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, 36 (11), 1052-63

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

Kitiwan Rojnueangnit  1   2 Jing Xie  1 Alicia Gomes  1 Angela Sharp  1 Tom Callens  1 Yunjia Chen  1 Ying Liu  1 Meagan Cochran  1 Mary-Alice Abbott  3 Joan Atkin  4 Dusica Babovic-Vuksanovic  5 Christopher P Barnett  6 Melissa Crenshaw  7 Dennis W Bartholomew  4 Lina Basel  8 Gary Bellus  9 Shay Ben-Shachar  10 Martin G Bialer  11 David Bick  12 Bruce Blumberg  13 Fanny Cortes  14 Karen L David  15 Anne Destree  16 Anna Duat-Rodriguez  17 Dawn Earl  18 Luis Escobar  19 Marthanda Eswara  20 Begona Ezquieta  21 Ian M Frayling  22 Moshe Frydman  23 Kathy Gardner  24 Karen W Gripp  25 Concepcion Hernández-Chico  26 Kurt Heyrman  27 Jennifer Ibrahim  28 Sandra Janssens  29 Beth A Keena  30 Isabel Llano-Rivas  31 Kathy Leppig  32 Marie McDonald  33 Vinod K Misra  34 Jennifer Mulbury  35 Vinodh Narayanan  36 Naama Orenstein  37 Patricia Galvin-Parton  38 Helio Pedro  39 Eniko K Pivnick  40 Cynthia M Powell  41 Linda Randolph  42 Salmo Raskin  43 Jordi Rosell  44 Karol Rubin  45 Margretta Seashore  46 Christian P Schaaf  47 Angela Scheuerle  48 Meredith Schultz  49 Elizabeth Schorry  50 Rhonda Schnur  51 Elizabeth Siqveland  52 Amanda Tkachuk  9 James Tonsgard  53 Meena Upadhyaya  22 Ishwar C Verma  54 Stephanie Wallace  18 Charles Williams  55 Elaine Zackai  30 Jonathan Zonana  56 Conxi Lazaro  57 Kathleen Claes  29 Bruce Korf  1 Yolanda Martin  26 Eric Legius  58 Ludwine Messiaen  1
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High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients Carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation

Kitiwan Rojnueangnit et al. Hum Mutat.

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.

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