EXON SCANNING OF THE ENTIRE TSC2 GENE FOR GERMLINE MUTATIONS IN 40 UNRELATED PATIENTS WITH TUBEROUS SCLEROSIS

Tuberous sclerosis complex (TSC) is a dominantly inherited multisystem disorder resulting in the development of hamartomatous growths in man y organs. Genetic heterogeneity has been demonstrated linking the fami lial cases to either TSC1 at 9q34,3, or TSC2 at 16p13,3, About two thi rds of the TSC cases are sporadic and appear to represent new mutation s. While both genes are thought to account for all familial cases, wit h each representing approximately 50% of the mutations, the proportion of sporadic cases with mutations in TSC1 and TSC2 is yet to be determ ined. We have examined the entire coding sequence of the TSC2 gene in 20 familial and 20 sporadic cases and identified a total of twenty one mutations representing 50% and 55% of familial and sporadic cases res pectively. Our rate of mutation detection is significantly higher than other published reports. Twenty out of 21 mutations are novel and inc lude 6 missense, 6 nonsense, 5 frameshifts, 2 splice alterations, a 34 bp deletion resulting in abnormal splicing, and an 18 bp deletion whi ch maintains the reading frame. The mutations are distributed througho ut the coding sequence with no specific hot spots. There is no apparen t correlation between mutation type and clinical severity of the disea se. Our results document that at least 50% of sporadic cases arise fro m mutations in the TSC2 gene, The location of the mutations described here, particularly the mis sense events, should be valuable for furthe r functional analysis of this tumor suppressor protein. Hum Mutat 12:4 08-416, 1998, (C) 1998 Wiley-Liss, Inc.