. 2015 Jan 13;84(2):141-7.

doi: 10.1212/WNL.0000000000001129. Epub 2014 Dec 5.

Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis

Miriam J Smith¹, Bertand Isidor¹, Christian Beetz¹, Simon G Williams¹, Sanjeev S Bhaskar¹, Wilfrid Richer¹, James O'Sullivan¹, Beverly Anderson¹, Sarah B Daly¹, Jill E Urquhart¹, Alan Fryer¹, Cecilie F Rustad¹, Samantha J Mills¹, Amir Samii¹, Daniel du Plessis¹, Dorothy Halliday¹, Sebastien Barbarot¹, Franck Bourdeaut¹, William G Newman², D Gareth Evans²

Affiliations

¹ From the Manchester Centre for Genomic Medicine (M.J.S., W.G.N., D.G.E.) and University of Manchester Biomedical Imaging Institute (S.J.M.), Manchester Academic Health Sciences Centre, and Centre for Imaging Sciences (S.J.M.), University of Manchester, UK; Service de Dermatologie (S.B.) and Service de Genetique Medicale (B.I.), CHU Nantes, France; Institut für Klinische Chemie und Laboratoriumsdiagnostik Universitätsklinikum Jena (C.B.), Germany; Centre for Genomic Medicine (S.G.W., S.S.B., J.O., B.A., S.B.D., J.E.U., W.G.N., D.G.E.), St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, UK; INSERM U830 (W.R., F.B.), Laboratoire de Genetique et Biologie des Cancers, Paris, France; Department of Clinical Genetics (A.F.), Alder Hey Children's Hospital, Liverpool, UK; Department of Medical Genetics (C.F.R.), Oslo University Hospital, Norway; International Neuroscience Institute (A.S.), Hannover, Germany; Department of Cellular Pathology and Greater Manchester Neurosciences Centre (D.d.P.), Salford Royal Hospitals NHS Foundation Trust; Department of Clinical Genetics (D.H.), Oxford Radcliffe Hospitals NHS Trust, UK; and Institut Curie (F.B.), SIRIC and Departement d'Oncologie Pediatrique d'Adolescents et Jeunes Adultes, Paris, France.
² From the Manchester Centre for Genomic Medicine (M.J.S., W.G.N., D.G.E.) and University of Manchester Biomedical Imaging Institute (S.J.M.), Manchester Academic Health Sciences Centre, and Centre for Imaging Sciences (S.J.M.), University of Manchester, UK; Service de Dermatologie (S.B.) and Service de Genetique Medicale (B.I.), CHU Nantes, France; Institut für Klinische Chemie und Laboratoriumsdiagnostik Universitätsklinikum Jena (C.B.), Germany; Centre for Genomic Medicine (S.G.W., S.S.B., J.O., B.A., S.B.D., J.E.U., W.G.N., D.G.E.), St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, UK; INSERM U830 (W.R., F.B.), Laboratoire de Genetique et Biologie des Cancers, Paris, France; Department of Clinical Genetics (A.F.), Alder Hey Children's Hospital, Liverpool, UK; Department of Medical Genetics (C.F.R.), Oslo University Hospital, Norway; International Neuroscience Institute (A.S.), Hannover, Germany; Department of Cellular Pathology and Greater Manchester Neurosciences Centre (D.d.P.), Salford Royal Hospitals NHS Foundation Trust; Department of Clinical Genetics (D.H.), Oxford Radcliffe Hospitals NHS Trust, UK; and Institut Curie (F.B.), SIRIC and Departement d'Oncologie Pediatrique d'Adolescents et Jeunes Adultes, Paris, France. gareth.evans@cmft.nhs.uk William.newman@manchester.ac.uk.

PMID: 25480913
PMCID: PMC4336087
DOI: 10.1212/WNL.0000000000001129

Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis

Miriam J Smith et al. Neurology. 2015.

. 2015 Jan 13;84(2):141-7.

doi: 10.1212/WNL.0000000000001129. Epub 2014 Dec 5.

Authors

Affiliations

¹ From the Manchester Centre for Genomic Medicine (M.J.S., W.G.N., D.G.E.) and University of Manchester Biomedical Imaging Institute (S.J.M.), Manchester Academic Health Sciences Centre, and Centre for Imaging Sciences (S.J.M.), University of Manchester, UK; Service de Dermatologie (S.B.) and Service de Genetique Medicale (B.I.), CHU Nantes, France; Institut für Klinische Chemie und Laboratoriumsdiagnostik Universitätsklinikum Jena (C.B.), Germany; Centre for Genomic Medicine (S.G.W., S.S.B., J.O., B.A., S.B.D., J.E.U., W.G.N., D.G.E.), St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, UK; INSERM U830 (W.R., F.B.), Laboratoire de Genetique et Biologie des Cancers, Paris, France; Department of Clinical Genetics (A.F.), Alder Hey Children's Hospital, Liverpool, UK; Department of Medical Genetics (C.F.R.), Oslo University Hospital, Norway; International Neuroscience Institute (A.S.), Hannover, Germany; Department of Cellular Pathology and Greater Manchester Neurosciences Centre (D.d.P.), Salford Royal Hospitals NHS Foundation Trust; Department of Clinical Genetics (D.H.), Oxford Radcliffe Hospitals NHS Trust, UK; and Institut Curie (F.B.), SIRIC and Departement d'Oncologie Pediatrique d'Adolescents et Jeunes Adultes, Paris, France.
² From the Manchester Centre for Genomic Medicine (M.J.S., W.G.N., D.G.E.) and University of Manchester Biomedical Imaging Institute (S.J.M.), Manchester Academic Health Sciences Centre, and Centre for Imaging Sciences (S.J.M.), University of Manchester, UK; Service de Dermatologie (S.B.) and Service de Genetique Medicale (B.I.), CHU Nantes, France; Institut für Klinische Chemie und Laboratoriumsdiagnostik Universitätsklinikum Jena (C.B.), Germany; Centre for Genomic Medicine (S.G.W., S.S.B., J.O., B.A., S.B.D., J.E.U., W.G.N., D.G.E.), St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, UK; INSERM U830 (W.R., F.B.), Laboratoire de Genetique et Biologie des Cancers, Paris, France; Department of Clinical Genetics (A.F.), Alder Hey Children's Hospital, Liverpool, UK; Department of Medical Genetics (C.F.R.), Oslo University Hospital, Norway; International Neuroscience Institute (A.S.), Hannover, Germany; Department of Cellular Pathology and Greater Manchester Neurosciences Centre (D.d.P.), Salford Royal Hospitals NHS Foundation Trust; Department of Clinical Genetics (D.H.), Oxford Radcliffe Hospitals NHS Trust, UK; and Institut Curie (F.B.), SIRIC and Departement d'Oncologie Pediatrique d'Adolescents et Jeunes Adultes, Paris, France. gareth.evans@cmft.nhs.uk William.newman@manchester.ac.uk.

PMID: 25480913
PMCID: PMC4336087
DOI: 10.1212/WNL.0000000000001129

Abstract

Objectives: We aimed to determine the proportion of individuals in our schwannomatosis cohort whose disease is associated with an LZTR1 mutation.

Methods: We used exome sequencing, Sanger sequencing, and copy number analysis to screen 65 unrelated individuals with schwannomatosis who were negative for a germline NF2 or SMARCB1 mutation. We also screened samples from 39 patients with a unilateral vestibular schwannoma (UVS), plus at least one other schwannoma, but who did not have an identifiable germline or mosaic NF2 mutation.

Results: We identified germline LZTR1 mutations in 6 of 16 patients (37.5%) with schwannomatosis who had at least one affected relative, 11 of 49 (22%) sporadic patients, and 2 of 39 patients with UVS in our cohort. Three germline mutation-positive patients in total had developed a UVS. Mosaicism was excluded in 3 patients without germline mutation in NF2, SMARCB1, or LZTR1 by mutation screening in 2 tumors from each.

Conclusions: Our data confirm the relationship between mutations in LZTR1 and schwannomatosis. They indicate that germline mutations in LZTR1 confer an increased risk of vestibular schwannoma, providing further overlap with NF2, and that further causative genes for schwannomatosis remain to be identified.

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Figures

**Figure 1. Pedigrees of *LZTR1* mutation–positive families**
(A) Family 1; (B) family 2; (C) family 3; (D) family 4; (E) family 5; and (F) family 6. Asterisks indicate family members screened for the mutation. Black stripe indicates an asymptomatic mutation carrier.

**Figure 2. Cerebellopontine angle tumor in an *LZTR1* mutation carrier**
MRIs showing (A) contact image sensors image taken in 2006, (B) postcontrast image taken in 2006, and (C) postcontrast image taken in 2013 showing cystic degeneration around the tumor. White arrows indicate the location of the tumor.

**Figure 3. Flow diagram for schwannomatosis mutation screening**
The diagram indicates an ideal mutation screening strategy for schwannomatosis mutations, assuming availability of all samples.

See this image and copyright information in PMC

References

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Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis

Affiliations

Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Miscellaneous