Identification of a second major locus predisposing to an autosomal dominant inherited disorder of multiple schwannomas. L. Messiaen1, J. Xie1, A. P. Poplawski1, Y. F. Liu1, A. R. Gomes1, P. Madanecki2, C. Fu1, M. R. Crowley3, D. K. Crossman3, L. Armstrong4, D. Babovic-Vuksanovic5, A. Bergner6, J. O. Blakeley6, A. Blumenthal7, M. S. Daniels8, H. Feit9, K. Gardner10, S. Hurst7, C. Kobelka11, C. Lee12, R. Nagy13, K. A. Rauen12, J. M. Slopis8, P. Suwannarat11, J. A. Westman13, A. Zanko12, B. R. Korf1, 3, A. Piotrowski1, 2 1) Dept Genetic, Univ Alabama, Birmingham, Birmingham, AL; 2) Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland; 3) Heflin Center for Genomic Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA; 4) Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; 5) Department of Medical Genetics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; 6) Johns Hopkins Comprehensive Neurofibromatosis Center, Baltimore, Maryland, USA; 7) Lakeridge Health Corporation, Oshawa, Ontario, Canada; 8) Clinical Cancer Genetics Program, MD Anderson Center, University of Texas, Houston, Texas, USA; 9) Henry Ford Hospital, Department of Neurology, Detroit, Michigan, USA; 10) Department of Neurology, Veterans Administration Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, Philadelphia, USA; 11) Kaiser Permanente Genetics Northern California, San Francisco, California, USA; 12) Department of Pediatrics, Division of Medical genetics, University of California at San Francisco, San Francisco, California, USA; 13) Division of Human Genetics, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Schwannomatosis, the third major form of neurofibromatosis, is characterized by development of multiple schwannomas without bilateral vestibular schwannomas, congenital cataracts or ependymomas, manifestations typically found in neurofibromatosis type 2. Constitutional mutations in the SWI/SNF chromatin-remodeling complex gene SMARCB1 on chromosome 22q have been found only in ~50% of familial and <10% of sporadic schwannomatosis patients, suggesting additional predisposing genes exist. Genetic analysis of schwannomas in patients with a SMARCB1 germline mutation reveals a complex mechanism. The mutated germline SMARCB1 allele is retained in the schwannomas, whereas part of the other chromosome 22q copy containing the wild-type SMARCB1 and the nearby NF2 gene is lost, followed by mutation of the remaining wild-type NF2 gene, in cis with the germline mutated SMARCB1 first-hit. We studied 20 probands (6 familial, 11 sporadic, and 3 cases with unknown family history), all without a 1st hit SMARCB1 mutation detected in blood or schwannomas, but with a 22q deletion and a different NF2 mutation in every schwannoma. We hypothesized that an alternative gene on chromosome 22 might carry a first hit predisposing to schwannomatosis in this group of patients. We selectively enriched for 3.72 Mb of evolutionary conserved chromosome 22 sequences and initially performed massive parallel sequencing in 8 of these unrelated SMARCB1-negative schwannomatosis patients. As pathogenic germline mutations in one specific gene on 22q were found in 7/8 patients, targeted sequencing of this gene was pursued in the remaining 12 patients, resulting in detection of mutations in 16/20 (80%) of patients, but not in controls. Mutations were retained in all 25 schwannomas studied and segregated with the disorder within the families. The predicted effect of the mutations on protein function adds robust evidence they are disease causing. Our findings identify this gene as a second major locus predisposing to an autosomal dominant inherited disorder of multiple schwannomas.
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