Characterisation of six large deletions in TSC2 identified using long range PCR suggests diverse mechanisms including Alu mediated recombination

Editor—Tuberous sclerosis complex (TSC) is an autosomal dominant familial tumour syndrome (OMIM 19110 and 191092,http://www.ncbi.nlm.nih.gov/omim/). 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 and TSC2 .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 a TSC2 mutation and 20% have a TSC1 mutation. All reported TSC1 mutations are small point mutations causing nonsense changes or splice site changes, or small insertions/deletions causing frameshift mutations. In TSC2 , the majority (approximately 85%) are small mutations (point mutations causing splice, nonsense, or missense changes, or small insertion/deletions). The remaining 15% of reported TSC2 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 (http://zk.bwh.harvard.edu/ts).1-12 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 in TSC1 and TSC2 using 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 …