PTPN4 germline variants result in aberrant neurodevelopment and growth
Joanna J. Chmielewska,
Deepika Burkardt,
Jorge Luis Granadillo,
Rachel Slaugh,
Shamile Morgan,
Joshua Rotenberg,
Boris Keren,
Cyril Mignot,
Luis Escobar,
Peter Turnpenny,
Melissa Zuteck,
Laurie H. Seaver,
Rafal Ploski,
Magdalena Dziembowska,
Anthony Wynshaw-Boris,
Abidemi Adegbola
Affiliations
Joanna J. Chmielewska
Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland; Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland
Deepika Burkardt
Center for Human Genetics and Department of Genetics and Genome Sciences, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, USA
Jorge Luis Granadillo
Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
Rachel Slaugh
Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
Shamile Morgan
Houston Specialty Clinic, Houston, TX, USA
Joshua Rotenberg
Houston Specialty Clinic, Houston, TX, USA
Boris Keren
Département de Génétique, APHP, Sorbonne Université, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
Cyril Mignot
Département de Génétique, APHP, Sorbonne Université, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France
Luis Escobar
Medical Genetics and Neurodevelopmental Center, Peyton Manning Children’s Hospital, Indianapolis, IN, USA
Peter Turnpenny
University of Exeter Medical School and Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
Melissa Zuteck
Medical Genetics and Genomics, Spectrum Health/Helen Devos Children’s Hospital, Grand Rapids, MI, USA
Laurie H. Seaver
Medical Genetics and Genomics, Spectrum Health/Helen Devos Children’s Hospital, Grand Rapids, MI, USA; Department of Pediatrics and Human Development, Michigan State College of Human Medicine, Grand Rapids, MI, USA
Rafal Ploski
Department of Medical Genetics, Warsaw Medical University, Warsaw, Poland
Magdalena Dziembowska
Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland
Anthony Wynshaw-Boris
Center for Human Genetics and Department of Genetics and Genome Sciences, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, USA
Abidemi Adegbola
Center for Human Genetics and Department of Genetics and Genome Sciences, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, USA; Department of Psychiatry, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, USA; Corresponding author
Summary: Protein-tyrosine phosphatases (PTPs) are pleomorphic regulators of eukaryotic cellular responses to extracellular signals that function by modulating the phosphotyrosine of specific proteins. A handful of PTPs have been implicated in germline and somatic human disease. Using exome sequencing, we identified missense and truncating variants in PTPN4 in six unrelated individuals with varying degrees of intellectual disability or developmental delay. The variants occurred de novo in all five subjects in whom segregation analysis was possible. Recurring features include postnatal growth deficiency or excess, seizures, and, less commonly, structural CNS, heart, or skeletal anomalies. PTPN4 is a widely expressed protein tyrosine phosphatase that regulates neuronal cell homeostasis by protecting neurons against apoptosis. We suggest that pathogenic variants in PTPN4 confer risk for growth and cognitive abnormalities in humans.
