLI values for the new genes. (G) Network diagram of TADA+ genes. Only genes connected to gene networks are shown. Nodes represent genes, and edges represent protein-protein and pathway interactions between gene pairs. Modules are indicated by blue circles, with module labels derived from GO term enrichment tests (bold: significantly enriched).

**Figure 3.. Examples of Pathogenic SVs.**
(A-C) 71 bp *de novo* frameshift insertion in *SYNGAP1* comprising 65 bp of mtDNA and a 6 bp microduplication. (A) Schematic of *SYNGAP1*, with the insertion indicated by a red arrow. (B) Alignment of the insertion-containing contig sequence assembled by Manta, the reference sequence, and the mtDNA sequence inserted into chromosome 6. The microduplication is indicated in bold. (C) IGV visualization. The colored portions of reads represent mismatched bases, allowing precise breakpoint identification. The read depth increase reflects the 6 bp microduplication. (D-E) 13.4 kb inversion overlapping *SCN2A*. (D) Sequence trace showing the 5’ and 3’ breakpoints. (E) IGV visualization. The dark and light blue lines indicate anomalously mapped read pairs exhibiting the signature of an inversion.

**Figure 4.. Genomic Architecture of Rare Variants in ASD.**
(A) Burden analysis of sequence-level rare coding variants. Left, individuals with ASD versus non-ASD siblings. Middle, probands from MSSNG MPX families versus those from either SSC SPX families (having exactly one individual with ASD and at least one sibling without) or MSSNG non-MPX families (having exactly one individual with ASD and no siblings). Right, same as middle except siblings with ASD instead of probands. Burdens for other rare ASD-associated variants are given in Table S5A. Compared with sequence-level variants, many SV types had very high ORs, including chromosomal abnormalities (OR=4.9), genomic disorders (OR=8.3), and SVs impacting ASD genes (OR=24) (comparisons between MSSNG individuals with ASD and SSC non-ASD siblings). (B) Yield of ASD-associated rare variants (top) and stratified by variant type (bottom). “Multiple” indicates individuals with ASD-associated variants in more than one category. (C) Distributions of consensus phenotype measures for individuals with ASD having each type of ASD-associated rare variant, or no variant. *Nominally significant (p<0.05); **: significant after multiple testing correction.

**Figure 5.. Detailed View of the Genomic Architecture of Rare Variants in ASD.**
(A) *De novo* or rare inherited (gnomAD allele frequency <10⁻⁴) PTVs and *de novo* DMis variants in autosomal genes identified by the TADA+ analysis or evaluated as definitive by EAGLE. For X-linked genes, we identified hemizygous PTVs in males with frequency <10⁻⁴ in constrained genes (pLI > 0.95) found in the Genomics England neurology and neurodevelopmental disorders panel. (B) Recessive events (PTV-PTV events in genes from the Genomics England panel). (C) Chromosomal abnormalities. (D) Genomic disorders. (E) Large or gene-rich CNVs other than genomic disorders. (F) SVs disrupting ASD-associated genes. (G) UPDs. (H) TREs identified previously. (I) Pathogenic mtDNA variants. CPEO, chronic progressive external ophthalmoplegia; MNGIE, mitochondrial neurogastrointestinal encephalomyopathy.

**Figure 6.. PRS Analysis.**
(A) Reproducibility in ten pairs of monozygotic (MZ) twins from MSSNG. (B) PRS distributions in MSSNG, SSC, and 1000G. (C) Comparison between individuals with ASD and non-ASD siblings. (D) Over-transmission of polygenic risk from parents to children. (E) Odds ratio of individuals with ASD to those without in each PRS decile, relative to decile 1, in MSSNG and SSC combined. (F) Pedigrees showing the PRS for each individual in two large MPX families. (G) Association between PRS and the four consensus phenotype measures.

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References

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Genomic architecture of autism from comprehensive whole-genome sequence annotation

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Genomic architecture of autism from comprehensive whole-genome sequence annotation

Authors

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Abstract

Conflict of interest statement

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