Schwannomatosis (MIM 162091), the third major form of neurofibromatosis, is a late-onset tumour predisposition disorder that is clinically and genetically distinct from neurofibromatosis types 1 (MIM 162200) and 2 (MIM 101000). In approximately 50% of the schwannomatosis cases, germline mutations in SMARCB1 have been identified (Smith et al., Neurogenetics 2012). Genetic analysis of the schwannomas showed that mutation of SMARCB1 is often followed by loss of heterozygosity at the 22q region and subsequent mutation of the NF2 gene. Together, these three events result in biallelic loss of the SMARCB1 and NF2 tumour suppressor genes in the schwannomas. In 22q-related schwannomatosis cases without constitutional SMARCB1 mutations, Piotrowski (2014) identified germline mutations in LZTR1 (Piotrowski et al., Nat Genet 2014). Mutations in LZTR1 may account for up to 80% of the schwannomatosis cases lacking mutations in SMARCB1.

The LZTR1 gene (21 exons) spans ~16.8 kb of genomic DNA and is located on 22q11.21, 20 Mb from the p-telomere. The P455-A1 probemix contains one probe for each exon of the gene with the exception of exon 4 and 17. Two probes are included for exon 21. This probemix furthermore contains 11 flanking probes targeting the 22q11 and 22q12 chromosomal regions surrounding LZTR1. In addition, 14 reference probes are included in this probemix, detecting several different autosomal chromosomal locations.

This SALSA^® MLPA^® probemix is designed to detect deletions/duplications of one or more sequences in the aforementioned gene(s) in a DNA sample. Heterozygous deletions of recognition sequences should give a 35-50% reduced relative peak height of the amplification product of that probe. Note that a mutation or polymorphism in the sequence detected by a probe can also cause a reduction in relative peak height, even when not located exactly on the ligation site! In addition, some probe signals are more sensitive to sample purity and small changes in experimental conditions. Therefore, deletions and duplications detected by MLPA should always be confirmed by other methods. Not all deletions and duplications detected by MLPA will be pathogenic; users should always verify the latest scientific literature when interpreting their findings. We have no information on what percentage of defects in these genes is caused by deletions/duplications of complete exons. Finally, note that most defects in this gene are expected to be small (point) mutations which will not be detected by this SALSA^® MLPA^® test.