Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in the skin and other organs, including brain, heart, lung, kidney and bones. TSC is caused by mutations in TSC1 and TSC2. Here, we present the TSC1 and TSC2 variants identified in 168 Danish individuals out of a cohort of 327 individuals suspected of TSC. A total of 137 predicted pathogenic or likely pathogenic variants were identified: 33 different TSC1 variants in 42 patients, and 104 different TSC2 variants in 126 patients. In 40 cases (24%), the identified predicted pathogenic variant had not been described previously. In total, 33 novel variants in TSC2 and 7 novel variants in TSC1 were identified. To assist in the classification of 11 TSC2 variants, we investigated the effects of these variants in an in vitro functional assay. Based on the functional results, as well as population and genetic data, we classified 8 variants as likely to be pathogenic and 3 as likely to be benign.
Highlights
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in the skin and other organs, including brain, heart, lung, kidney and bones
Molecular testing of TSC1 and TSC2 in 327 Danish individuals suspected of TSC resulted in the identification of 137 different variants in a total of 168 individuals
We identified five novel variants, including one in TSC1 and four in TSC2, that were absent from genome aggregation database (gnomAD) and were predicted to be >99% likely to affect splicing according to web-based tools (MaxEntScan[22], NNSPLICE23, and Human Splice Finder24) combined in Alamut Visual biosoftware
Summary
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in the skin and other organs, including brain, heart, lung, kidney and bones. TSC2 mutations are identified in the majority of TSC patients and, in general, cause a more severe phenotype than TSC1 mutations[8,9]. Exceptions to this rule are observed[10,11]. Large genomic deletions that affect both TSC2 and the adjacent PKD1 (OMIM# 601313) locus are associated with a subset of patients with TSC and severe, early-onset autosomal dominant polycystic kidney disease
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