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      Identification and characterization of NF1 and non-NF1 congenital pseudarthrosis of the tibia based on germline NF1 variants: genetic and clinical analysis of 75 patients

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          Abstract

          Background

          Congenital pseudarthrosis of the tibia (CPT) is a rare disease. Some patients present neurofibromatosis type 1 (NF1), while some others do not manifest NF1 (non-NF1). The etiology of CPT, particularly non-NF1 CPT, is not well understood. Here we screened germline variants of 75 CPT cases, including 55 NF1 and 20 non-NF1. Clinical data were classified and analyzed based on NF1 gene variations to investigate the genotype-phenotype relations of the two types of patients.

          Results

          Using whole-exome sequencing and Multiplex Ligation-Dependent Probe Amplification, 44 out of 55 NF1 CPT patients (80.0%) were identified as carrying pathogenic variants of the NF1 gene. Twenty-five variants were novel; 53.5% of variants were de novo, and a higher proportion of their carriers presented bone fractures compared to inherited variant carriers. No NF1 pathogenic variants were found in all 20 non-NF1 patients. Clinical features comparing NF1 CPT to non-NF1 CPT did not show significant differences in bowing or fracture onset, lateralization, tissue pathogenical results, abnormality of the proximal tibial epiphysis, and follow-up tibial union after surgery. A considerably higher proportion of non-NF1 patients have cystic lesion (Crawford type III) and used braces after surgery.

          Conclusions

          We analyzed a large cohort of non-NF1 and NF1 CPT patients and provided a new perspective for genotype-phenotype features related to germline NF1 variants. Non-NF1 CPT in general had similar clinical features of the tibia as NF1 CPT. Germline NF1 pathogenic variants could differentiate NF1 from non-NF1 CPT but could not explain the CPT heterogeneity of NF1 patients. Our results suggested that non-NF1 CPT was probably not caused by germline NF1 pathogenic variants. In addition to NF1, other genetic variants could also contribute to CPT pathogenesis. Our findings would facilitate the interpretation of NF1 pathogenic variants in CPT genetic counseling.

          Supplementary information

          The online version of this article (10.1186/s13023-019-1196-0) contains supplementary material, which is available to authorized users.

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          Most cited references46

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          InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines.

          In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published updated standards and guidelines for the clinical interpretation of sequence variants with respect to human diseases on the basis of 28 criteria. However, variability between individual interpreters can be extensive because of reasons such as the different understandings of these guidelines and the lack of standard algorithms for implementing them, yet computational tools for semi-automated variant interpretation are not available. To address these problems, we propose a suite of methods for implementing these criteria and have developed a tool called InterVar to help human reviewers interpret the clinical significance of variants. InterVar can take a pre-annotated or VCF file as input and generate automated interpretation on 18 criteria. Furthermore, we have developed a companion web server, wInterVar, to enable user-friendly variant interpretation with an automated interpretation step and a manual adjustment step. These tools are especially useful for addressing severe congenital or very early-onset developmental disorders with high penetrance. Using results from a few published sequencing studies, we demonstrate the utility of InterVar in significantly reducing the time to interpret the clinical significance of sequence variants.
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            Neurofibromatosis type 1

            Neurofibromatosis type 1 is a complex autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Nearly all individuals with neurofibromatosis type 1 develop pigmentary lesions (café-au-lait macules, skinfold freckling and Lisch nodules) and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Although no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Similarly, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.
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              The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins.

              The von Recklinghausen neurofibromatosis locus, NF1, encodes a protein with homology restricted to the catalytic region of the RAS GTPase-activating protein, GAP, and with extensive homology to the IRA1 and IRA2 gene products of the yeast S. cerevisiae. A segment of the NF1 cDNA gene, expressed in yeast, can complement loss of IRA function and can inhibit both wild-type and mutant activated human H-ras genes that are coexpressed in yeast. Yeast expressing the NF1 segment have increased H-ras GTPase-stimulating activity. These studies indicate that the NF1 gene product can interact with RAS proteins and demonstrate structural and functional similarities and differences among the GAP, IRA1, IRA2, and NF1 proteins.
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                Author and article information

                Contributors
                01 718 494 5242 , nanbert.zhong@opwdd.ny.gov
                meihaiboprof@outlook.com
                Journal
                Orphanet J Rare Dis
                Orphanet J Rare Dis
                Orphanet Journal of Rare Diseases
                BioMed Central (London )
                1750-1172
                18 September 2019
                18 September 2019
                2019
                : 14
                : 221
                Affiliations
                [1 ]GRID grid.440223.3, Department of Pediatric Orthopaedics, , Hunan Children’s Hospital, The Pediatric Academy of the University of South China, ; 86# Ziyuan Road, Changsha, Hunan Province 410007 People’s Republic of China
                [2 ]GRID grid.440223.3, Pediatrics Research Institute of Hunan Province, , Hunan Children’s Hospital, ; 86 Ziyuan Road, Changsha, Hunan Province People’s Republic of China
                [3 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Center for Medical Genetics, School of Life Sciences, , Central South University, ; 110 Xiangya Road, Changsha, Hunan Province People’s Republic of China
                [4 ]GRID grid.440223.3, Pathology Department, , Hunan Children’s Hospital, ; 86 Ziyuan Road, Changsha, Hunan Province People’s Republic of China
                [5 ]ISNI 0000 0000 9813 9625, GRID grid.420001.7, New York State Institute for Basic Research in Developmental Disabilities, ; Staten Island, NY USA
                Author information
                http://orcid.org/0000-0002-9434-1716
                Article
                1196
                10.1186/s13023-019-1196-0
                6751843
                31533797
                f406abb0-797b-4b12-99a0-3b5de3be72f6
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 15 May 2019
                : 4 September 2019
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Infectious disease & Microbiology
                neurofibromatosis 1,whole exome sequencing,genomic variation,genotype,phenotype

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