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PMID: 31595648 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Human mutation ·Vol. 41 ·No. 1 ·2020-00-00 ·页码 299-315

Koczkowska M, Callens T, Chen Y, Gomes A, Hicks AD, Sharp A, Johns E, Uhas KA, Armstrong L, Bosanko KA, Babovic-Vuksanovic D, Baker L, Basel DG, Bengala M, Bennett JT, Chambers C, Clarkson LK, Clementi M, Cortés FM, Cunningham M, D'Agostino MD, Delatycki MB, Digilio MC, Dosa L, Esposito S, Fox S, Freckmann ML, Fauth C, Giugliano T, Giustini S, Goetsch A, Goldberg Y, Greenwood RS, Griffis C, Gripp KW, Gupta P, Haan E, Hachen RK, Haygarth TL, Hernández-Chico C, Hodge K, Hopkin RJ, Hudgins L, Janssens S, Keller K, Kelly-Mancuso G, Kochhar A, Korf BR, Lewis AM, Liebelt J, Lichty A, Listernick RH, Lyons MJ, Maystadt I, Martinez Ojeda M, McDougall C, McGregor LK, Melis D, Mendelsohn N, Nowaczyk MJM, Ortenberg J, Panzer K, Pappas JG, Pierpont ME, Piluso G, Pinna V, Pivnick EK, Pond DA, Powell CM, Rogers C, Ruhrman Shahar N, Rutledge SL, Saletti V, Sandaradura SA, Santoro C, Schatz UA, Schreiber A, Scott DA, Sellars EA, Sheffer R, Siqveland E, Slopis JM, Smith R, Spalice A, Stockton DW, Streff H, Theos A, Tomlinson GE, Tran G, Trapane PL, Trevisson E, Ullrich NJ, Van den Ende J, Schrier Vergano SA, Wallace SE, Wangler MF, Weaver DD, Yohay KH, Zackai E, Zonana J, Zurcher V, Claes KBM, Eoli M, Martin Y, Wimmer K, De Luca A, Legius E, Messiaen LM

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.

Keywords
NF1 genotype-phenotype correlation p.Arg1276 p.Lys1423 p.Met1149
MeSH 主题词
Alleles Amino Acid Substitution Cross-Sectional Studies Genetic Association Studies Genetic Predisposition to Disease Heterozygote Humans Mutation, Missense Neurofibromatosis 1/diagnosis,genetics Neurofibromin 1/genetics Phenotype
化学物质
Neurofibromin 1
作者与单位
共 108 位作者,点击展开单位 / ORCID
Koczkowska Magdalena
Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Callens Tom
Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Chen Yunjia
Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Gomes Alicia
Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Hicks Alesha D
Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Sharp Angela
Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Johns Eric
Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Uhas Kim Armfield
Children's Healthcare of Atlanta at Scottish Rite, Atlanta, Georgia.
Armstrong Linlea
Department of Medical Genetics, BC Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
Bosanko Katherine Armstrong
Division of Clinical Genetics and Metabolism, Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Babovic-Vuksanovic Dusica
Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota.
Baker Laura
Division of Medical Genetics, Al DuPont Hospital for Children, Wilmington, Delaware.
Basel Donald G
Children's Hospital of Wisconsin, Milwaukee, Wisconsin.
Bengala Mario
U.O.C Laboratorio di Genetica Medica, Dipartimento di Oncoematologia, Fondazione Policlinico di Tor Vergata, Rome, Italy.
Bennett James T
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
Chambers Chelsea
Department of Neurology, University of Virginia Medical Center, Charlottesville, Virginia.
Clarkson Lola K
Greenwood Genetic Center, Greenwood, South Carolina.
Clementi Maurizio
Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova, Italy.
Cortés Fanny M
Center for Rare Diseases, Clinica Las Condes, Santiago, Chile.
Cunningham Mitch
Division of Genetic, Genomic, and Metabolic Disorders, Detroit Medical Center, Children's Hospital of Michigan, Detroit, Michigan.
D'Agostino M Daniela
Division of Medical Genetics, McGill University Health Centre, Montréal, Quebec, Canada.
Delatycki Martin B
Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
Digilio Maria C
Medical Genetics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Dosa Laura
SOC Genetica Medica, AOU Meyer, Florence, Italy.
Esposito Silvia
Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Fox Stephanie
Division of Medical Genetics, McGill University Health Centre, Montréal, Quebec, Canada.
Freckmann Mary-Louise
Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
Fauth Christine
Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Giugliano Teresa
Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
Giustini Sandra
Department of Dermatology and Venereology, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.
Goetsch Allison
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Goldberg Yael
The Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel.
Greenwood Robert S
Division of Child Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
Griffis Cristin
Children's Hospital of Wisconsin, Milwaukee, Wisconsin.
Gripp Karen W
Division of Medical Genetics, Al DuPont Hospital for Children, Wilmington, Delaware.
Gupta Punita
Neurofibromatosis Diagnostic and Treatment Program, St. Joseph's Children's Hospital, Paterson, New Jersey.
Haan Eric
Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
Hachen Rachel K
Neurofibromatosis Program, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Haygarth Tamara L
Carolinas HealthCare System, Levine Children's Specialty Center, Charlotte, North Carolina.
Hernández-Chico Concepción
Department of Genetics, Hospital Universitario Ramón y Cajal, Institute of Health Research (IRYCIS) and Center for Biomedical Research-Network of Rare Diseases (CIBERER), Madrid, Spain.
Hodge Katelyn
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Hopkin Robert J
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Hudgins Louanne
Division of Medical Genetics, Stanford University School of Medicine, Stanford, California.
Janssens Sandra
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Keller Kory
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon.
Kelly-Mancuso Geraldine
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Kochhar Aaina
Department of Medical Genetics and Metabolism, Valley Children's Healthcare, Madera, California.
Korf Bruce R
Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Lewis Andrea M
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Liebelt Jan
The South Australian Clinical Genetics Service at the Women's and Children's Hospital, North Adelaide, South Australia, Australia.
Lichty Angie
Greenwood Genetic Center, Greenwood, South Carolina.
Listernick Robert H
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Lyons Michael J
Greenwood Genetic Center, Greenwood, South Carolina.
Maystadt Isabelle
Center for Human Genetics, Institute of Pathology and Genetics (IPG), Gosselies, Belgium.
Martinez Ojeda Mayra
Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.
McDougall Carey
Division of Human Genetics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
McGregor Lesley K
The South Australian Clinical Genetics Service at the Women's and Children's Hospital, North Adelaide, South Australia, Australia.
Melis Daniela
Section of Pediatrics, Department of Translational Medical Sciences, Federico II University, Naples, Italy.
Mendelsohn Nancy
Genomics Medicine Program, Children's Hospital Minnesota, Minneapolis, Minnesota.
Nowaczyk Malgorzata J M
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Ortenberg June
Division of Medical Genetics, McGill University Health Centre, Montréal, Quebec, Canada.
Panzer Karin
University of Iowa Stead Family Children's Hospital, Iowa City, Iowa.
Pappas John G
Division of Clinical Genetic Services, Department of Pediatrics, NYU School of Medicine, New York, New York.
Pierpont Mary Ella
Department of Pediatrics and Opthalmology, University of Minnesota, Minneapolis, Minnesota.
Piluso Giulio
Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
Pinna Valentina
Molecular Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
Pivnick Eniko K
Department of Pediatrics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee.
Pond Dinel A
Genomics Medicine Program, Children's Hospital Minnesota, Minneapolis, Minnesota.
Powell Cynthia M
Department of Genetics and Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
Rogers Caleb
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon.
Ruhrman Shahar Noa
The Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel.
Rutledge S Lane
Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Saletti Veronica
Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Sandaradura Sarah A
Division of Clinical Genetics, Department of Paediatrics and Child Health, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.
Santoro Claudia
Specialistic and General Surgery Unit, Department of Woman and Child, Referral Centre of Neurofibromatosis, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
Schatz Ulrich A
Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Schreiber Allison
Cleveland Clinic, Genomic Medicine Institute, Cleveland, Ohio.
Scott Daryl A
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Sellars Elizabeth A
Division of Clinical Genetics and Metabolism, Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Sheffer Ruth
Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Siqveland Elizabeth
Genomics Medicine Program, Children's Hospital Minnesota, Minneapolis, Minnesota.
Slopis John M
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Smith Rosemarie
Division of Genetics, Department of Pediatrics, Maine Medical Center, Portland, Maine.
Spalice Alberto
Child Neurology Division, Department of Pediatrics, Sapienza University of Rome, Rome, Italy.
Stockton David W
Division of Genetic, Genomic, and Metabolic Disorders, Detroit Medical Center, Children's Hospital of Michigan, Detroit, Michigan.
Streff Haley
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Theos Amy
Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.
Tomlinson Gail E
Division of Pediatric Hematology-Oncology, Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas.
Tran Grace
Department of Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Trapane Pamela L
Division of Pediatric Genetics, Department of Pediatrics, University of Florida College of Medicine, Jacksonville, Florida.
Trevisson Eva ORCID
Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova, Italy.
Ullrich Nicole J
Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.
Van den Ende Jenneke
Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
Schrier Vergano Samantha A
Division of Medical Genetics and Metabolism, Children's Hospital of the King's Daughters, Norfolk, Virginia.
Wallace Stephanie E
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
Wangler Michael F ORCID
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Weaver David D
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Yohay Kaleb H
Department of Neurology, New York University School of Medicine, Langone Medical Center, New York, New York.
Zackai Elaine
Division of Human Genetics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
Zonana Jonathan
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon.
Zurcher Vickie
Cleveland Clinic, Genomic Medicine Institute, Cleveland, Ohio.
Claes Kathleen B M ORCID
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Eoli Marica
Division of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Martin Yolanda
Department of Genetics, Hospital Universitario Ramón y Cajal, Institute of Health Research (IRYCIS) and Center for Biomedical Research-Network of Rare Diseases (CIBERER), Madrid, Spain.
Wimmer Katharina ORCID
Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
De Luca Alessandro ORCID
Molecular Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
Legius Eric
Department of Human Genetics, KU Leuven, Leuven, Belgium.
Messiaen Ludwine M ORCID
Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Article Info
Journal
Human mutation
Abbr.
Hum Mutat
ISSN
1098-1004
Published
2020-00-00
电子出版
2019-00-26
页码
299-315
Language
English
Country/Region
United States
NLM ID
9215429
基金资助
NICHD NIH HHS · U54 HD090255 · United States
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