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

Arkadiusz Piotrowski, Jing Xie, Ying F. Liu, Andrzej B. Poplawski, Alicia R. Gomes, Piotr Madanecki, Chuanhua Fu, Michael R. Crowley, David K. Crossman, Linlea Armstrong, Dusica Babovic-Vuksanovic, Amanda Bergner, Jaishri O. Blakeley, Andrea L. Blumenthal, Molly S. Daniels, Howard Feit, Kathy Gardner, Stephanie Hurst, Christine Kobelka, Chung LeeRebecca Nagy, Katherine A. Rauen, John M. Slopis, Pim Suwannarat, Judith A. Westman, Andrea Zanko, Bruce R. Korf, Ludwine M. Messiaen

Research output: Contribution to journalArticlepeer-review

127 Scopus citations


Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50% of familial and <10% of sporadic schwannomatosis cases. 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.

Original languageEnglish (US)
Pages (from-to)182-187
Number of pages6
JournalNature Genetics
Issue number2
StatePublished - Feb 2014

ASJC Scopus subject areas

  • Genetics


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