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. 2009 Jan;46(1):68-72.
doi: 10.1136/jmg.2008.060152.

Familial occurrence of schwannomas and malignant rhabdoid tumour associated with a duplication in SMARCB1

J J Swensen  1 , J Keyser, C M Coffin, J A Biegel, D H Viskochil, M S Williams
Affiliations

Familial occurrence of schwannomas and malignant rhabdoid tumour associated with a duplication in SMARCB1

J J Swensen et al. J Med Genet. 2009 Jan.

Abstract

Background: The role of germline and somatic SMARCB1 gene mutations in malignant rhabdoid tumour (MRT) predisposition is well known. Germline SMARCB1 mutations have also recently been identified in a subset of individuals with schwannomatosis. Surprisingly, MRT predisposition and schwannomatosis have never been reported to co-occur in a family. The correlation between genotype and phenotype for mutations in SMARCB1 has not been determined.

Results: We have identified a germline 2631 bp duplication that includes exon 6 of SMARCB1 in a unique family with a four generation history of MRT predisposition and schwannomatosis. This duplication segregates with disease in individuals affected with both conditions, linking MRT predisposition and schwannomatosis as components of the same syndrome in this family.

Conclusion: The unique combination of tumours that result from the duplication described in this report may provide important clues about the mechanisms that influence the phenotype associated with a given SMARCB1 mutation.

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Figures

Figure 1
Figure 1
Pedigree of family K18853. Individuals with malignant rhabdoid tumour (MRT), confirmed schwannomatosis (schw) and clinically suspected schwannomatosis (skin lumps) are noted. Confirmed duplication carriers (dup+) and non-carriers (dup−) are marked. Individual IV.3 is unaffected at age 7 years.
Figure 2
Figure 2
(A) Haematoxylin and eosin (H&E) stained section of the AT/RT from IV.1. (B) Immunohistochemical Smarcb1 (BAF47/INI1) stain of the atypical teratoid/rhabdoid tumour (AT/RT) from IV.1. Endothelial cell nuclei show positive staining. (C) H&E stained section of the epithelioid schwannoma from III.1. Note rounded epithelioid schwann cells arranged singly and in small aggregates. (D) Immunohistochemical Smarcb1 stain of the epithelioid schwannoma from III.1. Neoplastic cell nuclei are immunonegative. Original magnification ×500.
Figure 3
Figure 3
(A) Array comparative genomic hybridisation (CGH) results in a 50 skb window encompassing SMARCB1. The top plot shows all probes. Each point in the bottom plot represents the average of the probes in a 700 bp window; the raised horizontal bar marks the duplication. Nucleotides are numbered at top (from NCBI Build 36.1). (B) Sequences from the telomeric (Tel) and centromeric (Cen) ends of the duplication are aligned with the sequence of the duplication junction. The region of similarity is boxed. (C) Diagram of SMARCB1. Exons are represented by vertical bars, and exon 1 is at left. The arrow represents the duplicated region. (D) Locations of polymerase chain reaction (PCR) primers, represented by small arrows (labelled A–E). Each large arrow represents one segment of the duplication. (E) Confirmation of the duplication through analysis of the peak height ratios of an intronic SMARCB1 SNP (rs2070457) in DNA sequences of three different PCR products amplified from III.4. The “C” allele is present on both segments of the duplication; the wild-type (WT) chromosome carries the “A” allele. All three copies (WT and mutant) of the duplicated region amplified in the product at top; the WT chromosome and the centromeric duplication segment amplified in the product at centre; the telomeric duplication segment amplified in the product at bottom.
Figure 4
Figure 4
Agarose gel electrophoresis of a duplication specific polymerase chain reaction (PCR) product (primers C + E) amplified from the DNA of affected individuals in K18853. DNA samples from random unaffected individuals (R) were included as negative controls. Samples prepared from blood (bl) and paraffin embedded tumour (tu) are noted.
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