Rare Complete Knockouts in Humans: Population Distribution and Significant Role in Autism Spectrum Disorders
Open accessAbstract
To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤ 5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.
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Rare complete gene knockouts in humans have a significant role in ASD and major mental illness.
“Recent work has highlighted that rare complete gene knockouts in humans have a significant role in ASD and major mental illness.68”
From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [68]
The Results section, “Enrichment of Rare Complete Knockouts in ASD,” reports roughly two-fold enrichment in ASD cases and estimates a 3% contribution to ASD. The paper does not establish a significant role for these knockouts in major mental illness more broadly; a search for that claim found no supporting passage. (LLM, conf=0.89)
Experimental — accuracy not yet measuredThe male preponderance of ASD is not largely explained by genetic variation on the sex chromosomes.
“A small proportion of cases are associated with X-linked variants7, but the male preponderance of ASD is not largely explained by genetic variation on sex chromosomes.”
From A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex (2022) · cites this paper as [7]
For a sample of nearly 1000 ASD cases and well matched controls, the ARRA ASD sequencing consortium (AASC) found no significant associations, except for variation acting recessively.
“For a sample of nearly 1000 ASD case and well matched controls the ARRA ASD sequencing consortium (AASC) found no significant associations [7], except for variation acting recessively [6].”
From Integrated Model of De Novo and Inherited Genetic Variants Yields Greater Power to Identify Risk Genes (2013) · cites this paper as [6]
Rare inherited recessive or X-linked loss-of-function SNVs confer an additional 5% of ASD risk.
“and an additional 5% conferred by rare inherited recessive or X-linked loss-of-function (LoF) SNVs.11,16”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [16]
Rare ASD risk variants can be inherited from unaffected parents or can arise de novo during meiosis.
“Rare variants can be inherited from unaffected parents (26,28,34,35) or arise as de novo mutations during the meiotic divisions of gametogenesis (21)(22)(23)(24)(25)(26)(27)(30)(31)(32)36,37).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [34]
Transmitted protein-disrupting variants can strongly influence ASD risk when inherited dominantly, with odds ratios around 3, or when biallelic disruption acts recessively or X-linked, with odds ratios above 2.
“Transmitted variants that disrupt protein function can also have a strong influence on risk when inherited and acting dominantly (odds ratios ∼3) (26) or if resulting in biallelic disruption and acting in a recessive (34,35) or X-linked (34) manner (odds ratio above 2).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [34]
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References 46 · Cited by 266
- Authors
- Lim, E. T., Raychaudhuri, S., Sanders, S. J., Stevens, C., Sabo, A., MacArthur, D. G., Neale, B. M., Kirby, A., Ruderfer, D. M., Fromer, M., Lek, M., Liu, L., Flannick, J., Ripke, S., Nagaswamy, U., Muzny, D., Reid, J. G., Hawes, A., Newsham, I., Wu, Y., Lewis, L., Dinh, H., Gross, S., Wang, L.-S., Lin, C.-F., Valladares, O., Gabriel, S. B., dePristo, M., Altshuler, D. M., Purcell, S. M., State, M. W., Boerwinkle, E., Buxbaum, J. D., Cook, E. H., Gibbs, R. A., Schellenberg, G. D., Sutcliffe, J. S., Devlin, B., Roeder, K., & Daly, M. J.
- Affiliations
- Broad Institute (US)
- Yale University (US)
- Baylor College of Medicine (US)
- Carnegie Mellon University (US)
- University of Pennsylvania (US)
- Icahn School of Medicine at Mount Sinai (US)
- University of Illinois Chicago (US)
- Vanderbilt University (US)
- University of Pittsburgh (US)
- Corresponding author
- Daly, Mark J.
- ORCID
- Lim, Elaine T.
- Raychaudhuri, Soumya
- Sanders, Stephan J.
- Stevens, Christine
- Sabo, Aniko
- MacArthur, Daniel G.
- Neale, Benjamin M.
- Ruderfer, Douglas M.
- Fromer, Menachem
- Lek, Monkol
- Liu, Li
- Flannick, Jason
- Ripke, Stephan
- Muzny, Donna
- Reid, Jeffrey G.
- Newsham, Irene
- Wu, Yuanqing
- Dinh, Huyen
- Lin, Chiao-Feng
- Valladares, Otto
- Gabriel, Stacey B.
- Altshuler, David M.
- Purcell, Shaun M.
- State, Matthew W.
- Boerwinkle, Eric
- Buxbaum, Joseph D.
- Cook, Edwin H.
- Gibbs, Richard A.
- Schellenberg, Gerard D.
- Sutcliffe, James S.
- Devlin, Bernie
- Roeder, Kathryn
- Daly, Mark J.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 77
- Issue
- 2
- Pages
- 235-242
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3613849
- OpenAlex
- W2083272036
- Cited by
- 266
- References
- 46
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 9 · 2023: 20 · 2022: 12 · 2021: 12 · 2020: 15 · 2019: 13 · 2018: 19 · 2017: 20 · 2016: 24 · 2015: 38 · 2014: 41 · 2013: 31
- FWCI
- 24.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 387 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1rc2hl103010-01)
- National Heart, Lung, and Blood Institute (HL 102923, RC2HL102925, HL-102924, HL-102925, RC2HL102926, RC2HL102923, UC2HL102924, RC2HL-103010, UC2HL102925, HL 103010, UC2HL102923, UC2HL103010, RC2HL102924, UC2HL102926, HL-102926)
- National Institute of Mental Health (R01MH061009, R01MH089025, U24MH081810, R01MH089175, R01MH089004, R37MH057881, R01MH089208, U24MH068457, R01MH057881, R01MH089482)
- National Human Genome Research Institute (U54HG003067, U54HG003273)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD055751)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- autism spectrum disorder, loss-of-function mutations, homozygous variant, compound heterozygosity, hemizygous mutation, X chromosome, autosomal genes, genetic risk factors, exome sequencing, nonsense mutation
- MeSH terms
- Child Development Disorders, Pervasive, Child, Preschool, Demography, Female, Homozygote, Humans, Male, Risk Factors, Genetic Variation, Linkage Disequilibrium, Case-Control Studies, Gene Deletion, Loss of Heterozygosity, Chromosomes, Human, X
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