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

Abstract

Tuberous sclerosis complex is an inherited tumour suppressor syndrome, caused by a mutation in either the TSC1 or TSC2 gene. The disease is characterised by a broad phenotypic spectrum that can include seizures, mental retardation, renal dysfunction, and dermatological abnormalities. The TSC1 gene was 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 collection of 225 unrelated patients, only 29 small mutations were detected, suggesting that TSC1 mutations are under-represented among TSC patients. Almost all TSC1 mutations were small changes leading to a truncated protein, except 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 the disease causing mutation in 13% of our unrelated set of TSC patients, with more than half of the mutations clustered in exons 15 and 17, and no obvious 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.

Unusually mild tuberous sclerosis phenotype is associated withTSC2R905Q mutation

“…Previous work has addressed the phenotypic differences between familial and sporadic TSC, between patients with TSC1 and TSC2 mutations, the possible relation between the phenotype and the type of mutation, and intrafamilial and interfamilial variability 17, 23, 24, 26, 31–33, 38–45. To date, the majority of studies that have addressed genotype–phenotype correlations included only individuals that fulfilled the diagnostic criteria for TSC.…”

“…22 Genotype-phenotype analyses performed in large series of TSC patients have consistently shown milder severity of nearly all clinical features in patients with TSC1 compared with TSC2 mutations. 17,23,24 However, the TSC phenotype is highly variable for both TSC1 and TSC2 mutations, as well as within and between families, 7 so that it is impossible to distinguish an individual patient with a TSC1 mutation from a patient with a TSC2 mutation on clinical grounds alone.…”

Primary Intestinal Lymphangiectasia as a First Manifestation of Tuberous Sclerosis Complex

“…1). Genetic testing identified a variant in the TSC1 gene (c.1498C>T;p.Arg500Ter), which has been previously reported as pathogenic (5).…”

Genotype–phenotype correlations in tuberous sclerosis: Who and how to treat

“…With these questions in mind, it is of critical importance to identify patients at risk for severe manifestations of Tsc1, to start thinking about therapy for the group of children most disabled by this disease. Mutational analysis in patients with TSC suggests that a wide degree of phenotypic variation can be seen with a particular genotype 23. Mutations in TSC1 appear to be associated with a milder phenotype, and these patients may have lower rates of mental retardation, autistic disorder, severe facial angiofibroma, seizures (including infantile spasms), renal disease, and retinal hamartomas 24–28…”