Exploring the unique epidemiological features, clinical manifestations, and genetic research of NF1 in the Republic of Bashkortostan
Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant genetic disorder caused by mutations in the NF1 gene. As one of the most common rare genetic diseases, it affects approximately 1 in 2,500-3,500 newborns worldwide 1 .
Although NF1 is relatively rare globally, it presents with diverse clinical manifestations affecting the skin, nervous system, bones, and other systems, significantly impacting patients' quality of life.
In the Republic of Bashkortostan within the Russian Federation, this disease exhibits unique epidemiological characteristics and clinical presentations, providing valuable research opportunities for scientists and opening new pathways for understanding NF1 pathogenesis and treatment methods.
The NF1 gene is located on chromosome 17 and encodes neurofibromin, a protein crucial for regulating cell growth 5 .
Approximately half of NF1 cases result from spontaneous mutations rather than inheritance 3 , meaning the condition can appear in any family regardless of history.
NF1 research in the Republic of Bashkortostan has achieved significant breakthroughs, with a 2025 study revealing the region's unique epidemiological characteristics of NF1. The research shows that the prevalence of NF1 in this region is 13.5/100,000 2 , consistent with globally reported prevalence rates, confirming the stability of NF1 across different populations.
However, further analysis of clinical manifestations revealed distinct characteristics among Bashkortostan NF1 patients. Most notably, the incidence of cognitive dysfunction is relatively high at 15%, with 75% being severe cases 2 .
Beyond cognitive deficits, the study systematically documented the frequency of various brain lesions in Bashkortostan NF1 patients, providing important evidence for understanding the complete disease profile.
| Clinical Manifestation | Incidence Rate (%) | Notes |
|---|---|---|
| Cognitive Deficits | 15 | 75% are severe cases |
| Optic Pathway Glioma | 6 | Significantly lower than global data |
| Brain Cysts | 5 | Possible region-specific manifestation |
| Hydrocephalus | 4.23 | - |
| Brain Tumors | 3.86 | - |
| Epilepsy | 3.7 | - |
Optic pathway gliomas occur in only 6% of Bashkortostan NF1 patients, significantly lower than the global average of 15-20% 2 .
Brain cysts occur in 5% of patients, potentially related to region-specific factors such as genetic background or unique genotype-phenotype associations 2 .
In Bashkortostan, NF1 diagnosis follows the same clinical diagnostic criteria established by the National Institutes of Health (NIH) as other regions. Diagnosis is confirmed when a patient meets two or more of the following criteria: six or more café-au-lait spots; axillary or inguinal freckling; two or more neurofibromas of any type or one plexiform neurofibroma; optic pathway glioma; two or more Lisch nodules; characteristic bone lesions; and having a first-degree relative with NF1 1 9 .
However, Bashkortostan research revealed an important issue: the detection rate of NF1-related cognitive deficits and learning difficulties is significantly lower than the global average 2 .
This phenomenon is not because these problems don't exist in the region's patients, but reflects deficiencies in the healthcare system's ability to identify and diagnose these manifestations.
The study found that Bashkortostan faces a series of challenges in NF1 diagnosis and treatment, primarily reflected in the accessibility of medical resources.
| Medical Resource Category | Current Status | Existing Challenges |
|---|---|---|
| Geneticists | Adequate numbers | - |
| Brain MRI Examination | Difficult to access timely | Long waiting times, delayed diagnosis |
| Neurologist Consultation | Difficult to access timely | Uneven resource distribution |
| Ophthalmologist Consultation | Difficult to access timely | Particularly for optic pathway glioma screening |
| Psychologist/Psychotherapist Consultation | Difficult to access timely | Impairs identification and management of cognitive impairments |
Current NF1 treatment primarily focuses on symptom management and complication handling. Multidisciplinary team collaboration is the ideal treatment model, including neurologists, ophthalmologists, orthopedic surgeons, oncologists, and psychologists 5 .
For Bashkortostan, establishing such multidisciplinary diagnosis and treatment models, particularly improving accessibility to psychological and neurological services, is key to enhancing patient care quality.
While Bashkortostan researchers deeply explored local NF1 characteristics, the global NF1 genetic research field also witnessed a breakthrough development. A large-scale study published in Nature Communications in 2025 challenged the traditional understanding of NF1, opening new perspectives for our comprehension of this disease 4 .
Traditionally, NF1 has been considered a completely penetrant disorder, meaning all individuals carrying pathogenic gene variants would exhibit clinical symptoms, with a prevalence of approximately 1/3,000. However, this new study adopted a genotype-first approach, analyzing multiple large-sample cohorts including the Penn Medicine Biobank (PMBB) and Ambry Genetics patient database, with surprising results.
1 in 752
Prevalence of NF1 pathogenic variants (0.13%)
1 in 432
Prevalence of NF1 pathogenic variants (0.24%)
This means the carrier rate of NF1 pathogenic variants in the population is 3-6 times higher than the expected prevalence based on clinical symptoms 4 .
Further analysis revealed that among 58 NF1 pathogenic variant carriers in the PMBB cohort, only 23 (39.7%) had a clinical NF1 diagnosis; while among 281 carriers in the Ambry cohort, 152 (54%) were clinical NF1 patients, and 129 (46%) had no NF1 diagnosis 4 . Combining both cohorts, nearly half (48.7%) of NF1 pathogenic variant carriers lacked a clinical NF1 diagnosis.
Why don't these individuals carrying pathogenic variants show symptoms? Researchers found that somatic mosaicism is the main factor. In clinical NF1 patients, the average variant allele frequency (VAF) of NF1 pathogenic variants was 0.47, while in the asymptomatic carrier group, the average VAF was 0.29-0.35 4 .
This indicates that these individuals have pathogenic variants present in only a portion of their cells, rather than all cells carrying the variant - this is the somatic mosaicism phenomenon, which results in milder or absent disease manifestations.
Although asymptomatic carriers may lack typical NF1 symptoms, studies indicate they still need to pay attention to health risks. Research shows that regardless of clinical symptoms, NF1 pathogenic variants are associated with increased malignancy rates 4 .
| Research Cohort | Group | Cancer Risk Characteristics | Age at First Cancer Diagnosis |
|---|---|---|---|
| Ambry Cohort | Clinical NF1 Group | Malignancy rate significantly higher than control | - |
| PV-only Group (no NF1 diagnosis) | Malignancy rate significantly higher than control | Significantly older than clinical NF1 group and control group | |
| PV-only Group | Increased risk of ovarian cancer, sarcoma, adrenal cancer, CNS cancers, and hematologic malignancies | - |
These findings have important implications for NF1 research in Bashkortostan. They suggest that there may also be a large number of undetected NF1 pathogenic variant carriers in the region who, while not exhibiting typical symptoms, may still face certain health risks, particularly malignancy risks. Future screening and diagnosis strategies need to consider this factor.
Based on Bashkortostan's regional characteristics and the latest global research advances, future development directions for NF1 research in this region can focus on the following key areas:
Creating a detailed clinical and genetic database of Bashkortostan NF1 patients forms the foundation for future research. This database should include comprehensive patient clinical information, genotype data, family history, and environmental exposure factors.
Addressing the issue of uneven medical resources in Bashkortostan requires developing stratified diagnosis and treatment strategies. This includes training primary care physicians to recognize basic NF1 features and establishing teleconsultation systems.
Combining new global discoveries about NF1 pathogenic variant incomplete penetrance and somatic mosaicism, Bashkortostan researchers can focus on exploring genotype-phenotype correlations unique to the local population.
Based on research findings, developing specific interventions for Bashkortostan NF1 patients is a key goal. This includes early identification strategies for cognitive deficits and cancer screening guidelines for asymptomatic carriers.
To advance NF1 research, scientists rely on a series of advanced research tools and methods. The following are key "scientific toolkits" in NF1 research:
| Research Tool/Method | Function Description | Application in NF1 Research |
|---|---|---|
| Exome Sequencing | Analyzes all protein-coding genes | Identifies pathogenic mutations in the NF1 gene |
| Multiplex Ligation-dependent Probe Amplification (MLPA) | Detects large fragment deletions/duplications | Discovers complete NF1 gene deletions (accounting for 4%-5%) |
| Next-Generation Sequencing (NGS) | Massive parallel sequencing technology | Simultaneously detects mutations in multiple genes |
| Brain MRI | Provides detailed brain images | Detects optic pathway gliomas, brain cysts, and other lesions |
| Phenome-Wide Association Study (PheWAS) | Analyzes genotype-phenotype associations | Reveals relationships between NF1 variants and various clinical manifestations |
| Cytogenetic Analysis | Analyzes chromosome structure and number | Detects large-scale rearrangements of chromosomes containing the NF1 gene |
Establish regional NF1 registry and database; Train primary care physicians in NF1 recognition; Initiate genetic studies on local population.
Implement telemedicine services for remote consultations; Conduct genotype-phenotype correlation studies; Develop cognitive screening protocols.
Establish multidisciplinary NF1 clinics; Implement targeted interventions based on research findings; Contribute to international NF1 research collaborations.
NF1 research in Bashkortostan is at a critical moment. Local researchers have already revealed unique clinical manifestations of NF1 patients in the region, such as higher brain cyst incidence and lower optic pathway glioma occurrence. Simultaneously, the global scientific community's new understanding of NF1's genetic basis, particularly discoveries about incomplete penetrance and somatic mosaicism phenomena, provides new perspectives for understanding this disease.
Future research needs to combine global cutting-edge science with local characteristics, utilizing advanced genetic research technologies while fully considering Bashkortostan's unique population genetic background and environmental factors.
Through this approach, it will be possible not only to improve medical service quality for local NF1 patients but also to make unique contributions to global NF1 research.
Every medical breakthrough begins with in-depth study of a region, a population, a disease. Bashkortostan's NF1 research is a beacon on this long medical road, illuminating the path of hope for local patients while contributing unique light to global scientific exploration.