Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype–phenotype study in neurofibromatosis type 1. Issue 1 (26th October 2019)

• Record Type: Journal Article
• Authors: Koczkowska, Magdalena; Callens, Tom; Chen, Yunjia; Gomes, Alicia; Hicks, Alesha D.; Sharp, Angela; Johns, Eric; Uhas, Kim Armfield; Armstrong, Linlea; Bosanko, Katherine Armstrong; Babovic‐Vuksanovic, Dusica; Baker, Laura; Basel, Donald G.; Bengala, Mario; Bennett, James T.; Chambers, Chelsea; Clarkson, Lola K.; Clementi, Maurizio; Cortés, Fanny M.; Cunningham, Mitch; D'Agostino, M. Daniela; Delatycki, Martin B.; Digilio, Maria C.; Dosa, Laura; Esposito, Silvia; Fox, Stephanie; Freckmann, Mary‐Louise; Fauth, Christine; Giugliano, Teresa; Giustini, Sandra; Goetsch, Allison; Goldberg, Yael; Greenwood, Robert S.; Griffis, Cristin; Gripp, Karen W.; Gupta, Punita; Haan, Eric; Hachen, Rachel K.; Haygarth, Tamara L.; Hernández‐Chico, Concepción; Hodge, Katelyn; Hopkin, Robert J.; Hudgins, Louanne; Janssens, Sandra; Keller, Kory; Kelly‐Mancuso, Geraldine; Kochhar, Aaina; Korf, Bruce R.; Lewis, Andrea M.; Liebelt, Jan; Lichty, Angie; Listernick, Robert H.; Lyons, Michael J.; Maystadt, Isabelle; Martinez Ojeda, Mayra; McDougall, Carey; McGregor, Lesley K.; Melis, Daniela; Mendelsohn, Nancy; Nowaczyk, Malgorzata J.M.; Ortenberg, June; Panzer, Karin; Pappas, John G.; Pierpont, Mary Ella; Piluso, Giulio; Pinna, Valentina; Pivnick, Eniko K.; Pond, Dinel A.; Powell, Cynthia M.; Rogers, Caleb; Ruhrman Shahar, Noa; Rutledge, S. Lane; Saletti, Veronica; Sandaradura, Sarah A.; Santoro, Claudia; Schatz, Ulrich A.; Schreiber, Allison; Scott, Daryl A.; Sellars, Elizabeth A.; Sheffer, Ruth; Siqveland, Elizabeth; Slopis, John M.; Smith, Rosemarie; Spalice, Alberto; Stockton, David W.; Streff, Haley; Theos, Amy; Tomlinson, Gail E.; Tran, Grace; Trapane, Pamela L.; Trevisson, Eva; Ullrich, Nicole J.; Van den Ende, Jenneke; Schrier Vergano, Samantha A.; Wallace, Stephanie E.; Wangler, Michael F.; Weaver, David D.; Yohay, Kaleb H.; Zackai, Elaine; Zonana, Jonathan; Zurcher, Vickie; Claes, Kathleen B. M.; Eoli, Marica; Martin, Yolanda; Wimmer, Katharina; De Luca, Alessandro; Legius, Eric; Messiaen, Ludwine M.;
• Is Part Of: Human mutation. Volume 41:Issue 1(2020)
• Page Start: 299
• Page End: 315
• Publication Date: 2019-10-26
• Subjects: genotype–phenotype correlation -- NF1 -- p.Arg1276 -- p.Lys1423 -- p.Met1149; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23929
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating 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 carries a p.Met1149 missense variant, this finding will contribute to 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.