title: High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.
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.
authors.affiliation: Department of Genetics, Medical Genomics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama.|Department of Pediatrics, Faculty of Medicine, Thammasat University, Bangkok, Thailand.
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authors.affiliation: Department of Genetics, Medical Genomics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama.
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authors.affiliation: Department of Genetics, Medical Genomics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama.
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authors.affiliation: Department of Genetics, Medical Genomics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama.
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mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D003062:Codon; D015331:Cohort Studies; D004392:Dwarfism / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D025542:Neurofibromin 1 / Q000737:chemistry / Q000235:genetics*; D009634:Noonan Syndrome / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D055815:Young Adult
chemical_list: D003062:Codon; D025542:Neurofibromin 1
keywords: Legius syndrome; NF1; neurofibromatosis type 1; p.Arg1809; phenotype-genotype correlations