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SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the NF1 phenotype
  1. Gill Spurlock (spurlock{at}cardiff.ac.uk)
  1. Institute of Medical Genetics, Heath Park, Cardiff, United Kingdom
    1. Emma Bennett (bennettej{at}cardiff.ac.uk)
    1. Institute of Medical Genetics, Heath Park, Cardiff, United Kingdom
      1. Nadia Chuzhanova (nchuzhanova{at}uclan.ac.uk)
      1. School of Computing, Engineering and Physical Sciences, University of Cantral Lancashire, Preston, United Kingdom
        1. Nick Thomas (thomasns{at}cardiff.ac.uk)
        1. Institute of Medical Genetics, Heath Park, Cardiff, United Kingdom
          1. Hoi Jim (jimh{at}cardiff.ac.uk)
          1. Institute of Medical Genetics, Heath Park, Cardiff, United Kingdom
            1. Lucy Side (lucy.side{at}orh.nhs.uk)
            1. Department of Clinical Genetics, The Churchill, Oxford, United Kingdom
              1. Sally Davies (daviessj8{at}cardiff.ac.uk)
              1. Institute of Medical Genetics, Heath Park, Cardiff, United Kingdom
                1. Eric Haan (eric.haan{at}cywhs.sa.gov.au)
                1. Department of Paediatrics, University of Adelaide, Australia
                  1. Bronwyn Kerr (bronwyn.kerr{at}cmmc.nhs.uk)
                  1. Regional Genetic Service, St Mary's Hospital, Manchester, United Kingdom
                    1. Susan M Huson (susan.huson{at}cmmc.nhs.uk)
                    1. Regional Genetic Service, St Mary's Hospital, Manchester, United Kingdom
                      1. Meena Upadhyaya (upadhyaya{at}cardiff.ac.uk)
                      1. Institute of Medical Genetics, Heath Park, Cardiff, United Kingdom

                        Abstract

                        Objective: Mutations of the SPRED1 gene, one of a family of Sprouty (Spry)/Spred proteins known to 'down-regulate’ mitogen-activated protein kinase (MAPK) signalling, have been identified in patients with a mild neurofibromatosis type1 phenotype with pigmentary changes but no neurofibromas (Legius syndrome).To ascertain the frequency of SPRED1 mutations as a cause of this phenotype and to investigate whether other SPRED/SPRY genes may be causal, a panel of unrelated mild NF1 patients were screened for mutations of the SPRED1-3 and the SPRY1-4 genes.

                        Methods: 85 patients with a mild NF1 phenotype were screened for SPRED1 mutations. 44 patients negative for both NF1 and SPRED1 mutations were then screened for SPRED2- 3 and SPRY1-4 mutations. Complexity analysis was applied to analyse the flanking sequences surrounding the identified SPRED1 mutations for the presence of direct and inverted repeats or symmetric sequence elements in order to infer probable mutational mechanism.

                        Results: SPRED1 mutations were identified in six cases, 5 were novel and included 3 nonsense (R16X, E73X, R262X), 2 frameshift (c.1048_c1049 delGG, c.149_1152del 4bp), and a single missense mutation (V44D). Short direct or inverted repeats detected immediately adjacent to some SPRED1 mutations may have led to the formation of the microdeletions and base pair substitutions.

                        Discussion: The identification of SPRED1 gene mutation in NF1-like patients has major implications for counselling NF1 families.

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