10 One of the major goals of the conference was to revisit the clinical diagnostic criteria published subsequent to the first International TSC Consensus Conference in 1998.11 Since 1998, one additional manuscript regarding the diagnostic criteria has been published that was designed to provide more guidance to practitioners by including pictures

of the major and minor findings.12 At the 2012 meeting, the most significant change recommended to the diagnostic criteria was the incorporation of genetic testing. Although the TSC1 and TSC2 genes were discovered before the 1998 conference, molecular testing was not widely available at that time. Molecular testing of the TSC1 and TSC2 genes yields a positive mutation result for 75-90% of TSC-affected individuals categorized as “definite” by the 1998 Consensus Conference Clinical Diagnostic Criteria. 2 The use of molecular testing in medicine has expanded learn more greatly since the 1990s, becoming widely accepted as invaluable in the diagnosis of diseases with a genetic basis. Utilization of genetic testing for TSC was addressed along with refinement of clinical criteria. Comprehensive and reliable screens for TSC1 and TSC2

mutations are well-established, and many pathogenic mutations have been identified (www.lovd.nl/TSC1, www.lovd/TSC2). The recommendation of the Genetics isocitrate dehydrogenase inhibitor Panel was to make identification of a pathogenic mutation in TSC1 or TSC2 an independent diagnostic criterion, sufficient

for the diagnosis or prediction of TSC regardless of the clinical findings ( Table part A). This will facilitate the diagnosis of TSC in some, particularly young individuals, allowing earlier implementation of surveillance and treatment with potential for better clinical outcomes. A “pathogenic” mutation was defined as a mutation that clearly prevents protein synthesis and/or inactivates the function of the TSC1 or TSC2 proteins (e.g., nonsense mutation or frameshift mutations, large genomic deletions) or is a missense mutation whose effect on protein function has been established by functional assessment. 13 and 14TSC1 and TSC2 genetic variants whose functional effect is less certain are not definitely pathogenic and would Fossariinae not be considered a major diagnostic criterion. A significant fraction (10-25%) of TSC patients have no mutation identified by conventional genetic testing. Therefore, a normal result does not exclude TSC. Nonetheless, if the mutation in an affected relative is known, testing for that mutation has very high predictive value for family members. Assembled experts at the Consensus Conference agreed with the recommendation that identification of a pathogenic mutation in TSC1 or TSC2 is an independent diagnostic criterion. In addition to diagnosis by genetic analysis, the clinical diagnostic criteria used to establish the diagnosis of TSC were also reviewed at the conference.