Tuberous Sclerosis (TSC) is an autosomal dominant disorder with high penetrance. Defects in the TSC1 or TSC2 genes are the main cause of TSC. The proteins encoded by these genes are hamartin and tuberin, respectively. TSC has an incidence of roughly 1 in 6000 newborns, and is in most patients caused by de novo mutations (sporadic cases) with an absence of family history. TSC causes non-malignant tumour growth in multiple organs including skin, central nervous system and other vital organs. Well-known clinical manifestations include epilepsy, behavioural problems, skin abnormalities and lung- and kidney disease. The majority of cardiac rhabdomyomas is associated with tuberous sclerosis.
Approximately 75% of TSC cases are linked to the TSC2 gene on chromosome 16p13, the remaining are linked to the TSC1 gene on chromosome 9q34. The majority of variations found in these genes are nonsense, missense, frameshift, or splice site mutations, while less than 10% of the TSC cases are due to copy number variation in TSC1 or TSC2.
The TSC2 gene (42 exons) spans ~41 kb of genomic DNA and is located on 16p13.3, 2 Mb from the p-telomere. The P337-B1 probemix contains one probe for each exon of the gene and two probes for exon 1. This probemix furthermore contains two probes for the PKD1 gene, located downstream of TSC2. In addition, 8 reference probes are included in this probemix, detecting several different autosomal chromosomal locations. All TSC2 probes in the P337 probemix differ from the probes included in the P046 probemix and can be used to confirm P046 results.
This SALSA® MLPA® probemix is designed to detect deletions/duplications of one or more sequences in the aforementioned gene 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. 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.