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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

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

Abstract

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.

KEYWORDS:

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

PMID:
26178382
PMCID:
PMC5049609
DOI:
10.1002/humu.22832
[Indexed for MEDLINE]
Free PMC Article

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