Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Mutations in Autism Spectrum Disorder


Nature  515, 216–221 (13 November 2014)

The contribution of de novo coding mutations to autism spectrum disorder

Ivan Iossifov,

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA

Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA

Molecular & Medical Genetics, Oregon Health & Science University, Portland, Oregon 97208, USA

Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA

Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA

Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China

Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA

Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, Connecticut 06520, USA

National Institute of Biological Sciences, Beijing 102206, China

New York Genome Center, New York, New York 10013, USA

Department of Medical Biology, Bulent Ecevit University School of Medicine, 67600 Zonguldak, Turkey

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA

Howard Hughes Medical Institute, Seattle, Washington 98195, USA

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, USA


Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.

Autism spectrum disorder (ASD) is characterized by impaired social interaction and communication, repetitive behaviour and restricted interests. It has a strong male bias, especially in high-functioning affected individuals. The contribution from transmission has long been suspected from increased sibling risk, but more recently the role of germline de novo (DN) mutation has been established, first from large-scale copy number variation in simplex families, and subsequently from exome sequencing. The smaller DN variants observed by DNA sequencing pinpoint candidate gene targets. These developments have promoted a new model for causation, and re-evaluation of sibling risk.

Here we report whole exome sequencing of the Simons Simplex Collection (SSC) and an extensive list of DN mutated targets, including 27 recurrent LGD (nonsense, frameshift and splice site) targets. The size and uniformity of this study allow an unprecedented evaluation of genetic vulnerability to ASD. We subdivide target sets by mutation type (missense and LGD) and affected child status (gender and non-verbal IQ, to which we refer throughout as ‘IQ’), and explore the overlap between target sets and their enrichment for certain gene categories. We make estimates of the number of genes vulnerable to a given mutation type and the proportion of simplex autism resulting from DN mutation for each affected subpopulation.

We report on 2,517 of ~2,800 SSC families including ~800 that were previously published. We sequenced 2,508 affected children, 1,911 unaffected siblings and the parents of each family. Within the SSC, the overall gender bias in affected individuals, 7 males to 1 female, is nearly twice that typically reported. Exomes were analysed at Cold Spring Harbor Laboratory (CSHL), Yale School of Medicine, and University of Washington. Pipelines were blind with respect to affected status. For uniformity, all data were reanalysed with the CSHL pipeline, allowing comparison of analysis tools. All calls were validated or strongly supported.

From the clinical perspective, early diagnosis and family counselling are complicated if there are hundreds of genetic targets, especially if few are known with certainty. Sequencing of more cohorts is thus clearly warranted. From the therapeutic perspective, the good news is that in almost all cases DN mutations occur in probands in whom a normal allele is also present. It is theoretically possible that enhancing activity of the remaining alleles might alleviate symptoms. So in our view, the long-term prognosis for treating ASD is positive. Moreover, ASD targets overlap with targets for intellectual disability and schizophrenia, so mechanism-based treatments might work for different diagnostic categories. In the intermediate term, functional clustering suggests that treatments might be tailored to a smaller number of convergent pathways.

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