Version May 2024
INTRODUCTION — Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder that is characterized by pleomorphic features involving many organ systems, including multiple benign hamartomas of the brain, eyes, heart, lung, liver, kidney, and skin.
The genetics and pathogenesis of TSC will be reviewed here. Other aspects of TSC are discussed elsewhere. (See "Tuberous sclerosis complex: Clinical features" and "Tuberous sclerosis complex: Management and prognosis" and "Renal manifestations of tuberous sclerosis complex" and "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)
GENETICS
TSC1 and TSC2 pathogenic variants — TSC is an autosomal dominant genetic disorder caused by heterozygous pathogenic variants in either the TSC complex subunit 1 (TSC1) or the TSC complex subunit 2 (TSC2) tumor suppressor genes. These variants cause overactivation of the mechanistic target of rapamycin (mTOR) pathway and tumor formation in multiple organs [1]. (See 'Mechanism of tumor formation' below.)
Pathogenic variants in TSC1 and TSC2 were first identified in genetic linkage analysis of families with TSC [2,3]. Both genes were subsequently cloned and the spectrum of pathogenic variants in TSC patients described [4-6]. Most TSC1 and TSC2 pathogenic variants result in loss of functional protein products [7].
The TSC1 gene — Pathogenic variants in TSC1 account for approximately one-third of TSC cases with identified pathogenic variants [7-9]. The TSC1 gene, which maps to chromosome 9q34, spans 50 kb of genomic deoxyribonucleic acid (DNA) and contains 23 exons [4]. TSC1 encodes a protein termed hamartin, which is widely expressed in normal tissues [10]. Hamartin forms a complex with the tuberin protein that is encoded by the TSC2 gene [11,12]. The functions of these proteins are described below. (See 'Mechanism of tumor formation' below.)
Several different types of TSC1 pathogenic variants have been identified, most of which result in a truncated protein with loss of function [13]. These include small deletions and insertions (58 percent), nonsense variants (23 percent), splicing variants (11 percent), missense variants (6 percent), and large deletions and rearrangements (3 percent) [7].
The TSC2 gene — Pathogenic variants in TSC2 account for approximately two-thirds of TSC cases with identified pathogenic variant [7-9]. The TSC2 gene, which maps to chromosome 16p13.3, spans 45 kB of genomic DNA and contains 42 exons [5]. The gene is ubiquitously expressed in all normal adult tissues [14].
TSC2 encodes the tuberin protein. Tuberin forms a complex with the hamartin protein, the product of the TSC1 gene [11,12].
TSC2 functions in normal brain development [15] and in withdrawal of the normal cardiomyocyte from the cell cycle during terminal differentiation [16]. This latter finding is potentially relevant in view of the benign cardiac tumors (rhabdomyomas) that are seen in TSC. (See "Tuberous sclerosis complex: Clinical features", section on 'Cardiovascular manifestations'.)
As with TSC1, the majority of pathogenic variants identified in TSC2 are loss-of-function variants [17-19]. These include small deletions and insertions (38 percent); missense (26 percent), nonsense (15 percent), and splice variants (17 percent); and large deletions and rearrangements (5 percent) [7].
Certain TSC2 missense variants inhibit tuberin phosphorylation, preventing the formation of the tuberin-hamartin complex [20]. Other pathogenic variants in both TSC1 and TSC2 also disrupt the interaction between these two proteins [21].
Molecular genetic testing — A disease-causing pathogenic variant can be identified by conventional molecular genetic testing (eg, gene-targeted sequence analysis and deletion/duplication analysis) in 85 to 90 percent of patients who meet the diagnostic criteria for TSC [7,8,22,23]. With next-generation sequencing, targeted TSC1/TSC2 gene panels can identify a causative pathogenic variant in >90 percent of patients with TSC but still not in all [8,9,24]. (See "Tuberous sclerosis complex: Evaluation and diagnosis", section on 'Genetic testing'.)
Mosaicism and noncoding pathogenic variants probably account for most of those with no pathogenic variant identified. In one report of 53 individuals with TSC who had no pathogenic variant identified after conventional genetic assessment, next-generation sequencing of tissue samples, including blood, saliva, and skin tumor biopsies, identified pathogenic variants in 45 (85 percent) [8]. Among these 45 subjects, mosaicism was present in 28 individuals, and intronic pathogenic variants were found in 18. These data suggest that next-generation sequencing with full gene analysis and testing of TSC-related tumors can increase the detection rate of pathogenic variants.
De novo versus familial TSC — De novo germline pathogenic variants account for approximately 80 percent of TSC cases, with TSC2 pathogenic variants being approximately two times as common as TSC1 pathogenic variants among de novo cases. The prevalence of TSC1 and TSC2 pathogenic variants is approximately equal among familial TSC cases [6].
There are several different explanations for the apparently nonfamilial cases.
●Most often, such cases result from a de novo pathogenic variant in the egg or sperm prior to fertilization.
●Parental somatic mosaicism, where a subset of the parent's somatic and germ cells carry the pathogenic variant, or gonadal mosaicism, in which mosaicism is confined to the parental germline [25-27]. In germline mosaicism, there may be more than one egg or sperm that contains the pathogenic variant, which can result in more than one sibling affected with the disease (ie, there is an appreciable recurrence risk).
●In a child with no affected parents or siblings, TSC may be the result of somatic mosaicism where the pathogenic variant occurred de novo after fertilization during one of the early cell divisions [25].
Once a de novo germline pathogenic variant occurs in an individual, their offspring will have a 50 percent chance of inheriting TSC, which then follows an autosomal dominant pattern of inheritance in later generations. (See "Tuberous sclerosis complex: Evaluation and diagnosis", section on 'Genetic testing'.)
Penetrance and expressivity
●Penetrance – The penetrance of TSC is complete, meaning that all individuals with a TSC1 or TSC2 pathogenic variant will manifest some features of TSC. However, the phenotype can be subtle in some cases [7,9].
●Highly variable expressivity – TSC is highly variable in its expression, that is, in the range of phenotypic changes such as age of onset, severity of disease, and different signs and symptoms that result from a specific genotype. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Penetrance and expressivity'.)
Thus, the severity of disease in TSC can vary substantially among affected individuals within the same family, and particularly from one family to another [28,29]. The variability is due to multiple causes. These include:
•Somatic mosaicism (individuals who have low-level mosaicism for a TSC-associated pathogenic variant may be very mildly affected) [27].
•Differences between TSC1 and TSC2 pathogenic variants. (See 'Genotype-phenotype correlations' below.)
•The requirement for a secondary somatic pathogenic variant in the wildtype copy of the gene for the development of many pathologic features of TSC [30,31]. The latter feature is consistent with the two-hit hypothesis of Knudson, in which one pathogenic variant is inherited and the second is acquired in somatic tissues [32]. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Pathogenesis'.)
Genotype-phenotype correlations
TSC2 variants
●TSC2 variants have a tendency for a more severe phenotype – Most studies have found that TSC2 pathogenic variants tend to have a more severe neurologic phenotype and a higher risk of renal malignancy than TSC1 pathogenic variants, but the relationship is not strict [6,18,33-38]. As examples, a prospective study of 92 children with TSC who had genetic testing and evaluation of cognition, language, and motor development found that significant developmental delays at age 24 months were present in approximately three-quarters of those with a TSC2 pathogenic variant and only one-quarter of patients with a TSC1 pathogenic variant [39]. Another report analyzed 120 pathogenic variants (22 involving TSC1 and 98 involving TSC2) in 150 patients with TSC and found that mental disability was significantly more frequent in patients with pathogenic variants involving TSC2 compared with TSC1 (67 versus 31 percent) [18]. A similar difference was noted in a study of 252 patients with pathogenic variants in TSC1 or TSC2 [6]. In addition, the same report found that hypomelanotic macules were more common in patients with TSC2 pathogenic variants [6].
However, some studies have found that patients with pathogenic variants involving TSC1 and TSC2 could not be distinguished on the basis of their clinical features [17]. Further confounding this type of analysis is the fact that mosaicism for a TSC-associated "severe" pathogenic variant can result in a patient with mild features.
In a later series, glioneuronal hamartomas with low fluid-attenuated inversion recovery (FLAIR) and T1-weighted signal intensity ("cyst-like") on brain magnetic resonance imaging (MRI) were found in all groups of patients but were significantly more frequent in patients with TSC2 pathogenic variants than in those with TSC1 pathogenic variants (relative risk [RR] 2.7, 95% CI 1.28-5.62) [40]. Furthermore, these glioneuronal hamartomas were correlated with a history of infantile spasms, epilepsy, and severe refractory epilepsy. (See "Tuberous sclerosis complex: Clinical features", section on 'Seizures and epilepsy'.)
●Some TSC2 variants have a mild phenotype – While TSC2 pathogenic variants may generally have a more severe phenotype, mild forms of familial TSC2 have been reported [9,33,34,41]. In a study that identified 19 families with pathogenic variants at codon 905 of the TSC2 gene, individuals with the R905Q pathogenic variant had unusually mild features of TSC, and many did not meet standard diagnostic criteria for TSC [41]. By contrast, other missense changes at this same amino acid (R905W and R905G) were associated with more severe disease phenotype. These clinical findings also correlated with the results of in vitro functional analysis of the three pathogenic proteins.
TSC1 variants — TSC1 pathogenic variants are underrepresented in patients presenting with de novo disease [7,17,18,33,42]; individuals representing a single occurrence in a family (simplex cases) are more likely to have a TSC2 than a TSC1 pathogenic variant (ratio 3.4:1) [7,9]. This difference may be due in part to ascertainment bias created by the possibility that TSC1 pathogenic variants result in a less severe disease phenotype (particularly mental disability). This less severe phenotype, in the absence of a family history of TSC, may lead to delayed identification of de novo cases [33,42]. (See 'De novo versus familial TSC' above.)
TSC2/PKD1 contiguous gene syndrome — A small number of patients have deletions that inactivate both the TSC2 gene and the polycystin 1 (PKD1) gene that is located nearby, a disorder that is called the TSC2/PKD1 contiguous gene syndrome. Affected patients have the clinical features of both TSC and polycystic kidney disease, and they typically present with early-onset renal cystic disease. (See "Renal manifestations of tuberous sclerosis complex", section on 'TSC2/PKD1 contiguous gene syndrome'.)
PATHOGENESIS
Mechanism of tumor formation — Several lines of evidence support the view that the TSC genes function as tumor suppressor genes:
●Inactivating variants or complete loss of TSC genes are found in patients with TSC, and loss of heterozygosity at these gene loci characterize TSC-associated tumors (eg, hamartomas, angiofibromas, and lymphangioleiomyomas) [30,43-47].
●In animal models, germline variants that disrupt either TSC2 or TSC1 predispose to hereditary clear cell renal cell carcinoma as well as multiple subependymal and extrarenal tumors such as subcortical hamartomas, similar to those encountered in patients with TSC [48-50].
●Reintroduction of wildtype, but not mutant, TSC protein suppresses tumor formation [51].
Role of mTOR — The most important advancement in our understanding of TSC is the delineation of the role of the hamartin-tuberin complex (figure 1) through inhibition of cellular signaling mediated by the mechanistic target of rapamycin (mTOR) [11,52-54]. The mTOR pathway is important for regulating cell growth and proliferation via protein translation (in response to nutrition), cell cycle progression, and response to hypoxia [55].
Pathogenic loss-of-function variants in TSC1, which encodes hamartin, or TSC2, which encodes tuberin, lead to destabilization of the hamartin-tuberin complex, the main negative modulator of the mTOR signaling pathway. This complex normally functions via GTPase-activating protein activity to cleave guanosine triphosphate (GTP) from Ras homolog enriched in brain (Rheb), a regulator of mTOR, and inhibit Rheb activity [9,55,56]. mTOR interacts with raptor (regulatory protein associated with mTOR) and other components to form mTOR complex 1 (mTORC1). When activated via Rheb, mTORC1 leads to phosphorylation of downstream targets that regulate protein and lipid synthesis, cellular growth, mitochondrial proliferation, and autophagy.
Thus, pathogenic TSC1 or TSC2 variants lead to inactivation of the tuberin-hamartin complex, loss of GTPase activity, an increase of GTP-activated Rheb, and hyperactivation of mTORC1 activity, thereby releasing an inhibitory influence on the cell cycle [9,55,56]. The net result is that cells spend less time in G1, the resting phase of the cell cycle, and quiescent cells are induced to enter the cell cycle [57,58]. Increased mTOR activity results in the formation of glioneuronal hamartomas in the brain and hamartomas in other organs [56]. Increased mTOR activity during development may also impact the developing neural network, alter synaptic transmission, and shift the excitation/inhibition balance in favor of excitation; these changes could promote development of epilepsy and TSC-associated neuropsychiatric disorders (TAND) [56].
Recognition of the mTOR signaling pathway in the pathogenesis of TSC led to the development of mTOR inhibitors such as everolimus, the first agent for treatment of patients with TSC. (See "Tuberous sclerosis complex: Management and prognosis", section on 'Role of mTOR inhibitor therapy'.)
SUMMARY
●TSC disease genes – Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by pathogenic variants in two separate genes, TSC1 and TSC2. (See 'TSC1 and TSC2 pathogenic variants' above.)
●Genetic testing – With next-generation sequencing, targeted TSC1/TSC2 gene panels can identify a causative pathogenic variant in >90 percent of patients with TSC. (See 'Molecular genetic testing' above.)
●Inheritance – TSC is an autosomal dominant condition, but de novo germline pathogenic variants account for approximately 80 percent of TSC cases. These most often arise from a de novo pathogenic variant in the egg or sperm prior to fertilization. Other cases may be explained by parental somatic mosaicism, where a subset of somatic and/or germline cells carry the pathogenic variant, or by emergence of a de novo pathogenic variant after fertilization during one of the early cell divisions. (See 'De novo versus familial TSC' above.)
●Penetrance and expressivity – The penetrance of TSC1 and TSC2 pathogenic variants is complete, but the disease is highly variable in its expression. (See 'Penetrance and expressivity' above.)
●Genotype-phenotype correlations – TSC2 pathogenic variants tend to have a more severe neurologic phenotype and a higher risk of renal malignancy than TSC1 pathogenic variants, but the relationship is not strict, and the pathogenic variant result does not completely predict either the severity or nature of the disease complications. (See 'Genotype-phenotype correlations' above.)
●mTOR pathway – Pathogenic TSC1 or TSC2 variants lead to inactivation of the tuberin-hamartin complex and hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway. This leads to the various manifestations of TSC, including tumor formation in multiple organs and brain, epilepsy, and TSC-associated neuropsychiatric disorders (TAND). (See 'Role of mTOR' above.)
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