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Hum Mutat. 2015 Nov;36(11):1052-63. doi: 10.1002/humu.22832. Epub 2015 Aug 21.

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.

Author information

  • 1Department of Genetics, Medical Genomics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama.
  • 2Department of Pediatrics, Faculty of Medicine, Thammasat University, Bangkok, Thailand.
  • 3Department of Pediatrics, Tufts University School of Medicine, Springfield, Massachusetts.
  • 4Section of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, Ohio.
  • 5Medical Genetics, Mayo Clinic College of Medicine, Rochester, Minnesota.
  • 6Pediatric and Reproductive Genetics, SA Clinical Genetics Service, Women's and Children's Hospital/SA Pathology, North Adelaide, South Australia and Discipline of Pediatrics, University of Adelaide, Adelaide, Australia.
  • 7Department of Clinical Genetics, All Children's Hospital, John Hopkins Medicine and Department of Pediatrics, John Hopkins University School of Medicine, Baltimore, Maryland.
  • 8Raphael Recanati Genetics Institute, Beilinson Campus and Schneider Children's Medical Center of Israel/Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 9Department of Clinical Genetics and Metabolism, Children's Hospital, University of Colorado, Denver-Aurora, Colorado.
  • 10The Genetic Institute, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv, Israel.
  • 11Department of Pediatrics, North Shore LIJ Health System, Manhasset, New York.
  • 12Section of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.
  • 13Kaiser Permanente Oakland, Oakland, California.
  • 14Center for Rare Diseases, Clinica Las Condes, Santiago, Chile.
  • 15Department of Medicine, Division of Genetics, New York Methodist Hospital, Brooklyn, New York.
  • 16Institute of Pathology and Genetics (IPG), Gosselies, Belgium.
  • 17Department of Neuropediatrics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
  • 18Department of Pediatrics, Division of Genetic Medicine, University of Washington, and Seattle Children's Hospital, Seattle, Washington.
  • 19Medical Genetics and Neurodevelopment Center, St Vincent Children's Hospital, Indianapolis, Indiana.
  • 20Sutter Memorial Hospital, Sacramento, California.
  • 21Department of Biochemistry, Hospital Universitario Gregorio Marañón, Institute of Health Research (IiSGM), Madrid, Spain.
  • 22Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
  • 23Chaim Sheba Medical Center, Tel Hashomer, Israel.
  • 24Department of Neurology, Veterans Administration Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, Pennsylvania.
  • 25Division of Medical Genetics, AI duPont Hospital for Children, Wilmington, Delaware.
  • 26Department of Genetics, Hospital Universitario Ramón y Cajal, Institute of Health Research (IRYCIS). Center for Biomedical Research-Network of Rare Diseases (CIBERER), Madrid, Spain.
  • 27Children's Health Center-Pediatrics, Appleton, Wisconsin.
  • 28St. Joseph's Children's Hospital, Paterson, New Jersey.
  • 29Center for Medical Genetics, Ghent University Hospital, Gent, Belgium.
  • 30Division of Human Genetics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
  • 31Department of Genetics, Hospital Universitario Cruces, BioCruces Health Research Institute, Biscay, Spain.
  • 32Genetic Services, Group Health Cooperative and Department of Pathology, University of Washington, Seattle, Washington.
  • 33Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina.
  • 34Department of Pediatrics, Division of Genetics and Metabolic Disorders, The Wayne State University School of Medicine, Detroit, Michigan.
  • 35Department of Pediatrics and Neurology, University of Rochester Medical center, Rochester, New York.
  • 36Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, Arizona.
  • 37Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
  • 38Stony Brook Children's, Stony Brook Medicine, Stony Brook, New York.
  • 39Medical Genetics, Hackensack University Medical Center, Hackensack, New Jersey.
  • 40Department of Pediatrics, Division of Medical Genetics and Department of Ophthalmology University of Tennessee Health Science Center and Le Bonheur Children's Hospita l, Memphis, Tennessee.
  • 41Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina.
  • 42Division of Medical Genetics, Children's Hospital Los Angeles, Los Angeles, California.
  • 43Group for Advanced Molecular Investigation (NIMA), School of Health and Biosciences, Pontificia Universidade Catolica do Parana (PUCPR), Curibita, Brasil.
  • 44Genetics Service, Hospital Son Espases, Palma de Mallorca, Spain.
  • 45University of Minnesota Children's Hospital, Minneapolis, Minnesota.
  • 46Department of Pediatrics and Genetics, Yale School of Medicine, New Haven, Connecticut.
  • 47Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
  • 48Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
  • 49Nationwide Children's Hospital, Columbus, Ohio.
  • 50Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
  • 51Division of Genetics, Cooper Medical School of Rowan University, Camden, New Jersey.
  • 52Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.
  • 53Departments of Pediatrics and Neurology, University of Chicago/Pritzker School of Medicine, Chicago, Illinois.
  • 54Department of Genetic Medicine, Sri Ganga Ram Hospital, New Delhi, India.
  • 55Department of Pediatrics, Division of Genetics and Metabolism, University of Florida, Gainesville, Florida.
  • 56Departments of Pediatrics and Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon.
  • 57Molecular Diagnostics Unit, Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
  • 58Department of Human Genetics, KU Leuven, Leuven, Belgium.


Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.

© 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.


Legius syndrome; NF1; neurofibromatosis type 1; p.Arg1809; phenotype-genotype correlations

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