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Expanding the tuberous sclerosis phenotype: mild disease caused by a TSC1 splicing mutation
  1. Moira Blyth1,2,
  2. Michela Raponi3,
  3. Rebecca Treacy4,
  4. F Lucy Raymond4,5,
  5. John R W Yates4,5,
  6. Diana Baralle1,2
  1. 1Academic Unit of Genetic Medicine, Division of Human Genetics, University of Southampton, Southampton, UK
  2. 2Wessex Clinical Genetics Service, Southampton, UK
  3. 3Division of Human Genetics, University of Southampton, Southampton, UK
  4. 4East Anglian Medical Genetics Service, Addenbrooke's Hospital, Cambridge, UK
  5. 5Department of Medical Genetics, University of Cambridge, Cambridge, UK
  1. Correspondence to Dr D Baralle, Wessex Clinical Genetics Service, Mailpoint 105, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, UK; d.baralle{at}

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Tuberous sclerosis (TS) is an autosomal dominant disorder with variable expression, which causes epilepsy, mental retardation and hamartomas in many organ systems. TS is caused by mutations in two genes, TSC1 on 9q34 and TSC2 on 16p13.3. Mutations can be detected in approximately 85% of patients who meet the published consensus clinical diagnostic criteria.1–3 The remainder probably have mutations in intronic or promoter regions, which are not routinely screened, or are mosaic for the condition. Genotype–phenotype correlations have been slow to emerge in this disorder but TSC2 mutations tend to be associated with more severe disease than TSC1 mutations.2 3

Most TSC1 mutations are single base substitutions or small insertions/deletions, and cause protein truncation. A small number are putative splice site mutations but the effects on the proteins produced have not been studied in detail. Splicing is the process in which introns are excised from the RNA and exons joined together to form messenger RNA transcript, which is translated into the protein.

We present a family with an unusually mild phenotype caused by a novel TSC1 splice site (SS) mutation.

Case reports

This proband was admitted to hospital following an episode of unconsciousness with cyanosis at 4.5 months of age. Cranial CT scan showed …

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  • MB and MR contributed equally to this study.

  • Funding DB and MR, who performed the splicing studies, are supported by grant funding from Action Medical Research and EURASNET.

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.