A framework for the interpretation of de novo mutation in human disease

doi:10.1038/ng.3050

. 2014 Sep;46(9):944-50.

doi: 10.1038/ng.3050. Epub 2014 Aug 3.

A framework for the interpretation of de novo mutation in human disease

Kaitlin E Samocha¹, Elise B Robinson², Stephan J Sanders³, Christine Stevens⁴, Aniko Sabo⁵, Lauren M McGrath⁶, Jack A Kosmicki⁷, Karola Rehnström⁸, Swapan Mallick⁹, Andrew Kirby¹⁰, Dennis P Wall¹¹, Daniel G MacArthur¹⁰, Stacey B Gabriel¹², Mark DePristo¹³, Shaun M Purcell¹⁴, Aarno Palotie¹⁵, Eric Boerwinkle¹⁶, Joseph D Buxbaum¹⁷, Edwin H Cook Jr¹⁸, Richard A Gibbs⁵, Gerard D Schellenberg¹⁹, James S Sutcliffe²⁰, Bernie Devlin²¹, Kathryn Roeder²², Benjamin M Neale², Mark J Daly²

Affiliations

¹ 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [4] Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
² 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
³ 1] Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
⁴ 1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
⁶ Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁷ 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
⁸ 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [2] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
⁹ Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
¹¹ 1] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
¹² Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
¹³ Synapdx, Lexington, Massachusetts, USA.
¹⁴ 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [4] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [5] Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [6] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁵ 1] Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [3] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
¹⁶ 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. [2] Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.
¹⁷ 1] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [4] Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [5] Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [6] Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁸ Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA.
¹⁹ Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁰ Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee, USA.
²¹ Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, USA.
²² 1] Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA. [2] Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.

PMID: 25086666
PMCID: PMC4222185
DOI: 10.1038/ng.3050

A framework for the interpretation of de novo mutation in human disease

Kaitlin E Samocha et al. Nat Genet. 2014 Sep.

. 2014 Sep;46(9):944-50.

doi: 10.1038/ng.3050. Epub 2014 Aug 3.

Authors

Affiliations

¹ 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [4] Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
² 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
³ 1] Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
⁴ 1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
⁶ Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁷ 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
⁸ 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [2] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
⁹ Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
¹¹ 1] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
¹² Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
¹³ Synapdx, Lexington, Massachusetts, USA.
¹⁴ 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [4] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [5] Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [6] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁵ 1] Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [3] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
¹⁶ 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. [2] Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.
¹⁷ 1] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [4] Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [5] Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [6] Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁸ Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA.
¹⁹ Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁰ Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee, USA.
²¹ Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, USA.
²² 1] Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA. [2] Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.

PMID: 25086666
PMCID: PMC4222185
DOI: 10.1038/ng.3050

Abstract

Spontaneously arising (de novo) mutations have an important role in medical genetics. For diseases with extensive locus heterogeneity, such as autism spectrum disorders (ASDs), the signal from de novo mutations is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. Here we provide a statistical framework for the analysis of excesses in de novo mutation per gene and gene set by calibrating a model of de novo mutation. We applied this framework to de novo mutations collected from 1,078 ASD family trios, and, whereas we affirmed a significant role for loss-of-function mutations, we found no excess of de novo loss-of-function mutations in cases with IQ above 100, suggesting that the role of de novo mutations in ASDs might reside in fundamental neurodevelopmental processes. We also used our model to identify ∼1,000 genes that are significantly lacking in functional coding variation in non-ASD samples and are enriched for de novo loss-of-function mutations identified in ASD cases.

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Conflict of interest statement

Competing financial interests: The authors declare no competing financial interests.

Figures

**Figure 1**
The expected and observed fraction of genes with a *de novo* loss-of-function mutation in ASD cases and unaffected controls for four gene sets of interest^–,,. “Betancur” refers to a set of genes reported as disrupted in individuals with ASD or autistic features; of the 112 on the list, we could evaluate 111. “FMRP” refers to the genes whose mRNAs are bound and regulated by the Fragile X Mental Retardation Protein (FMRP), as identified by Darnell and colleagues. The “constrained” category is a set of 1,003 genes that we defined as significantly lacking rare missense variation, indicating intolerance to mutation. The targets of FMRP that are also considered constrained by our metric make up the “Constrained FMRP” category. * indicates p < 0.01; ** indicates p < 10⁻⁴.

**Figure 2**
The distribution of missense Z scores and Z scores of *de novo* loss-of-function mutations identified in unaffected individuals, autism spectrum disorder (ASD) cases, and intellectual disability cases. (a) The distribution of missense Z scores. The red line indicates a Z score of 3.09, or the threshold for inclusion into the set of 1,003 constrained genes. (b) The missense Z scores for genes containing *de novo* LoF in unaffected individuals, ASD cases, and intellectual disability cases^–,,,. Black bars indicate the mean Z score of each group: 0.94, 1.68, and 2.46 for unaffected individuals, ASD cases, and intellectual disability cases, respectively. While the missense Z scores of the *de novo* LoF mutations found in unaffected siblings matched the overall distribution (Wilcoxon p=0.8325, n.s. = not significant), *de novo* LoF mutations found in both ASD and intellectual disability cases were significantly shifted towards more extreme constraint values (p < 10⁻⁶ for both). All p-values for deviation from the overall distribution are listed on the right side of the figure in bold. In addition, the distribution of missense Z scores between each of the three *de novo* lists were all individually significant at p < 0.05.

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References

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[1] Ng SB, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nature genetics. 2010;42:790–3. - PMC - PubMed

[2] Ng SB, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nature genetics. 2010;42:790–3. - PMC - PubMed

[3] Iossifov I, et al. De Novo Gene Disruptions in Children on the Autistic Spectrum. Neuron. 2012;74:285–299. - PMC - PubMed

[4] Iossifov I, et al. De Novo Gene Disruptions in Children on the Autistic Spectrum. Neuron. 2012;74:285–299. - PMC - PubMed

[5] Neale BM, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485:242–245. - PMC - PubMed

[6] Neale BM, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485:242–245. - PMC - PubMed

[7] O’Roak BJ, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485:246–250. - PMC - PubMed

[8] O’Roak BJ, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485:246–250. - PMC - PubMed

[9] Sanders SJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237–241. - PMC - PubMed

[10] Sanders SJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237–241. - PMC - PubMed

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A framework for the interpretation of de novo mutation in human disease

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A framework for the interpretation of de novo mutation in human disease

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