ABSTRACT
Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder marked by hamartoma growth in multiple organ systems. We performed mutational analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. We identified mutations in 72% (199/257) of de novo and 77% (53/68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in two previous large studies. We showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. We also observed results consistent with two similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. On performing meta-analyses of our data and the other two largest studies in the literature, we found significant correlations for several features that individual studies did not have sufficient power to conclude. Male patients showed more frequent neurologic and eye symptoms, renal cysts, and ungual fibromas. Correlating genotypes with phenotypes should facilitate the disease management of tuberous sclerosis complex.
Subject(s)
Genetic Predisposition to Disease/genetics , Phenotype , Tuberous Sclerosis/genetics , Tuberous Sclerosis/pathology , Tumor Suppressor Proteins/genetics , Adolescent , Adult , Child , Child, Preschool , DNA Mutational Analysis , Female , Genotype , Humans , Infant , Male , Sex Factors , Tuberous Sclerosis/complications , Tuberous Sclerosis Complex 1 Protein , Tuberous Sclerosis Complex 2 Protein , United StatesSubject(s)
Polycystic Kidney Diseases/complications , Polycystic Kidney Diseases/genetics , Tuberous Sclerosis/genetics , Amino Acid Substitution , Chromosomes, Human, Pair 16 , Chromosomes, Human, Pair 4 , Chromosomes, Human, Pair 9 , Female , Gene Deletion , Gene Frequency , Genes, Dominant , Genetic Linkage , Genetic Markers , Humans , Incidence , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mutation, Missense , Pedigree , Penetrance , Polycystic Kidney Diseases/pathology , Proteins/genetics , Proteins/metabolism , Sequence Analysis, DNA , Severity of Illness Index , TRPP Cation Channels , Tryptophan/metabolism , Tuberous Sclerosis/epidemiology , Tuberous Sclerosis/metabolism , Tuberous Sclerosis/pathology , Tuberous Sclerosis Complex 1 Protein , Tuberous Sclerosis Complex 2 Protein , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
Tuberous sclerosis complex is an autosomal dominant disease of benign tumors occurring in multiple organ systems of the body. Either of two genes, TSC1 or TSC2, can be mutated, resulting in the tuberous sclerosis complex phenotype. The protein products of the tuberous sclerosis complex genes, hamartin (TSC1) and tuberin (TSC2), have been discovered to play important roles in several cell-signaling pathways. Knowledge regarding the function of the tuberin-hamartin complex has led to therapeutic intervention trials. Numerous pathogenic mutations have been elucidated in individuals affected with tuberous sclerosis complex. Information on the type and distribution of nearly 1000 mutations in the two genes is discussed. Mosaicism for tuberous sclerosis complex mutations has been documented, complicating provision of genetic counseling to families. Emerging genotype-phenotype correlations should provide guidance for better medical care of individuals with tuberous sclerosis complex.
