Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosiscomplex patients: no evidence for genotype-phenotype correlation

Tuberous sclerosis complex is an inherited tumour suppressor syndrome, caus ed by a mutation in either the TSC1 or TSC2 gene. The disease is characteri sed by a broad phenotypic spectrum that can include seizures, mental retard ation, renal dysfunction, and dermatological abnormalities. The TSC1 gene w as recently identified and has 23 exons, spanning 45 kb of genomic DNA, and encoding an 8.6 kb mRNA. After screening all 21 coding exons in our collec tion of 225 unrelated patients, only 29 small mutations were detected, sugg esting that TSC1 mutations are under-represented among TSC patients. Almost all TSC1 mutations were small changes leading to a truncated protein, exce pt for a splice site mutation and two in frame deletions in exon 7 and exon 15. No clear difference was observed in the clinical phenotype of patients with an in frame deletion or a frameshift or nonsense mutation. We found t he disease causing mutation in 13% of our unrelated set of TSC patients, wi th, more than half of the mutations clustered in exons 15 and 17, and no ob vious under-representation of mutations among sporadic cases. In conclusion , we find no support for a genotype-phenotype correlation for the group of TSC1 patients compared to the overall population of TSC patients.