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Eur J Hum Genet. 2015 Jul;23(7):963-8. doi: 10.1038/ejhg.2014.220. Epub 2014 Oct 22.

Expanding the mutational spectrum of LZTR1 in schwannomatosis.

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Department of Biomedical Experimental and Clinical Sciences, Medical Genetics, University of Florence, Florence, Italy.
Division of Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA.
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.
Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Diagnostic Genetics Unit, Azienda Ospedaliero-Universitaria 'Careggi', Florence, Italy.
Department of Woman and Child Health, Clinical Genetics Unit, University of Padua, Padua, Italy.
Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
Department of Human Genetics, Pathology and Laboratory Medicine, and Psychiatry, University of California, Los Angeles, CA, USA.


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.

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