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  • A novel missense mutation in the GTPase activating protein homology region of TSC2 in two large families with tuberous sclerosis complex

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A novel missense mutation in the GTPase activating protein homology region of TSC2 in two large families with tuberous sclerosis complex
  1. Leena Kharea,
  2. Galina D Strizhevaa,b,
  3. Julia N Baileyc,
  4. Kit-Sing Aud,
  5. Hope Northrupd,
  6. Moyra Smithe,
  7. Susan L Smalleyc,
  8. Elizabeth Petri Henskea
  1. aDepartment of Medical Oncology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA, bDepartment of Molecular Biology, Russian State Medical University, Moscow, Russia, cDepartment of Psychiatry, University of California School of Medicine, Los Angeles, CA, USA, dDivision of Medical Genetics, Department of Pediatrics, The University of Texas Medical School, Houston, TX, USA, eDepartment of Pediatrics, University of California, Irvine, CA, USA
  1. Dr Henske,EP_Henske{at}fccc.edu

https://doi.org/10.1136/jmg.38.5.347

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    Tuberous sclerosis complex (TSC) is an autosomal dominant disorder (OMIM 191092) characterised by autism, seizures, mental retardation, benign tumours of the brain, heart, kidney, lung, and skin, and malignant tumours of the kidney.1 TSC has a wide range of phenotypic variability, with some subjects severely affected and others only mildly affected. There are two TSC genes,TSC1 on chromosome 9q342 andTSC2 on chromosome 16p13.3Approximately two thirds of cases of TSC appear to result from de novo germline mutations.

    In 1994, an extended four generation family with 19 affected members was reported in which 34 members (17 affected with TSC and 17 unaffected) underwent both physical and psychiatric assessments.4 The majority of the affected subjects had mild physical expression of TSC, but there was significant clustering of neuropsychiatric disorders among affected subjects compared with their unaffected relatives. The disorders that were over-represented included mood disorder, anxiety disorder, and autism. The largest difference was observed in anxiety disorder, which was seen in 10 of the affected subjects and in two of the unaffected subjects (p=0.016). One affected child had pervasive developmental disorder and one had autism. Analysis of this family suggested that TSC could present phenotypically with mild physical signs and symptoms, but with significant neuropsychiatric disease. Linkage to theTSC2 gene locus on chromosome 16p13.3 was shown with a lod score of over 3.4

    We report here the identification of a missense mutation in exon 34 of the TSC2 gene in affected members of this family. We also examined a second four generation family5from the same geographical area as the …

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