Whole exome sequencing reveals that the majority of schwannomatosis cases remain unexplained after excluding SMARCB1 and LZTR1 germline variants

Excerpt

Schwannomatosis (MIM #162091) is characterized by the development of multiple schwannomas without vestibular nerve involvement (which is a characteristic of neurofibromatosis type 2—NF2—MIM #101000). About 10 % of patients have a family history of the disease, with the remaining 90 % presumed to be sporadic [7]. Germline mutations of NF2 are not observed [8], although schwannomas frequently harbor somatic NF2 mutations and often display chromosome 22 loss [6]. Rare cases with somatic mosaicism for NF2 alterations have also been described [5]. Germline mutations in SMARCB1 (INI1), located proximal to NF2 on chromosome 22, are found in ~30–60 % of familial and ~10 % of sporadic schwannomatosis patients [4, 10, 12]. Recently, another schwannomatosis-predisposing gene within the 22q candidate region has been identified. Piotrowski et al. [9] reported germline loss-of-function mutations in LZTR1 in 80 % of familial and sporadic schwannomatosis cases with combined chr22 loss and somatic NF2 mutation (MIM #615670). LZTR1 functions as an adaptor of the cullin 3-containing E3 ubiquitin ligase complex and has recently been implicated in glioblastoma multiforme development [3], indicating a broader role in tumorigenesis. We therefore sought to further explore the prevalence of LZTR1 mutations in a cohort of 23 sporadic schwannomatosis patients. …