High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.
Rojnueangnit, Kitiwan 1,2+; Xie, Jing 1+; Gomes, Alicia 1; Sharp, Angela 1; Callens, Tom 1; Chen, Yunjia 1; Liu, Ying 1; Cochran, Meagan 1; Abbott, Mary-Alice 3; Atkin, Joan 4; Babovic-Vuksanovic, Dusica 5; Barnett, Christopher P. 6; Crenshaw, Melissa 7; Bartholomew, Dennis W. 4; Basel, Lina 8; Bellus, Gary 9; Ben-Shachar, Shay 10; Bialer, Martin G. 11; Bick, David 12; Blumberg, Bruce 13; Cortes, Fanny 14; David, Karen L. 15; Destree, Anne 16; Duat-Rodriguez, Anna 17; Earl, Dawn 18; Escobar, Luis 19; Eswara, Marthanda 20; Ezquieta, Begona 21; Frayling, Ian M. 22; Frydman, Moshe 23; Gardner, Kathy 24; Gripp, Karen W. 25; Hernandez-Chico, Concepcion 26; Heyrman, Kurt 27; Ibrahim, Jennifer 28; Janssens, Sandra 29; Keena, Beth A 30; Llano-Rivas, Isabel 31; Leppig, Kathy 32; McDonald, Marie 33; Misra, Vinod K. 34; Mulbury, Jennifer 35; Narayanan, Vinodh 36; Orenstein, Naama 37; Galvin-Parton, Patricia 38; Pedro, Helio 39; Pivnick, Eniko K. 40; Powell, Cynthia M. 41; Randolph, Linda 42; Raskin, Salmo 43; Rosell, Jordi 44; Rubin, Karol 45; Seashore, Margretta 46; Schaaf, Christian P. 47; Scheuerle, Angela 48; Schultz, Meredith 49; Schorry, Elizabeth 50; Schnur, Rhonda 51; Siqveland, Elizabeth 52; Tkachuk, Amanda 9; Tonsgard, James 53; Upadhyaya, Meena 22; Verma, Ishwar C. 54; Wallace, Stephanie 18; Williams, Charles 55; Zackai, Elaine 30; Zonana, Jonathan 56; Lazaro, Conxi 57; Claes, Kathleen 29; Korf, Bruce 1; Martin, Yolanda 26; Legius, Eric 58; Messiaen, Ludwine 1
[Article]
Human Mutation.
36(11):1052-1063, November 2015.
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: 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 cafe-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.
(C) 2015 John Wiley & Sons, Ltd