Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs

Tuberous sclerosis (TSC) is a relatively common hamartoma syndrome caused b y mutations in either of two genes, TSC1 and TSC2. Here we report comprehen sive mutation analysis in 224 index patients with TSC and correlate mutatio n findings with clinical features, Denaturing high-performance liquid chrom atography, long-range polymerase chain reaction (PCR), and quantitative PCR were used for mutation detection. Mutations were identified in 186 (83%) o f 224 of cases, comprising 138 small TSC2 mutations, 20 large TSC2 mutation s, and 28 small TSC1 mutations. A standardized clinical assessment instrume nt covering 16 TSC manifestations was used. Sporadic patients with TSC1 mut ations had, on average, milder disease in comparison with patients with TSC 2 mutations, despite being of similar age. They had a lower frequency of se izures and moderate-to-severe mental retardation, fewer subependymal nodule s and cortical tubers, less-severe kidney involvement, no retinal hamartoma s, and less-severe facial angiofibroma. Patients in whom no mutation was fo und also had disease that was milder, on average, than that in patients wit h TSC2 mutations and was somewhat distinct from patients with TSC1 mutation s. Although there was overlap in the spectrum of many clinical features of patients with TSC1 versus TSC2 mutations, some features (grade 2-4 kidney c ysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver an giomyolipomas) were very rare or not seen at all in TSC1 patients. Thus bot h germline and somatic mutations appear to be less common in TSC1 than in T SC2. The reduced severity of disease in patients without defined mutations suggests that many of these patients are mosaic for a TSC2 mutation and/or have TSC because of mutations in an as-yet-unidentified locus with a relati vely mild clinical phenotype.