Transposable element insertion as a mechanism of SMARCB1 inactivation in atypical teratoid/rhabdoid tumor

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant brain tumor predominantly occurring in infants. Biallelic SMARCB1 mutations causing loss of nuclear SMARCB1/INI1 protein expression represent the characteristic genetic lesion. Pathogenic SMARCB1 mutations comprise single nucleotide variants, small insertions/deletions, large deletions, which may be also present in the germline (rhabdoid tumor predisposition syndrome 1), as well as somatic copy‐number neutral loss of heterozygosity (LOH). In some SMARCB1‐deficient AT/RT underlying biallelic mutations cannot be identified. Here we report the case of a 24‐months‐old girl diagnosed with a large brain tumor. The malignant rhabdoid tumor showed loss of nuclear SMARCB1/INI1 protein expression and the diagnosis of AT/RT was confirmed by DNA methylation profiling. While FISH, MLPA, Sanger sequencing and DNA methylation data‐based imbalance analysis did not disclose alterations affecting SMARCB1 , OncoScan array analysis revealed a 28.29 Mb sized region of copy‐number neutral LOH on chromosome 22q involving the SMARCB1 locus. Targeted next‐generation sequencing did also not detect a single nucleotide variant but instead revealed insertion of an AluY element into exon 2 of SMARCB1 . Specific PCR‐based Sanger sequencing verified the Alu insertion (SMARCB1 c.199_200 Alu ins) resulting in a frame‐shift truncation not present in the patient's germline. In conclusion, transposable element insertion represents a hitherto not widely recognized mechanism of SMARCB1 disruption in AT/RT, which might not be detected by several widely applied conventional diagnostics assays. This finding has particular clinical implications, if rhabdoid predisposition syndrome 1 is suspected, but germline SMARCB1 alterations cannot be identified.