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Am J Hum Genet. 2017 Apr 6;100(4):650-658. doi: 10.1016/j.ajhg.2017.02.005. Epub 2017 Mar 23.

De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome.

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Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Cancer Research UK Gene Function Laboratory and Breast Cancer Now Research Centre, Institute of Cancer Research, London SW3 6JB, UK.
Department of Genetics, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, the Netherlands.
Departments of Neurology, Pediatrics, and Psychiatry, University of California, San Francisco, 675 Nelson Rising Lane, Suite 405, San Francisco, CA 94143, USA.
Division of Pediatric Genetics, Metabolism & Genomic Medicine, University of Michigan Medical School, D5257 Medical Professional Building, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5718, USA.
Division of Medical Genetics, Department of Pediatrics, UCSF Benioff Children's Hospital, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143-0793, USA.
Clinical Genetics, Children's University Hospital, Temple Street, Dublin 1, Ireland; Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Dublin 1, Ireland.
Department of Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK.
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK.
North West Thames Regional Genetic Service (Kennedy Galton Centre), North West London Hospitals, Watford Road, London HA1 3UJ, UK.
Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Oxford OX3 0BP, UK; West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, UK.
Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, St. Michael's Hospital, Southwell Street, Bristol BS2 8EG, UK.
Center on Human Development and Disability, University of Washington, PO Box 357920, Seattle, WA 98195-7920, USA.
Department of Clinical Genetics, Karolinska University Hospital Solna, Karolinska Institutet, 171 77 Stockholm, Sweden.
Department of Medicine and Neurology, Habilitation Organization, Region Skåne, 291 89 Kristianstad, Sweden.
Department of Clinical Genetics, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
GeneDx, Gaithersburg, MD 20877, USA.
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Centre, Universiteitssingel 50, 9229 ER Maastricht, the Netherlands.
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Electronic address:


Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.


PPM1D; cell-cycle checkpoint; intellectual disability; stress-response pathway; syndrome; truncating mutation

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