title: Review and update of SPRED1 mutations causing Legius syndrome.
abstract: Legius syndrome presents as a mild neurofibromatosis type 1 (NF1) phenotype. Multiple café-au-lait spots and macrocephaly are present with or without axillary or inguinal freckling. Other typical NF1-associated features (Lisch nodules, bone abnormalities, neurofibromas, optic pathway gliomas, and malignant peripheral nerve sheath tumors) are systematically absent. Legius syndrome is caused by germline loss-of-function SPRED1 mutations, resulting in overactivation of the RAS-MAPK signal transduction cascade. The first families were identified in 2007. Here, we review all identified SPRED1 mutations and summarize molecular, clinical, and functional data. All mutations have been deposited in a database created using the Leiden Open Variation Database software and accessible at http://www.lovd.nl/SPRED1. At present, the database contains 89 different mutations identified in 146 unrelated probands, including 16 new variants described for the first time. The database contains a spectrum of mutations: 29 missense, 28 frameshift, 19 nonsense, eight copy number changes, two splicing, one silent, one in-frame deletion and a mutation affecting the initiation codon. Sixty-three mutations and deletions are definitely pathogenic or most likely pathogenic, eight SPRED1 mutations are probably benign rare variants, and 17 SPRED1 missense mutations are still unclassified and need further family and functional studies to help with the interpretation.
authors: Department of Human Genetics, Catholic University Leuven, Leuven, Belgium.
authors: Hilde
authors: H
authors: Brems
authors: Eric
authors: E
authors: Pasmant
authors: Rick
authors: R
authors: Van Minkelen
authors: Katharina
authors: K
authors: Wimmer
authors: Meena
authors: M
authors: Upadhyaya
authors: Eric
authors: E
authors: Legius
authors: Ludwine
authors: L
authors: Messiaen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019080:Cafe-au-Lait Spots / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D056726:Genetic Association Studies; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012097:Repressor Proteins; C504812:SPRED1 protein, human; C433763:Spred1 protein, mouse