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Tuberous Sclerosis

Inheritance patterns and prenatal diagnosis

Inheritance patterns
Autosomal dominant inheritance with very variable expression but essentially complete penetrance. Sporadic mutations account for over fifty per cent of new cases. A severely affected child may have a very mildly affected parent and great care must be taken when trying to establish the status of relatives in genetic counselling.

Prenatal diagnosis
The diagnosis of Tuberous Sclerosis is usually made according to accepted clinical diagnostic criteria. Two Tuberous Sclerosis associated genes have been identified TSC2 (encoding tuberin) and TSC1 (encoding hamartin). Molecular genetic diagnosis of TSC by analysis of a blood sample is now available but the genes are unusually large and complex. Mutations can be identified in about eighty per cent of cases. Identification of the family-specific mutation enables early pre-natal diagnosis by chorion villus biopsy for couples who wish to take this step. A small proportion of patients with Tuberous Sclerosis also have Polycystic Kidney disease. This is because the PKD1 gene that is associated with polycystic kidneys lies next to the TSC2 gene on chromosome 16. Extra tests are needed to identify the mutation in these unusual cases.

Situations in which molecular genetic testing is appropriate in persons/families with, or at risk of, Tuberous Sclerosis include:

  • Genetic counselling - Detection of a mutation in one of the two TSC genes in the affected member of a family means that relatives at risk can have their genetic status determined by an unequivocal blood test. This is a more simple approach than by conventional clinical and radiographic tests.
  • Prenatal diagnosis - Where a prospective parent has TSC, the identification of a causative mutation allows very reliable DNA-based prenatal diagnosis. The same is true for clinically unaffected couples who have an affected child, if they are concerned about the small recurrence risk posed by gonadal mosaicism (about one or two per cent). In families where the mutation cannot yet be identified, an ultrasound scan can be done at eighteen to twenty weeks to diagnose heart tumours with a further scan at twenty-two to twenty-three weeks to confirm the diagnosis.
  • Clinical diagnostic uncertainty - Detection of a mutation in one of the two TSC genes in a person presenting with one or more features suggestive of Tuberous Sclerosis, but which do not fulfil the accepted clinical diagnostic criteria for the disorder, can clarify the person's status. However, a negative gene test result doesn't help much and so this approach requires careful consideration.

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Medical text written November 1991 by Contact a family. Approved November 1991 by Professor R Mueller, Consultant in Clinical Genetics, St James University Hospital, Leeds, UK. Last updated September 2006 by Professor J Sampson, Consultant in Clinical Genetics, Institute of Medical Genetics, Cardiff, UK.

 

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