title: Expanding the mutational spectrum of LZTR1 in schwannomatosis.
abstract: Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. Constitutional inactivating variants in two genes, SMARCB1 and, very recently, LZTR1, have been reported. We performed exome sequencing of 13 schwannomatosis patients from 11 families without SMARCB1 deleterious variants. We identified four individuals with heterozygous loss-of-function variants in LZTR1. Sequencing of the germline of 60 additional patients identified 18 additional heterozygous variants in LZTR1. We identified LZTR1 variants in 43% and 30% of familial (three of the seven families) and sporadic patients, respectively. In addition, we tested LZTR1 protein immunostaining in 22 tumors from nine unrelated patients with and without LZTR1 deleterious variants. Tumors from individuals with LZTR1 variants lost the protein expression in at least a subset of tumor cells, consistent with a tumor suppressor mechanism. In conclusion, our study demonstrates that molecular analysis of LZTR1 may contribute to the molecular characterization of schwannomatosis patients, in addition to NF2 mutational analysis and the detection of chromosome 22 losses in tumor tissue. It will be especially useful in differentiating schwannomatosis from mosaic Neurofibromatosis type 2 (NF2). However, the role of LZTR1 in the pathogenesis of schwannomatosis needs further elucidation.
authors.affiliation: Department of Biomedical Experimental and Clinical Sciences, Medical Genetics, University of Florence, Florence, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Paganini
authors.affiliation: Division of Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Vivian Y
authors.initials: VY
authors.lastname: Chang
authors.affiliation: 1] Department of Biomedical Experimental and Clinical Sciences, Medical Genetics, University of Florence, Florence, Italy [2] FIORGEN Fondazione Farmacogenomica Polo Scientifico, Sesto Fiorentino, Florence, Italy.
authors.forename: Gabriele L
authors.initials: GL
authors.lastname: Capone
authors.affiliation: Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Vitte
authors.affiliation: Diagnostic Genetics Unit, Azienda Ospedaliero-Universitaria 'Careggi', Florence, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Benelli
authors.affiliation: Department of Biomedical Experimental and Clinical Sciences, Medical Genetics, University of Florence, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Barbetti
authors.affiliation: Department of Biomedical Experimental and Clinical Sciences, Medical Genetics, University of Florence, Florence, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Sestini
authors.affiliation: Department of Woman and Child Health, Clinical Genetics Unit, University of Padua, Padua, Italy.
authors.forename: Eva
authors.initials: E
authors.lastname: Trevisson
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Theo Jm
authors.initials: TJ
authors.lastname: Hulsebos
authors.affiliation: Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Giovannini
authors.affiliation: Department of Human Genetics, Pathology and Laboratory Medicine, and Psychiatry, University of California, Los Angeles, CA, USA.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: Department of Biomedical Experimental and Clinical Sciences, Medical Genetics, University of Florence, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Papi
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009442:Neurilemmoma / Q000235:genetics* / Q000378:metabolism; D017253:Neurofibromatoses / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C509917:LZTR1 protein, human; D014157:Transcription Factors