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 Koczkowska, Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Tom Callens, Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Yunjia Chen, Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Alicia Gomes, Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Alesha D. Hicks, Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Angela Sharp, Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Eric Johns, Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
Kim Armfield Uhas, Children's Healthcare of Atlanta at Scottish Rite, Atlanta, Georgia.
Linlea Armstrong, Department of Medical Genetics, BC Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
Katherine Armstrong Bosanko, Division of Clinical Genetics and Metabolism, Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Dusica Babovic-Vuksanovic, Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota.
Laura Baker, Division of Medical Genetics, Al DuPont Hospital for Children, Wilmington, Delaware.
Donald G. Basel, Children's Hospital of Wisconsin, Milwaukee, Wisconsin.
Mario Bengala, U.O.C Laboratorio di Genetica Medica, Dipartimento di Oncoematologia, Fondazione Policlinico di Tor Vergata, Rome, Italy.
James T. Bennett, Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
Chelsea Chambers, Department of Neurology, University of Virginia Medical Center, Charlottesville, Virginia.
Lola K. Clarkson, Greenwood Genetic Center, Greenwood, South Carolina.
Maurizio Clementi, Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova, Italy.
Fanny M. Cortés, Center for Rare Diseases, Clinica Las Condes, Santiago, Chile.
Mitch Cunningham, Division of Genetic, Genomic, and Metabolic Disorders, Detroit Medical Center, Children's Hospital of Michigan, Detroit, Michigan.
M Daniela D'Agostino, Division of Medical Genetics, McGill University Health Centre, Montréal, Quebec, Canada.
Martin B. Delatycki, Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
Maria C. Digilio, Medical Genetics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Laura Dosa, SOC Genetica Medica, AOU Meyer, Florence, Italy.
Silvia Esposito, Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Stephanie Fox, Division of Medical Genetics, McGill University Health Centre, Montréal, Quebec, Canada.
Mary-Louise Freckmann, Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
Christine Fauth, Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Teresa Giugliano, Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
Sandra Giustini, Department of Dermatology and Venereology, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.
Allison Goetsch, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Yael Goldberg, The Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel.
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.