Schwannomatosis Panel

Schwannomatosis is a tumor predisposition syndrome with overlapping clinical features with those of neurofibromatosis type 2 (NF2). Schwannomatosis is characterized by multiple schwannomas on cranial, spinal and peripheral nerves, similar to NF2. It can be distinguished from NF2 by the absence of vestibular schwannomas (BVS) and vision abnormalities. Schwannomatosis is clinically heterogeneous. Pain is the first symptom and usually begins during the third decade of life. However, painful skin lumps may develop during the second decade of life in affected individuals. Additional features include numbness, tingling, or weakness in the fingers and toes. Although, patients with schwannomatosis rarely develop other types of tumors, meningiomas have been reported in rare cases (Bacci et al. 2010; Christiaans et al. 2011). It was therefore suggested that meningiomas should be included in the phenotype of schwannomatosis (Bacci et al. 2010; Van Den Munckhof et al. 2012).

Schwannomatosis is a pan-ethnic condition with an incidence of approximately 1 in 40,000 live births (Plotkin et al. 2013).

About 15% of Schwannomatosis cases are familial. In these families, the condition is inherited in an autosomal dominant manner with variable expressivity and reduced penetrance. The remaining cases appear to be sporadic with no known affected relatives (Plotkin et al. 2013).

Schwannomatosis is caused by heterozygous germline variants in the SMARCB1 gene (Hulsebos et al. 2007) or the LZTR1 gene (Piotrowski et al. 2014; Paganini et al. 2015). To date, about 30 SMARCB1 and 50 LZTR1 variants have been reported in patients with Schwannomatosis. These variants are distributed along the entire coding regions of the genes, and include most types. They were found in patients from various ethnic groups. Large pathogenic germline deletions and duplications appear to be a rare cause of schwannomatosis. To date, only such pathogenic large duplication has been reported in the SMARCB1 gene (Hulsebos et al. 2016). Large pathogenic deletions or duplications in the LZTR1 gene have not been reported (Human Gene Mutation Database).

LZTR1 encodes leucine zipper-like transcriptional regulator 1, a member of the BTB-kelch superfamily. The tumor suppressor SMARCB1 encodes a subunit of the SWI/SNF ATP-dependent chromatin-remodeling complex (Euskirchen et al. 2012).

Pathogenic SMARCB1 variants account for about 50% of clinically diagnosed familial cases (Boyd et al. 2008) and 10% of sporadic cases (Rousseau et al. 2011).

Pathogenic LZTR1 variants account for about 43% of clinically diagnosed familial cases and 30% of sporadic cases (Paganini et al. 2015).

Large deletions or duplications in the SMARCB1 and LZTR1 gene appear to be a rare cause of shwannomatosis. To date, only one pathogenic large duplication in the SMARCB1 gene has been reported in a patient with shwannomatosis (Hulsebos et al. 2016). Pathogenic large deletions or duplications in the LZTR1 gene have not been reported (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).