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      Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

      research-article
      1 , , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 2 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC), 28 , 29 , 30
      Genetics in Medicine
      Nature Publishing Group US

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Purpose

          By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS).

          Methods

          We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups.

          Results

          We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended.

          Conclusion

          The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

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          Most cited references40

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          Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

          The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.
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            HGVS Recommendations for the Description of Sequence Variants: 2016 Update.

            The consistent and unambiguous description of sequence variants is essential to report and exchange information on the analysis of a genome. In particular, DNA diagnostics critically depends on accurate and standardized description and sharing of the variants detected. The sequence variant nomenclature system proposed in 2000 by the Human Genome Variation Society has been widely adopted and has developed into an internationally accepted standard. The recommendations are currently commissioned through a Sequence Variant Description Working Group (SVD-WG) operating under the auspices of three international organizations: the Human Genome Variation Society (HGVS), the Human Variome Project (HVP), and the Human Genome Organization (HUGO). Requests for modifications and extensions go through the SVD-WG following a standard procedure including a community consultation step. Version numbers are assigned to the nomenclature system to allow users to specify the version used in their variant descriptions. Here, we present the current recommendations, HGVS version 15.11, and briefly summarize the changes that were made since the 2000 publication. Most focus has been on removing inconsistencies and tightening definitions allowing automatic data processing. An extensive version of the recommendations is available online, at http://www.HGVS.org/varnomen.
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              Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference.

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                Author and article information

                Contributors
                eric.legius@uzleuven.be
                Journal
                Genet Med
                Genet Med
                Genetics in Medicine
                Nature Publishing Group US (New York )
                1098-3600
                1530-0366
                19 May 2021
                19 May 2021
                2021
                : 23
                : 8
                : 1506-1513
                Affiliations
                [1 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Department of Human Genetics, , KU Leuven and University Hospital, ; Leuven, Belgium
                [2 ]GRID grid.265892.2, ISNI 0000000106344187, Department of Genetics, , University of Alabama at Birmingham, ; Birmingham, AL USA
                [3 ]GRID grid.412116.1, ISNI 0000 0001 2292 1474, Assistance Publique-Hôpital Paris (AP-HP), Hôpital Henri-Mondor, UPEC, Service de Dermatologie, ; Créteil, France
                [4 ]GRID grid.421144.6, ISNI 0000 0004 5906 2417, Children’s Tumor Foundation, ; New York, NY USA
                [5 ]GRID grid.239552.a, ISNI 0000 0001 0680 8770, Division of Ophthalmology, , The Children’s Hospital of Philadelphia, ; Philadelphia, PA USA
                [6 ]GRID grid.1013.3, ISNI 0000 0004 1936 834X, Clinical Genetics, Royal North Shore Hospital, St. Leonards, NSW, , Australia and University of Sydney, ; Sydney, Australia
                [7 ]GRID grid.21107.35, ISNI 0000 0001 2171 9311, Johns Hopkins Comprehensive Neurofibromatosis Center, ; Baltimore, MD USA
                [8 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Department of Clinical Genomics, , Mayo Clinic College of Medicine, ; Rochester, MN USA
                [9 ]GRID grid.411173.1, ISNI 0000 0001 2184 6919, Department of Pathology, , Universidade Federal Fluminense, ; Niteroi, Brasil
                [10 ]GRID grid.451052.7, ISNI 0000 0004 0581 2008, Neurology, Guy’s and St. Thomas’ Hospital and NHS Trust, ; London, UK
                [11 ]GRID grid.239552.a, ISNI 0000 0001 0680 8770, Division of Oncology, The Children’s Hospital of Philadelphia, ; Philadelphia, PA USA
                [12 ]GRID grid.17091.3e, ISNI 0000 0001 2288 9830, Medical Genetics, , University of British Columbia, ; Vancouver, BC Canada
                [13 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Neurology, Washington University, ; St. Louis, MO USA
                [14 ]GRID grid.6582.9, ISNI 0000 0004 1936 9748, Institute of Human Genetics, , University of Ulm, ; Ulm, Germany
                [15 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Neurology, University Hospital of Hamburg-Eppendorf, ; Hamburg, Germany
                [16 ]GRID grid.1374.1, ISNI 0000 0001 2097 1371, Dermatology, , University of Turku and Turku University Hospital, ; Turku, Finland
                [17 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Department of Dermatology and Venereology, , University of Gothenburg, ; Gothenburg, Sweden
                [18 ]GRID grid.27860.3b, ISNI 0000 0004 1936 9684, Pediatrics, University of California Davis, ; Sacramento, CA USA
                [19 ]The Neurofibromatosis Institute, La Crescenta, CA USA
                [20 ]GRID grid.239573.9, ISNI 0000 0000 9025 8099, Medical Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, ; OH, USA
                [21 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Neuropathology, Massachusetts General Hospital, ; Boston, MA USA
                [22 ]GRID grid.168010.e, ISNI 0000000419368956, Medical Genetics, , Stanford University, ; Stanford, CA USA
                [23 ]GRID grid.4708.b, ISNI 0000 0004 1757 2822, Pediatric Dermatology, , University of Milan, ; Milan, Italy
                [24 ]GRID grid.2515.3, ISNI 0000 0004 0378 8438, Department of Neurology, , Boston Children’s Hospital, ; Boston, MA USA
                [25 ]GRID grid.223827.e, ISNI 0000 0001 2193 0096, Medical Genetics, University of Utah, ; Salt Lake City, UT USA
                [26 ]GRID grid.5361.1, ISNI 0000 0000 8853 2677, Institute of Human Genetics, Medical University of Innsbruck, ; Innsbruck, Austria
                [27 ]GRID grid.240324.3, ISNI 0000 0001 2109 4251, NYU Langone Health, ; New York, NY USA
                [28 ]GRID grid.451052.7, ISNI 0000 0004 0581 2008, Clinical Genetics, (Formerly) Manchester Center for Genomic Medicine, Manchester University Hospitals, NHS Foundation Trust, ; Manchester, UK
                [29 ]GRID grid.5379.8, ISNI 0000000121662407, Department of Genomic Medicine, St Mary’s Hospital, Manchester Academic Health Sciences Centre (MAHSC), Division of Evolution and Genomic Science, , University of Manchester, ; Manchester, UK
                [30 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Department of Neurology and Cancer Center, , Massachusetts General Hospital, ; Boston, MA USA
                [31 ]GRID grid.412966.e, ISNI 0000 0004 0480 1382, Department of Neurology, , Maastricht University Medical Center, ; Maastricht, Netherlands
                [32 ]GRID grid.410711.2, ISNI 0000 0001 1034 1720, Department of Genetics, , University of North Carolina, ; Chapel Hill, NC USA
                [33 ]GRID grid.5491.9, ISNI 0000 0004 1936 9297, Department of Human Development and Health, , University of Southampton, ; Southampton, UK
                [34 ]GRID grid.277151.7, ISNI 0000 0004 0472 0371, Centre Hospitalier Universitaire de Nantes, ; Nantes, France
                [35 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Department of Neurosurgery, , Massachusetts General Hospital, ; Boston, MA USA
                [36 ]Clalit Research Institute, & Schneider Children’s Medical Center, Ramat-Gan, Israel
                [37 ]GRID grid.239585.0, ISNI 0000 0001 2285 2675, Department of Genetics and Development, , Columbia University Medical Center, ; New York, NY USA
                [38 ]GRID grid.157868.5, ISNI 0000 0000 9961 060X, Department of Dermatology, , Centre Hospitalier Universitaire de Montpellier, ; Montpellier, France
                [39 ]GRID grid.411438.b, ISNI 0000 0004 1767 6330, Department of Clinical Genetics, , Hospital Universitari Germans Trias I Pujol, ; Badalona, Spain
                [40 ]GRID grid.410569.f, ISNI 0000 0004 0626 3338, Department of Ophthalmology, , University Hospitals Leuven, ; Leuven, Belgium
                [41 ]GRID grid.412714.5, ISNI 0000 0004 0426 1806, Department of Neurosurgery, , Hospital de Clinicas Gral San Martin, ; San Martin, Argentina
                [42 ]GRID grid.5608.b, ISNI 0000 0004 1757 3470, Department of Clinical Genetics, , University of Padova, ; Padova, Italy
                [43 ]GRID grid.41724.34, Department of Genetics, , University Hospital Rouen, ; Rouen, France
                [44 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Department of Head and Neck Surgery, David Geffen School of Medicine, , University of California–Los Angeles, ; Los Angeles, CA USA
                [45 ]GRID grid.410556.3, ISNI 0000 0001 0440 1440, Department of Clinical Genetics, , Oxford University Hospitals NHS Foundation Trust, ; Oxford, UK
                [46 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Department of Ophthalmology, , King’s College London, ; London, UK
                [47 ]GRID grid.11201.33, ISNI 0000 0001 2219 0747, Institute of Translational and Stratified Medicine, Peninsula Medical School, , University of Plymouth, ; Plymouth, UK
                [48 ]GRID grid.451349.e, Department of Genetics, , St George’s University Hospitals, ; London, UK
                [49 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Department of Medical Genetics, , Oslo University Hospital, ; Oslo, Norway
                [50 ]GRID grid.41724.34, Department of Dermatology, , University Hospital Rouen, ; Rouen, France
                [51 ]GRID grid.411439.a, ISNI 0000 0001 2150 9058, Department of Neurosurgery, , Hôpital Pitié Salpêtrière, ; Paris, France
                [52 ]GRID grid.51462.34, ISNI 0000 0001 2171 9952, Department of Pediatrics and Otolaryngology, , Memorial Sloan Kettering Cancer Center, ; New York, NY USA
                [53 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Department of Dermatology, , Massachusetts General Hospital, ; Boston, MA USA
                [54 ]GRID grid.414357.0, ISNI 0000 0004 0637 5049, Department of Dermatology, Hospital Aleman, ; Buenos Aires, Argentina
                [55 ]GRID grid.418701.b, ISNI 0000 0001 2097 8389, Institut Català d’Oncologia (ICO-IDIBELL-CIBERONC), Hospitalet de Llobregat, ; Barcelona, Spain
                [56 ]GRID grid.267313.2, ISNI 0000 0000 9482 7121, Department of Dermatology, , University of Texas, Southwestern, ; Dallas, TX USA
                [57 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Department of Neurosurgery and Otolaryngology, Mayo Clinic, ; Rochester, MN USA
                [58 ]GRID grid.413808.6, ISNI 0000 0004 0388 2248, Department of Pediatrics, , Ann and Robert H Lurie Children’s Hospital of Chicago, ; Chicago, IL USA
                [59 ]Bend, OR USA
                [60 ]GRID grid.413582.9, ISNI 0000 0001 0503 2798, Department of Neurosurgery, Alder Hey Children’s Hospital NHS, ; Liverpool, UK
                [61 ]GRID grid.17635.36, ISNI 0000000419368657, Department of Pediatrics, , University of Minnesota, ; Minneapolis, MN USA
                [62 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Cancer Genetics, Massachusetts General Hospital, ; Boston, MA USA
                [63 ]GRID grid.59025.3b, ISNI 0000 0001 2224 0361, Lee Kong Chian School of medicine, Nanyang Technological University, Singapore and Cancer Genetics Service, National Cancer Center, ; Singapore, Singapore
                [64 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Pediatrics, , Erasmus University Medical Center, ; Rotterdam, Netherlands
                [65 ]GRID grid.239560.b, ISNI 0000 0004 0482 1586, The Brain Tumor Institute, Gilbert Family Neurofibromatosis Institute, Children’s National Medical Center, ; Washington, DC USA
                [66 ]GRID grid.8404.8, ISNI 0000 0004 1757 2304, Department of Experimental and Clinical Biomedical Science “Mario Serio”, , University of Florence, ; Florence, Italy
                [67 ]Department of Neurology, John Radcliff Hospital, Oxford, UK
                [68 ]GRID grid.1374.1, ISNI 0000 0001 2097 1371, Institute of Biomedicine, , University of Turku and Turku University Hospital, ; Turku, Finland
                [69 ]GRID grid.420086.8, ISNI 0000 0001 2237 2479, National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, ; Bethesda, MD USA
                [70 ]GRID grid.410566.0, ISNI 0000 0004 0626 3303, Department of Medical Genetics, , University Hospital Ghent, ; Ghent, Belgium
                [71 ]GRID grid.8430.f, ISNI 0000 0001 2181 4888, School of Medicine, , Federal University of Minas Gerais, ; Belo Horizonte, Brazil
                [72 ]GRID grid.239546.f, ISNI 0000 0001 2153 6013, Department of Neurology, , Children’s Hospital Los Angeles, ; Los Angeles, CA USA
                [73 ]GRID grid.8158.4, ISNI 0000 0004 1757 1969, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, , University of Catania, ; Catania, Italy
                [74 ]The Institute for Health Science Research Germans Trias i Pujol (IGTP), Barcelona, Spain
                [75 ]Center of Medical Genetics, Munich, Germany
                [76 ]GRID grid.5379.8, ISNI 0000000121662407, Division of Informatics, Imaging and Data Sciences, , University of Manchester, ; Manchester, UK
                [77 ]GRID grid.24029.3d, ISNI 0000 0004 0383 8386, Clinical Genetics Department, , Cambridge University Hospitals NHS Foundation Trust, ; Cambridge, UK
                [78 ]GRID grid.410569.f, ISNI 0000 0004 0626 3338, Department of Pediatrics, , University Hospital Leuven, ; Leuven, Belgium
                [79 ]GRID grid.170205.1, ISNI 0000 0004 1936 7822, Department of Pediatrics and Neurology, , University of Chicago Medicine, ; Chicago, IL USA
                [80 ]GRID grid.5600.3, ISNI 0000 0001 0807 5670, Institute of Cancer Genetics, , Cardiff University, ; Cardiff, UK
                [81 ]GRID grid.14442.37, ISNI 0000 0001 2342 7339, Department of Pediatric Oncology, , Hacettepe University, ; Ankara, Turkey
                [82 ]GRID grid.413973.b, ISNI 0000 0000 9690 854X, Department of Clinical Genetics, , Children’s Hospital Westmead, ; Sydney, Australia
                [83 ]GRID grid.412523.3, Shanghai Ninth People’s Hospital Affiliated Shanghai Jiao Tong University School of Medicine, ; Shangai, China
                [84 ]GRID grid.417188.3, ISNI 0000 0001 0012 4167, Princess Margaret Cancer Centre, , Toronto Western Hospital, ; Toronto, ON Canada
                Article
                1170
                10.1038/s41436-021-01170-5
                8354850
                34012067
                98fa9704-80ec-49c6-99a1-aee30abea899
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/http://dx.doi.org/10.13039/100001545, Children’s Tumor Foundation;
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                © The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics 2021

                Genetics
                Genetics

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