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Characterisation of six large deletions in TSC2 identified using long range PCR suggests diverse mechanisms including Alu mediated recombination
  1. S L DABORA*,
  2. A A NIETO*,
  3. D FRANZ,
  4. S JOZWIAK§,
  1. *Division of Hematology, Brigham and Women's Hospital, 221 Longwood Avenue, LMRC 301, Boston, MA 02115, USA
  2. †Harvard Medical School, Boston, MA 02115, USA
  3. ‡Division of Pediatric Neurology, Children's Hospital Medical Center, Cincinnati, OH, USA
  4. §Department of Child Neurology, Children's Memorial Hospital, Warsaw, Poland
  5. ¶Department of Clinical Genetics, Erasmus University and University Hospital, 3015 GE Rotterdam, The Netherlands
  1. Dr Dabora or Dr Kwiatkowski, sdabora{at} or dk{at}

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Editor—Tuberous sclerosis complex (TSC) is an autosomal dominant familial tumour syndrome (OMIM 19110 and 191092, It is characterised by the development of benign tumours (hamartomas), most frequently in the brain, skin, and kidneys. It is highly penetrant although with variable expression. In the majority of cases, there is significant neurological morbidity as seizures and mental retardation are common. Two causative genes for TSC have been identified, TSC1 andTSC2.1 2 Reports on mutation analysis in TSC show over 300 unique mutations with a varied spectrum. In cases where a mutation can be identified, approximately 80% have aTSC2 mutation and 20% have aTSC1 mutation. All reportedTSC1 mutations are small point mutations causing nonsense changes or splice site changes, or small insertions/deletions causing frameshift mutations. InTSC2, the majority (approximately 85%) are small mutations (point mutations causing splice, nonsense, or missense changes, or small insertion/deletions). The remaining 15% of reportedTSC2 mutations are large deletions (ranging in size from 1 kb to 1 Mb). Other large rearrangements (inversions, insertions, translocations) have also been reported, but these account for <1% of reported TSC2 mutations (

Because TSC is often a devastating disorder with a high frequency of sporadic cases, there is significant demand for genetic testing. Much progress has been made in detecting small mutations inTSC1 and TSC2using a variety of techniques, such as heteroduplex (HD) analysis, single stranded conformation analysis (SSCP), protein truncation test (PTT), denaturing gradient gel electrophoresis (DGGE), and most recently denaturing high performance liquid chromatography (DHPLC).3 5 6 8-11 13 14 Although it is important for improving the overall mutation detection rate in TSC patients, there has been less effort to develop new techniques for identifying large deletions in TSC2, which make up a small …

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