Wiley, Human Mutation, 11(33), p. 1538-1546
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. Hum Mutat 33:1538-1546, 2012. © 2012 Wiley Periodicals, Inc.