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Clinical spectrum of individuals with pathogenic N F1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype–phenotype study in neurofibromatosis type 1
Author(s) -
Koczkowska Magdalena,
Callens Tom,
Chen Yunjia,
Gomes Alicia,
Hicks Alesha D.,
Sharp Angela,
Johns Eric,
Uhas Kim Armfield,
Armstrong Linlea,
Bosanko Katherine Armstrong,
BabovicVuksanovic 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 MaryLouise,
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.,
HernándezChico Concepción,
Hodge Katelyn,
Hopkin Robert J.,
Hudgins Louanne,
Janssens Sandra,
Keller Kory,
KellyMancuso 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.
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23929
Subject(s) - missense mutation , neurofibromatosis , cohort , biology , phenotype , genotype , genetics , population , medicine , gastroenterology , gene , environmental health
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.