Tuberous Sclerosis Complex (TSC) Panel

Tuberous Sclerosis Complex affects multiple organ systems including the skin (hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous facial plaques, ungual fibromas), brain (cortical tubers, astrocytomas, seizures, intellectual disability/developmental delay), kidney (cysts, renal cell carcinomas), heart (rhabdomyomas, arrhythmias), and lungs (lymphangioleiomyomatosis [LAM]) (Northrup et al. 2020. PubMed ID: 20301399). It affects about 1 in 5,800 children in the United States (Osborne et al. 1991. PubMed ID: 2039137). Nearly 100% of individuals with TSC have skin or dental findings detectable via physical examination. Individuals who meet specific clinical findings (major and minor features) and/or have a pathogenic variant in one of the TSC genes have a definite diagnosis of Tuberous Sclerosis (Northrup and Krueger. 2013. PubMed ID: 24053982). For brain abnormalities, such as subependymal giant cell astrocytomas, either surgical resection or mTOR inhibitors can be utilized depending on the presence of singular or multiple lesions. Surveillance of brain, kidney, lung, teeth and other pertinent organs for disease progression have previously been recommended at specific intervals (1-3 years) to include periodic magnetic resonance imaging (MRI), computed tomography (CT), echocardiogram, electroencephalograph (EEG), dermatologic and eye exams (Krueger and Northrup. 2013. PubMed ID: 24053983).

Tuberous Sclerosis Complex (TSC) is caused by pathogenic variants in the TSC1 and TSC2 genes. These genes are tumor suppressors that are involved in cellular proliferation and act through multiple signaling pathways (mTOR/AKT pathways) (Orlova and Crino. 2010. PubMed ID: 20146692). TSC is inherited in an autosomal dominant manner with two-thirds of cases resulting from de novo mutation events and one-third of cases inherited from an affected parent. It presents with near complete penetrance, but has variable expressivity. Phenotypes of TSC types can be similar, but TSC2 pathogenic variants are reported to cause a more severe clinical presentation (Northrup et al. 2020. PubMed ID: 20301399). Causative variants reported to date include nonsense, missense, splice site, small insertions and deletions, and large duplications and deletions (Human Gene Mutation Database). Truncating variants are found in the majority of TSC cases.

Pathogenic variants can be identified in approximately 95% of individuals with tuberous sclerosis (TSC). Individuals with a TSC pathogenic variant will have a germline TSC2 or TSC1 variant in about 69% and 26% of cases, respectively. Approximately 5% of cases will be due to a somatic mutation event. Individuals with an identifiable TSC pathogenic variant will have either a large deletion or duplication in up to 2% and 0.5% of cases in TSC2 and TSC1, respectively (Northrup et al. 2020. PubMed ID: 20301399).

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.