Evidence for a low‐penetrant extended phenotype of rhabdoid tumor predisposition syndrome type 1 from a kindred with gain of SMARCB1 exon 6

Abstract

To the Editor: We report a family in which gain of SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1) exon 6 segregates with malignant diseases including atypical teratoid/rhabdoid tumor (ATRT). Carriers display incomplete penetrance and late-onset malignancies. The index patient III.1 (Figure S1A) was diagnosed with a nonmetastatic ATRT at the age of 6 years. After resection and radiochemotherapy according to EURHAB, he has remained in complete remission for 15 years. His father II.2 was diagnosedwith a BRAFV600 wild-type hairy cell leukemia variant (HCL-v, co-expressing CD19, CD103, CD11c, CD25) at the age of 47 years. He went into remission with cladribine, and achieved a very good partial response with additional cycles of cladribine for a relapse 9 years later. At 54 years of age, he underwent surgery for an L2-3 spinal ependymoma. At age 57, a hemi-colectomy for steroid-resistant ulcerative colitis was performed. Sanger sequencing of SMARCB1 did not detect any pathogenic variants in peripheral blood lymphocytes (PBL) of the index patient III.1 (Figure S1B). However, a pattern suggesting gain of one copy of exon 6 of SMARCB1 was found by multiplex ligation-dependent probe amplification (MLPA) (Figure S1C). MLPA detected an apparently identical SMARCB1 exon 6 gain in PBL of his father II.2 and two of his sisters III.2 and III.4. Targeted next-generation sequencing confirmed the absence of a single nucleotide variant or small indel but could not identify the genomic integration site of the gained exon 6 sequences. SMARCB1pathogenic variantswereabsent inPBLof the indexpatient’s grandmother I.1, mother II.1, and of another sister III.3. No material was available from a cousin IV.1, daughter of III.4, who had died from surgical complications of a malignant brain tumor in infancy. The index patient’s grandfather I.2 had died from nonmalignant disease and could not be tested. In the 10 children of the grandfather I.2, a malignancy was only known in II.2. No detected carrier had any overt intellectual impairment, except for a learning disability in III.1 attributed to leukencephalopathy after intensive multimodal treatment at young age. High-resolution spinal and lower extremity MRI in III.1 and III.2 did not detect dorsal nerve root or peripheral nerve schwannoma. BAF47 staining was negative in the ATRT of III.1 and in the ependymoma of II.1 (Figure 1A-F). Infinium Methylation EPIC BeadChip DNA methylation analysis for the ATRT and the ependymoma did not assign a molecular diagnosis in the online Heidelberg classifier tool.1 However, t-distributed stochastic neighbor embedding (t-SNE) plotting associated the ATRT with the clinically favorable subclass of atypical teratoid/ rhabdoid tumor, tyrosinase subclass (ATRT-TYR) (Figure 1G) and the ependymoma with the myxopapillary subclass (Figure 1I). Copy number profiles confirmed a heterozygous loss of Chr 22 in both tumors (Figure 1H and J). In line with that MLPA detected large deletions of SMARCB1 in both tumors and indicated that the allele containing the exon 6 gain was retained in the tumors, whereas the wild-type allelewasdeleted (Figure S1C). RNA-sequencing of theATRT and ependymoma showed greatly reduced transcript of SMARCB1, but did not detect tandem-duplication or variant splicing of exon 6. No additional SMARCB1mutation was found in the HCL-v of II.2. Rhabdoid tumor predisposition syndrome type 1 (RTPS1) is characterized by early-onset ATRT, and less commonly extracranial rhabdoid tumors. Synchronous or metachronous tumors occur. Thus, RTPS1 is a negative prognosticator in ATRT. Underlying SMARCB1 mutations are usually truncating pathogenic variants in distinction to those in Schwannomatosis or Coffin-Siris syndrome.2 However, overlap between Schwannomatosis and ATRT has been observed.3 Though we formally cannot rule out an integration of the gained segment elsewhere in the genome, the combination of germline and somatic analyses strongly suggest this change to be pathogenic to one allele of SMARCB1, which is retained in the tumors lacking INI1 staining. Interestingly, SMARCB1 exon 6 duplications have previously been reported in a pedigree with ATRT and schwannoma.4 Another pedigree with a cribriform neuroepithelial tumor (CRINET) and incomplete penetrance of germline SMARCB1 exon 6 duplication is on record.5 A differential diagnosis of a CRINET was entertained for III.1, as CRINETs may resemble ATRT-TYR, but absence of any cribriform features and rosettes combined with an abundance of typical rhabdoid cells did not support this. No rhabdoid features were seen in the myxopapillary ependymoma of II.2. DNA methylation profiling failed to assign a significant score for the ATRT and the myxopapillary ependymomaon theHeidelberg classifier, but the t-SNEvery clearly suggested the ATRT to belong to the TYR subgroup and the spinal tumor to the subgroup of myxopapillary ependymoma.