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; Yunjia Chen, 1; Alicia Gomes, 1; D Hicks 1, Alesha; Angela Sharp, 1; Eric Johns, 1; Kim Armfield Uhas, 2; Linlea Armstrong, 3; Katherine Armstrong Bosanko, 4; Dusica Babovic-Vuksanovic, 5; Laura Baker, 6; G Basel 7, Donald; Mario Bengala, 8; T Bennett 9, James; 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,; Giustini, S; Allison Goetsch 24,; Yael Goldberg 25,; Robert, S Greenwood 26; Cristin Griffis, 7; W Gripp 6, Karen; 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,; R Korf 1, Bruce; 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; A Sellars 4, Elizabeth; Ruth Sheffer 55,; Elizabeth Siqveland 44,; John, M Slopis 56; Rosemarie Smith 57,; Spalice, Alberto; 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; E Wallace 9, Stephanie; 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,; M Messiaen 1, Ludwine

doi:10.1002/humu.23929

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.

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; 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; Giustini, S; 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. - In: HUMAN MUTATION. - ISSN 1059-7794. - 41:1(2020), pp. 299-315. [10.1002/humu.23929]