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Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276 and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1

Koczkowska, M.; Callens, T.; Chen, Y.; Gomes, A.; Hicks, A. D.; Sharp, A.; Johns, E.; Uhas, K. A.; Armstrong, L.; Bosanko, K. A.; Babovic-Vuksanovic, D.; Baker, L.; Basel, D. G.; Bengala, M.; Bennett, J. T.; Chambers, C.; Clarkson, L. K.; Clementi, M.; Cortes, F. M.; Cunningham, M.; D'Agostino, M. D.; Delatycki, M. B.; Digilio, M. C.; Dosa, L.; Esposito, S.; Fox, S.; Freckmann, M. L.; Fauth, C.; Giugliano, T.; Giustini, S.; Goetsch, A.; Goldberg, Y.; Greenwood, R. S.; Griffis, C.; Gripp, K. W.; Gupta, P.; Haan, E.; Hachen, R. K.; Haygarth, T. L.; Hernandez-Chico, C.; Hodge, K.; Hopkin, R. J.; Hudgins, L.; Janssens, S.; Keller, K.; Kelly-Mancuso, G.; Kochhar, A.; Korf, B. R.; Lewis, A. M.; Liebelt, J.; Lichty, A.; Listernick, R. H.; Lyons, M. J.; Maystadt, I.; Ojeda, M. M.; McDougall, C.; McGregor, L. K.; Melis, D.; Mendelsohn, N.; Nowaczyk, M. J. M.; Ortenberg, J.; Panzer, K.; Pappas, J. G.; Pierpont, M. E.; Piluso, G.; Pinna, V.; Pivnick, E. K.; Pond, D. A.; Powell, C. M.; Rogers, C.; Shahar, N. R.; Rutledge, S. L.; Saletti, V.; Sandaradura, S. A.; Santoro, C.; Schatz, U. A.; Schreiber, A.; Scott, D. A.; Sellars, E. A.; Sheffer, R.; Siqveland, E.; Slopis, J. M.; Smith, R.; Spalice, A.; Stockton, D. W.; Streff, H.; Theos, A.; Tomlinson, G. E.; Tran, G.; Trapane, P. L.; Trevisson, E.; Ullrich, N. J.; Van den Ende, J.; Schrier Vergano, S. A.; Wallace, S. E.; Wangler, M. F.; Weaver, D. D.; Yohay, K. H.; Zackai, E.; Zonana, J.; Zurcher, V.; Claes, K. B. M.; Eoli, M.; Martin, Y.; Wimmer, K.; De Luca, A.; Legius, E.; Messiaen, L. M.

Hum Mutat. 2019 Oct 9


We report 281 individuals carrying a pathogenic recurrent NF1 missense variants 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% CI, 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 to the "classic" NF1-affected cohorts (all P<0.0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all P<0.0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (P<0.0001) 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. This article is protected by copyright. All rights reserved.

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