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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.
Magdalena Koczkowska1 | Tom Callens1 | Yunjia Chen1 | Alicia Gomes1 | Alesha D. Hicks1 | Angela Sharp1 | Eric Johns1 | Kim Armfield Uhas2 | Linlea Armstrong3 | Katherine Armstrong Bosanko4 | Dusica Babovic‐Vuksanovic5 | Laura Baker6 | Donald G. Basel7 | Mario Bengala8 | James T. Bennett9 | Chelsea Chambers10 | Lola K. Clarkson11 | Maurizio Clementi12 | Fanny M. Cortés13 | Mitch Cunningham14 | M. Daniela D’Agostino15 | Martin B. Delatycki16 | Maria C. Digilio17 | Laura Dosa18 | Silvia Esposito19 | Stephanie Fox15 | Mary‐Louise Freckmann20 | Christine Fauth21 | Teresa Giugliano22 | Sandra Giustini23 | Allison Goetsch24 | Yael Goldberg25 | Robert S. Greenwood26 | Cristin Griffis7 | Karen W. Gripp6 | Punita Gupta27 | Eric Haan28 | Rachel K. Hachen29 | Tamara L. Haygarth30 | Concepción Hernández‐Chico31 | Katelyn Hodge32 | Robert J. Hopkin33 | Louanne Hudgins34 | Sandra Janssens35 | Kory Keller36 | Geraldine Kelly‐Mancuso33 | Aaina Kochhar37 | Bruce R. Korf1 | Andrea M. Lewis38 | Jan Liebelt39 | Angie Lichty11 | Robert H. Listernick24 | Michael J. Lyons11 | Isabelle Maystadt40 | Mayra Martinez Ojeda41 | Carey McDougall42 | Lesley K. McGregor39 | Daniela Melis43 | Nancy Mendelsohn44 | Malgorzata J. M. Nowaczyk45 | June Ortenberg15 | Karin Panzer46 | John G. Pappas47 | Mary Ella Pierpont48 | Giulio Piluso22 | Valentina Pinna49 | Eniko K. Pivnick50 | Dinel A. Pond44 | Cynthia M. Powell51 | Caleb Rogers36 | Noa Ruhrman Shahar25 | S. Lane Rutledge1† | Veronica Saletti19 | Sarah A. Sandaradura52 | Claudia Santoro53 | Ulrich A. Schatz21 | Allison Schreiber54 | Daryl A. Scott38 | Elizabeth A. Sellars4 | Ruth Sheffer55 | Elizabeth Siqveland44 | John M. Slopis56 | Rosemarie Smith57 | Alberto Spalice58 | David W. Stockton14 | Haley Streff38 | Amy Theos59 | --------------------------------------------------------------------------------------------------------------------------This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License;which permits use and distribution in any medium;provided the original work is properly cited;the use is non‐commercial and no modifications or adaptations are made. Magdalena Koczkowska;PhD;is also affiliated with the Department of Biology and Medical Genetics;Medical University of Gdansk;Gdansk;Poland. †This paper is dedicated to the memory of our wonderful colleague;S. Lane Rutledge;MD;who passed away on January 2;2019. Gail E. Tomlinson60 | Grace Tran61 | Pamela L. Trapane62 | Eva Trevisson12 | Nicole J. Ullrich63 | Jenneke Van den Ende64 | Samantha A. Schrier Vergano65 | Stephanie E. Wallace9 | Michael F. Wangler38 | David D. Weaver32 | Kaleb H. Yohay66 | Elaine Zackai42 | Jonathan Zonana67 | Vickie Zurcher54 | Kathleen B. M. Claes35 | Marica Eoli68 | Yolanda Martin31 | Katharina Wimmer21 | Alessandro De Luca49 | Eric Legius69 | Ludwine M. Messiaen1
2019-01-01
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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4732057
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simulazione ASN
Il report seguente simula gli indicatori relativi alla propria produzione scientifica in relazione alle soglie ASN 2023-2025 del proprio SC/SSD. Si ricorda che il superamento dei valori soglia (almeno 2 su 3) è requisito necessario ma non sufficiente al conseguimento dell'abilitazione. La simulazione si basa sui dati IRIS e sugli indicatori bibliometrici alla data indicata e non tiene conto di eventuali periodi di congedo obbligatorio, che in sede di domanda ASN danno diritto a incrementi percentuali dei valori. La simulazione può differire dall'esito di un’eventuale domanda ASN sia per errori di catalogazione e/o dati mancanti in IRIS, sia per la variabilità dei dati bibliometrici nel tempo. Si consideri che Anvur calcola i valori degli indicatori all'ultima data utile per la presentazione delle domande.
La presente simulazione è stata realizzata sulla base delle specifiche raccolte sul tavolo ER del Focus Group IRIS coordinato dall’Università di Modena e Reggio Emilia e delle regole riportate nel DM 589/2018 e allegata Tabella A. Cineca, l’Università di Modena e Reggio Emilia e il Focus Group IRIS non si assumono alcuna responsabilità in merito all’uso che il diretto interessato o terzi faranno della simulazione. Si specifica inoltre che la simulazione contiene calcoli effettuati con dati e algoritmi di pubblico dominio e deve quindi essere considerata come un mero ausilio al calcolo svolgibile manualmente o con strumenti equivalenti.