Home » All News » Human Mutation: Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1
Human Mutation: Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1
Published On: October 8, 2019
Shared by Brian Phillips
Magdalena Koczkowska 1, Tom Callens 1, Yunjia Chen 1, Alicia Gomes 1, Alesha D Hicks 1, Angela Sharp 1, Eric Johns 1, Kim Armfield Uhas 2, Linlea Armstrong 3, Katherine Armstrong Bosanko 4, Dusica Babovic-Vuksanovic 5, Laura Baker 6, Donald G Basel 7, Mario Bengala 8, James T Bennett 9, Chelsea Chambers 10, Lola K Clarkson 11, Maurizio Clementi 12, Fanny M Cortés 13, Mitch Cunningham 14, M Daniela D’Agostino 15, Martin B Delatycki 16, Maria C Digilio 17, Laura Dosa 18, Silvia Esposito 19, Stephanie Fox 15, Mary-Louise Freckmann 20, Christine Fauth 21, Teresa Giugliano 22, Sandra Giustini 23, Allison Goetsch 24, Yael Goldberg 25, Robert S Greenwood 26, Cristin Griffis 7, Karen W Gripp 6, Punita Gupta 27, Eric Haan 28, Rachel K Hachen 29, Tamara L Haygarth 30, Concepción Hernández-Chico 31, Katelyn Hodge 32, Robert J Hopkin 33, Louanne Hudgins 34, Sandra Janssens 35, Kory Keller 36, Geraldine Kelly-Mancuso 33, Aaina Kochhar 37, Bruce R Korf 1, Andrea M Lewis 38, Jan Liebelt 39, Angie Lichty 11, Robert H Listernick 24, Michael J Lyons 11, Isabelle Maystadt 40, Mayra Martinez Ojeda 41, Carey McDougall 42, Lesley K McGregor 39, Daniela Melis 43, Nancy Mendelsohn 44, Malgorzata J M Nowaczyk 45, June Ortenberg 15, Karin Panzer 46, John G Pappas 47, Mary Ella Pierpont 48, Giulio Piluso 22, Valentina Pinna 49, Eniko K Pivnick 50, Dinel A Pond 44, Cynthia M Powell 51, Caleb Rogers 36, Noa Ruhrman Shahar 25, S Lane Rutledge 1, Veronica Saletti 19, Sarah A Sandaradura 52, Claudia Santoro 53, Ulrich A Schatz 21, Allison Schreiber 54, Daryl A Scott 38, Elizabeth A Sellars 4, Ruth Sheffer 55, Elizabeth Siqveland 44, John M Slopis 56, Rosemarie Smith 57, Alberto Spalice 58, David W Stockton 14, Haley Streff 38, Amy Theos 59, Gail E Tomlinson 60, Grace Tran 61, Pamela L Trapane 62, Eva Trevisson 12, Nicole J Ullrich 63, Jenneke Van den Ende 64, Samantha A Schrier Vergano 65, Stephanie E Wallace 9, Michael F Wangler 38, David D Weaver 32, Kaleb H Yohay 66, Elaine Zackai 42, Jonathan Zonana 36, Vickie Zurcher 54, Kathleen B M Claes 35, Marica Eoli 67, Yolanda Martin 31, Katharina Wimmer 21, Alessandro De Luca 49, Eric Legius 68, Ludwine M Messiaen 1
Abstract
We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three non-truncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the “classic” NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with “classic” NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carry a p.Met1149 missense variant, this finding will contribute to a more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
Keywords: NF1; genotype-phenotype correlation; p.Arg1276; p.Lys1423; p.Met1149.
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