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Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas

Nature Genetics volume 46, pages 182–187 (2014)Cite this article

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Abstract

Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50% of familial and <10% of sporadic schwannomatosis cases1. We sequenced highly conserved regions along 22q from eight individuals with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identified in seven of the eight cases. LZTR1 sequencing in 12 further cases with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of an LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in ∼80% of 22q-related schwannomatosis cases lacking mutation in SMARCB1.

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Figure 1: Distribution of mutations identified in the LZTR1 gene in individuals with schwannomatosis.
Figure 2: Structural domains of LZTR1 and spatial predictions for missense alterations.
Figure 3: Pedigrees of families positive for LZTR1 mutation with information from relatives available for testing.

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Article 06 February 2020

Stylianos E. Antonarakis, Brian G. Skotko, … Roger H. Reeves

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Acknowledgements

We thank the patients for their participation in this study. A.P. is a recipient of a Children's Tumor Foundation Young Investigator Award (grant 2009-01-004). The study was supported in part by the Children's Tumor Foundation and by internal funds from the University of Alabama at Birmingham Medical Genomics Laboratory.

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Author notes

  1. Arkadiusz Piotrowski and Jing Xie: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics, Medical Genomics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Arkadiusz Piotrowski, Jing Xie, Ying F Liu, Andrzej B Poplawski, Alicia R Gomes, Chuanhua Fu, Bruce R Korf & Ludwine M Messiaen

  2. Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland

    Arkadiusz Piotrowski & Piotr Madanecki

  3. Heflin Center for Genomic Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Michael R Crowley, David K Crossman & Bruce R Korf

  4. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

    Linlea Armstrong

  5. Department of Medical Genetics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

    Dusica Babovic-Vuksanovic

  6. Johns Hopkins Comprehensive Neurofibromatosis Center, Baltimore, Maryland, USA

    Amanda Bergner & Jaishri O Blakeley

  7. Lakeridge Health Corporation, Oshawa, Ontario, Canada

    Andrea L Blumenthal & Stephanie Hurst

  8. Clinical Cancer Genetics Program, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA

    Molly S Daniels

  9. Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA

    Howard Feit

  10. Department of Neurology, Veterans Administration Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Kathy Gardner

  11. Kaiser Permanente Genetics Northern California, San Francisco, California, USA

    Christine Kobelka & Pim Suwannarat

  12. Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, San Francisco, California, USA

    Chung Lee, Katherine A Rauen & Andrea Zanko

  13. Department of Internal Medicine, Division of Human Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, USA

    Rebecca Nagy & Judith A Westman

  14. Department of Neuro-Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA

    John M Slopis

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  1. Arkadiusz Piotrowski
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Contributions

The study was conceived and coordinated by A.P. and L.M.M. Patient phenotyping was performed by L.A., D.B.-V., A.B., J.O.B., A.L.B., M.S.D., H.F., K.G., S.H., C.K., C.L., R.N., K.A.R., J.M.S., P.S., J.A.W., A.Z. and B.R.K. Clinical data were collected by A.R.G. Design of the target enrichment library was performed by A.P. Paired-end next-generation sequencing was performed by M.R.C. and D.K.C. Detection of variants, filtering and annotation were performed by A.P., P.M., D.K.C. and L.M.M. NF2 and SMARCB1 mutation analyses and loss of heterozygosity studies were performed by A.B.P. Multiplex ligation-dependent probe amplification analyses were performed by C.F. LZTR1 mutation analyses and confirmatory tests were performed by J.X. and A.B.P. Prediction of protein structure and effects of missense mutations was performed by Y.F.L. and L.M.M. Analysis of mutational databases and statistical analyses were performed by J.X., Y.F.L. and L.M.M. The manuscript was written by A.P., J.X., A.B.P., Y.F.L. and L.M.M. All authors contributed to the manuscript.

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Correspondence to Ludwine M Messiaen.

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The authors declare no competing financial interests.

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Piotrowski, A., Xie, J., Liu, Y. et al. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat Genet 46, 182–187 (2014). https://doi.org/10.1038/ng.2855

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