Genetic and Clinical Features of Tuberous Sclerosis Patients from the Republic of Bashkortostan

Rustam Nailevich Mustafin ^* 

1. Federal State Budgetary Institution of Higher Education Bashkir State Medical University, 450008, Ufa, Lenin St., 3, Russia

* Correspondence: Rustam Nailevich Mustafin 

Academic Editor: Andre Megarbane

Received: September 29, 2025 | Accepted: January 05, 2026 | Published: January 08, 2026

OBM Genetics 2026, Volume 10, Issue 1, doi:10.21926/obm.genet.2601323

Recommended citation: Mustafin RN. Genetic and Clinical Features of Tuberous Sclerosis Patients from the Republic of Bashkortostan. OBM Genetics 2026; 10(1): 323; doi:10.21926/obm.genet.2601323.

© 2026 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

1. Introduction

Tuberous sclerosis (TS) is a hereditary tumor syndrome with an incidence of 1:6000 to 1:12000 (average 1:9000) newborns. The cause of TS is germline heterozygous pathogenic variants in the tumor suppressor genes TSC1 and TSC2 (the name is derived from the abbreviation Tuberous Sclerosis) with confirmed pathogenicity [1]. The disease is characterized by a variety of clinical manifestations in various organs and systems (Figure 1), the development of hamartomas (a type of benign tumor) of the brain in the form of subependymal nodes in 90% and cortical tubers in 85% of patients; renal angiomyolipomas in 75% [2] of patients with TS; cardiac rhabdomyomas in 90% of newborns [1], as well as pulmonary lymphangioleiomyomatosis in 40% [2,3] of patients. Subependymal giant cell astrocytomas are detected in 5–20% of patients with TS [2]. Patients with TS are characterized by skin lesions, including depigmentation spots in 90% [3,4], facial angiofibromas in 83%, shagreen plaques in 50%, and fibrous plaques on the forehead and scalp in 25% of patients [4]. Epilepsy is detected in 63-93% of patients with TS, which first appears during the first year of life and is closely associated with impaired neurocognitive development [1]. 30% of patients with TS have autism spectrum disorder (ASD), of which 90% have intellectual disability. For differential analysis of autism spectrum disorder, consultations with a psychiatrist and psychologist are necessary to exclude other mental disorders, such as attention deficit hyperactivity disorder, schizophrenia, anxiety disorders, and intellectual disability [5].

Figure 1 Clinical manifestations of tuberous sclerosis and their frequency.

The TSC1 and TSC2 genes encode the proteins hamartin and tuberin, respectively, which, together with the TBC1D7 molecule, inhibit the serine/threonine protein kinase mTORC1 (mammalian target of rapamycin complex 1), which is essential for cell proliferation and growth. Therefore, pathogenic variants in the TSC1 or TSC2 genes lead to hyperactivation of mTORC1 and carcinogenesis [6]. Pathogenic variants in the TSC1 and TSC2 genes that cause TS exhibit extreme diversity and lack mutational hotspots. A meta-analysis of molecular genetic studies from different countries revealed no significant differences in the types of pathogenic variants. Among nucleotide substitutions, the ratio C>G/G>C was 3:1, and C>T/G>A was 2:1 [7]. The TSC1 gene is located on 9q34.13, consists of 23 exons, and encodes a 1164-amino-acid protein with a molecular weight of 130 kDa. Pathogenic variants in the TSC1 gene, primarily nonsense variants and small deletions, account for 10–15% of all TS cases worldwide. The TSC2 gene is located on 6p13.3, spans 45 exons, and encodes the 200 kDa protein tuberin, which consists of 1807 amino acids. Pathogenic variants in the TSC2 gene account for 75-80% of TS cases and are primarily represented by missense variants and deletions. A more severe course of TS was determined in patients with pathogenic variants in the TSC2 gene [6]. A study of 325 patients with TS, identifying the characteristics of the clinical manifestations of the disease with different types of pathogenic variants, showed that patients with pathogenic variants in the TSC2 gene had a greater number of depigmentation spots and more pronounced learning difficulties compared to patients with pathogenic variants in the TSC1 gene (17% of all causes of TS in this sample) [8].

The ClinVar database currently contains data on 5,253 germline variants in the TSC1 gene, of which 655 are pathogenic, 132 are likely pathogenic, 2,128 are of uncertain significance, 516 have conflicting pathogenicity data, 1,474 are likely benign, and 320 are benign. The majority of these variants—2,252—are missense variants, 224 are nonsense variants, and 141 are splice site alterations. In addition, 533 deletions, 263 duplications, and 329 insertions have been described.

The ClinVar database contains 11,587 germline variants in the TSC2 gene, of which 1,237 are pathogenic, 291 are likely pathogenic, 4,066 are of uncertain significance, 1,391 have conflicting pathogenicity data, 3,701 are likely benign, and 984 are benign. Of these, 4,960 are missense variants, 362 are nonsense variants, 414 are splice site variants, 1,093 are deletions, 552 are duplications, and 725 are insertions (Figure 2). Identification of pathogenic variants in the TSC1 and TSC2 genes is important for confirming the diagnosis of TS and prescribing effective treatment with mTOR inhibitors, which include rapamycin (sirolimus) and its analogues (everolimus). According to meta-analyses, these drugs reduce the size of astrocytomas of the brain, angiolipomas of the kidneys [2], with a significant decrease in the frequency of seizures [9], including in children aged 1 year and older in relation to astrocytomas, angiofibromas of the face, and tumors of the optic nerves [10]. Moreover, the use of mTOR inhibitors by pregnant women with TS in their fetus reduces the size of cardiac rhabdomyomas in the fetus [11]. Sirolimus ointments are used for the treatment of facial angiofibromas, with a 0.2% concentration of the drug being most effective [12].

Figure 2 Spectrum of variants in the TSC1 and TSC2 genes worldwide, according to ClinVar data.

1.1 Purpose of the Study

To analyze the clinical and molecular genetic characteristics of tuberous sclerosis in the Republic of Bashkortostan (RB).

2. Materials and Methods

A retrospective analysis of data on patients with TS from RB, registered with geneticists at the Republican Medical Genetic Center (RMGC) with an established diagnosis of TS, was conducted. All studies were conducted in compliance with biomedical ethics and GCP (Good Clinical Practice) standards. The clinical manifestations of TS are described in patients from RB, as well as in patients with identified pathogenic variants in the TSC1 and TSC2 genes. Pathogenic variants were identified using next-generation sequencing (NGS) for intragenic pathogenic variants and multiplex ligase-dependent probe amplification (MLPA) for extended deletions. Blood samples were collected with the patients' consent and sent to molecular genetic laboratories. For qualitative binary data, statistical analysis was performed using an interactive 2 × 2 contingency table and the calculation of association statistics (Pearson's χ² test) with Yates's continuity correction developed by V.P. Leonov, as well as analysis of four-field contingency tables available at https://medstatistic.ru/calculators/calchi.html. The odds ratio (OR) was calculated manually using the formula: OR = (A × D)/(B × C). All patients signed informed consent. The study protocol was approved by the Local Ethics Committee (Protocol No. 5 dated December 7, 2009). 23 programs were used for pathogenicity assessment for newly discovered variants: SIFT_pred; SIFT4G_pred; Polyphen2_HDIV_pred; Polyphen2_HVAR_pred; LRT_pred; MutationTaster_pred; MutationAssessor_pred; FATHMM_pred; PROVEAN_pred; MetaSVM_pred; MetaLR_pred; MetaRNN_pred; M-CAP_pred; PrimateAI_pred; DEOGEN2_pred; BayesDel_addAF_pred; BayesDel_noAF_pred; ClinPred_pred; LIST-S2_pred; ESM1b_pred; AlphaMissense_pred; fathmm-MKL_coding_pred; fathmm-XF_coding_pred. For the new variants we identified, pathogenicity has been determined according to most of these programs.

3. Results

In RB, 88 patients with TS (49 men and 39 women, ratio (1.26:1)) from 82 families were registered. The prevalence of TS was calculated for the entire period of TS patient registration at the Republican Medical Genetic Center—from 1996 to 2025—over the past 29 years. The age range of patients with tuberous sclerosis in the republic ranged from 1 to 61 years (average age 25 years). The age distribution of patients is shown in Figure 3. Taking into account the population of RB in 2025 - 4,046,094 people, the incidence rate was 1:46,000, and the prevalence of TS was 2.17:100,000 people, while the global average is 11:100,000 people (5.5 times more often). This discrepancy may be due to regional factors and to the lack of visits by TS patients to genetic counselors. Therefore, it is essential to report this condition to physicians across various specialties. Sporadic cases resulting from de novo pathogenic variants in parental germ cells accounted for the majority—85% (73 individuals) of patients with TS.

Figure 3 Distribution of patients with tuberous sclerosis by age in the Republic of Bashkortostan.

Analysis of the clinical manifestations of TS in RB reveals differences in the frequency of certain manifestations compared with global data (Table 1). Depigmentation spots were detected in 78 patients (88%), fibrous plaques on the forehead in 28 (31.8%), shagreen plaques on the skin in 36 (42%), subependymal giant cell astrocytoma in 16 (19%), and renal cysts in 19 (22%). Cardiac rhabdomyomas were detected in 6 of 8 patients with TS in children under 2 years of age (75%), in 30 of 78 patients over 2 years of age (38%). Epilepsy was diagnosed in 67% of patients with tuberous sclerosis from the Republic of Bashkortostan (58 people), which is not statistically significantly different from the data from a study of tuberous sclerosis in the world (78%), р = 0.082 [1]. Considering the average incidence of TS worldwide of 1:9000 [1] and the Earth's population of 8251771647, we can calculate the average number of patients with TS worldwide, which is 916864.

Table 1 Differences between clinical manifestations of tuberous sclerosis in patients from the RB and data from around the world.

Molecular genetic studies to detect mutations in the TSC1 and TSC2 genes were performed on 28 patients with TS. Pathogenic variants in the TSC1 gene were identified in 5 patients (Table 2), accounting for 18% of the 28 patients with molecular confirmation of the disease. Mutations in the TSC2 gene were identified in 23 patients with TS (Table 3), representing 82% of the 28 patients with a molecularly confirmed diagnosis of TS.

Table 2 Features of clinical manifestations of tuberous sclerosis in patients with pathogenic variants in the TSC1 gene from the Republic of Bashkortostan.

Table 3 Features of clinical manifestations of tuberous sclerosis in patients with pathogenic variants in the TSC2 gene from the Republic of Bashkortostan.

For patients with identified mutations, disease severity was assessed based on age and the presence of epilepsy. In patients with TSC1 gene mutations (aged 2 to 22 years, with a mean age of 12 years), no significant correlation was found between disease symptom severity and age. For patients with epilepsy, an association was found with the presence of subependymal nodes, suggesting that the cause of epilepsy is an organic brain tumor. In patients with TSC2 gene mutations (aged 1 to 30 years, with a mean age of 10 years), no significant association between the severity of tuberous sclerosis and age was found. Of the 23 patients in this group, epilepsy was diagnosed in 16 (70%). However, epilepsy was associated with a higher incidence of cognitive impairment (63% compared to 43% in patients without epilepsy). The incidence of other symptoms, including brain tumors, was comparable between the two groups.

Statistically significantly less frequently, compared to global data, facial angiofibromas, pulmonary lymphangioleiomyomatosis, brain hamartomas, gingival fibromas, and autism spectrum disorders were registered in patients with TS from RB. However, a statistically similar frequency of detection of such manifestations characteristic of TS as depigmentation spots (χ² = 0, p = 1), fibrous plaques on the head (χ² = 1.554; p = 0.213), shagreen plaques on the skin (χ² = 3.998; p = 0.046), cardiac rhabdomyomas (χ² = 7.792; p = 0.006), subependymal giant cell astrocytoma (χ² = 1.339; p = 0.248), polycystic kidney disease (χ² = 1.663; p = 0.198), epilepsy (67%, χ² = 3.034; p = 0.082) was determined.

An analysis of the characteristics of TS manifestations in patients with pathogenic variants in the TSC2 gene compared to those in patients with pathogenic variants in the TSC1 gene, as well as between patients with extended deletions and point pathogenic variants of TSC2, did not reveal any significant differences. In all patients, pathogenic variants were identified across multiple gene loci, indicating the absence of mutagenesis hotspots and genotypic correlations. A pathogenic variant in the TSC1 gene: exon8:c.682C>T(p Arg228Ter) was previously detected in a TS patient from Germany [13]. Pathogenic variant TSC1:exon18:c.2287C>T(p.Gln763Ter), rs118203671, has been described in patients with TS from the Netherlands [14], the USA [8], and Brazil [15]. Figure 4 shows the localization of pathogenic variants in the TSC1 gene identified in this study.

Figure 4 Localization of the described pathogenic variants in patients with TS from the Republic of Bashkortostan in relation to the exons of the TSC1 gene.

The pathogenic variant TSC2:exon3:c.268C>T (p.Gln90X) was previously identified in TS patients from the USA [8,16,17], Taiwan [18], and China [19]. Variant TSC2:exon9:c.976-15G>A was also identified in Germany [20] and the USA [17,21]. Variant TSC2:exon17:c.1831C>T (p.Arg611Trp) has been previously identified in TS patients from India [22], the USA [8,21], China [23], and Mexico [24]. Variant TSC2:NM_00548:exon19:c.2083C>T (p.Gln695X) was described in TS patients from the UK [25], China [26], and the USA [8]. The pathogenic variant TSC2:exon26:c.3095G>C(p.Arg1032Pro) was described in TS patients from the Netherlands [27]. Splice site mutation TSC2:exon30:c.3610+1G>A was previously described in TS patients from the UK [25] and the USA [17]. Nonsense mutation TSC2:exon34:c.4174C>T(p.Gln1392X) was previously described in TS patients from China [28] and Mexico [24]. Pathogenic frameshift variant TSC2:exon34:c.4242dupT(p.Lys1415fs) was previously described in a TS patient from the USA [8]. Figure 5 shows the localization of pathogenic variants in the TSC2 gene identified in the present study.

Figure 5 Localization of the described pathogenic variants in patients with TS from the Republic of Bashkortostan in relation to the exons of the TSC2 gene. Green color indicates frameshift variants, blue color indicates nonsense variants, yellow color indicates missense variants, and orange color indicates splicing variants.

Thus, of the 5-point variants in the TSC1 gene identified in TS patients from RB, 3 have not previously been described in the literature. The variants are distributed across different exons, without hotspots of mutagenesis, and include 1 double-nucleotide deletion, 1 missense variant, and 3 nonsense variants. Of the 19 point variants in the TSC2 gene identified in TS patients from RB, 8 have also been reported in the literature in TS patients from other countries, and 11 are previously undescribed. Variants in the TSC2 gene in patients with RB are distributed across different exons without hotspots of mutagenesis and include 6 nonsense variants, 4 splice-site variants, 4 missense variants, 3 deletions, and 2 duplications.

It should be noted that 8 of the 28 TS patients with identified pathogenic variants are receiving the mTOR inhibitor everolimus, a rapamycin analogue. Patient follow-up is planned to assess the drug's effectiveness and document the observed results. This requires repeat ultrasound examinations of internal organs, a brain MRI, echocardiography, a brain EEG, and consultations with a neurologist, an epileptologist, a psychotherapist, and a psychologist. Since a comparative analysis (see Table 1) of the manifestations of TS in patients from RB compared with data from around the world revealed a statistically significant lower incidence of subependymal nodes, cortical tubers, and tumors of the kidneys and lungs, repeated instrumental examinations of patients are necessary. To accurately identify cognitive impairments and autism spectrum disorders, all TS patients must be consulted by psychologists, neurologists, and psychotherapists, with the data recorded in their outpatient records and their progress monitored. The use of mTOR inhibitors in TS patients in RB with a molecularly confirmed diagnosis demonstrates a high level of patient care. Given that, according to the scientific literature [2,9,10,11,12], mTOR inhibitors have shown effectiveness against tumor and convulsive syndromes in patients with TS, it is planned to screen for pathogenic variants in the TSC1 and TSC2 genes in all patients prescribed these drugs.

The frequency of clinical signs of TS in the RB was compared not only with average indicators but also with the lowest reported frequencies in individual publications (Table 4). As can be seen from the Table 5, according to data from various researchers, there are statistical results similar to the frequency of occurrence in RB for such clinical manifestations of TS as subependymal nodes [15], facial angiofibromas [8,14,28], cognitive impairment and cortical tubers [14], and renal angiomyolipomas [8,23,28]. Therefore, it can be assumed that the differences observed from the global average in this study may reflect regional characteristics associated with the influence of pathogenic variants in the TSC1/TSC2 genes that cause TS in RB.

Table 4 Differences in clinical manifestations of tuberous sclerosis in patients from RB with data from around the world.

Table 5 Comparison of clinical manifestations of TS in patients from the RB compared with global data.

4. Discussion and Conclusion

Clinical manifestations of TS in RB are highly diverse and show a similar frequency of occurrence for most disease features compared to global data. Statistically significant differences in the identified subependymal nodules, facial angiofibromas, cortical tubers, renal angiomyolipomas, gingival fibromas, and pulmonary lymphangiomyomatosis from global data are likely due to the specific genetic causes of TS in RB (the nature of pathogenic variants). This is evidenced by comparing the frequency of TS features in RB with data from individual original studies. Molecular genetic confirmation of the TS diagnosis was obtained in 28 of 86 patients from RB (33%). Of the five pathogenic variants in the TSC1 gene previously not described in the scientific literature, three were identified. Of the 19 pathogenic point variants in the TSC2 gene, 11 were also previously unidentified by other researchers, demonstrating the importance of studying TS in RB not only for effective patient treatment but also for scientific research. Molecular genetic confirmation of the TS diagnosis in patients from RB allowed eight patients to begin treatment with mTOR inhibitors. The plan is to prescribe the drug to all TSC patients in need through the "Circle of Goodness" program, according to the organization's established criteria: children with a detected mutation in the TSC1 or TSC2 genes, children with cognitive impairment or dysphagia under 18 years of age, and children with the tuberous sclerosis symptom complex. This requires searching for pathogenic variants in the TSC1/TSC2 genes using sequencing and MLPA in all TSC patients, with a description of the results. Accordingly, an algorithm for monitoring TS patients can be proposed for physicians of all specialties (Figure 6).

Figure 6 Scheme of the algorithm for monitoring patients with TS.

Author Contributions

The author did all the research work for this study.

Competing Interests

The author has declared that no competing interests exist.