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

Magdalena KoczkowskaTom CallensYunjia ChenAlicia GomesAlesha D HicksAngela SharpEric JohnsKim Armfield UhasLinlea ArmstrongKatherine Armstrong BosankoDusica Babovic-VuksanovicLaura BakerDonald G BaselMario BengalaJames T BennettChelsea ChambersLola K ClarksonMaurizio ClementiFanny M CortésMitch CunninghamM Daniela D'AgostinoMartin B DelatyckiMaria C DigilioLaura DosaSilvia EspositoStephanie FoxMary-Louise FreckmannChristine FauthTeresa GiuglianoSandra GiustiniAllison GoetschYael GoldbergRobert S GreenwoodCristin GriffisKaren W GrippPunita GuptaEric HaanRachel K HachenTamara L HaygarthConcepción Hernández-ChicoKatelyn HodgeRobert J HopkinLouanne HudginsSandra JanssensKory KellerGeraldine Kelly-MancusoAaina KochharBruce R KorfAndrea M LewisJan LiebeltAngie LichtyRobert H ListernickMichael J LyonsIsabelle MaystadtMayra Martinez OjedaCarey McDougallLesley K McGregorDaniela MelisNancy MendelsohnMalgorzata J M NowaczykJune OrtenbergKarin PanzerJohn G PappasMary Ella PierpontGiulio PilusoValentina PinnaEniko K PivnickDinel A PondCynthia M PowellCaleb RogersNoa Ruhrman ShaharS Lane RutledgeVeronica SalettiSarah A SandaraduraClaudia SantoroUlrich A SchatzAllison SchreiberDaryl A ScottElizabeth A SellarsRuth ShefferElizabeth SiqvelandJohn M SlopisRosemarie SmithAlberto SpaliceDavid W StocktonHaley StreffAmy TheosGail E TomlinsonGrace TranPamela L TrapaneEva TrevissonNicole J UllrichJenneke Van den EndeSamantha A Schrier VerganoStephanie E WallaceMichael F WanglerDavid D WeaverKaleb H YohayElaine ZackaiJonathan ZonanaVickie ZurcherKathleen B M ClaesMarica EoliYolanda MartinKatharina Wimmer Alessandro De LucaEric LegiusLudwine M Messiaen

Published in: Human mutation (2019)

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.

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