According to the international OMIM database, the number of nosological forms of orphan hereditary diseases (OHDs) is about 7000–8000. The majority of these (more than 80%) are considered to be rare, i.e. the prevalence is less than 1 case per 1 million population [1]. A total of 10–20% of nosological forms fall on common OHDs, however, the number of patients with such disorders exceeds 60% [2, 3]. According to the research, the OHD burden on the population varies between 5–17 per 1000 people [4], and the pediatric population accounts for the major share (> 2%) due to the lower survival rate and adaptability of children with severe diseases. In 30% of cases, OHDs manifest at birth, while in 87% of cases these manifest by the end of puberty [5]. The issue of OHDs is very important for both healthcare and society in general since many cases of such disorders are characterized by high disability and mortality rates: at least 35% of childhood mortality in developed economies is associated with OHDs [2, 3].

Variability and heterogeneity of the OHD cumulative prevalence and diversity reported for various countries and populations, which are also manifested in genetic heterogeneity, are typical for OHDs [6]. Current knowledge about the genetic burden in human populations, diversity, prevalence, and heterogeneity of OHDs among children is scarce; the main reports issued both in Russia and abroad are focused on the analysis of data by hospitals or on certain ethnic populations [2, 7–16]. In the Russian Federation, the clinical population genetic studies of OHDs in the pediatric population involving recording of the maximum number of disorders in distinct federal entities are conducted only by the Research Centre for Medical Genetics and are under development. Differentiation of populations by both the prevalence of certain diseases and the cumulative prevalence of OHDs has been shown, which confirms the need to study each region in order to ensure the possibility of optimizing the region-specific care provided to patients [17–20].

The study aimed to assess OHDs in the pediatric population of the Republic of North Ossetia – Alania (RNO-A).

METHODS

We performed a medical genetic examination of the population of RNO-A. People of various age groups in all eight rural districts and the city of Vladikavkaz were examined in order to identify OHDs. The population survey was conducted in accordance with the examination protocol developed by the team of the Research Centre for Medical Genetics more than 40 years ago for small populations of the Russian Federation (populations of districts and towns) and tested in 15 Russian regions (110 rural districts) over this period. The protocol was published earlier [21–24]. Patients with congenital and presumably hereditary diseases were found via physicians and paramedical staff of medical institutions of the Republic using the questionnaire developed. The questionnaire represents the list of symptoms (neurological, ophthalmological, dermatological, skeletal, endocrinological, genetic, etc.) of various OHDs distributed across the main medical specialties. In addition to the lists obtained, we used the data from the medical and social examination service and from other medical and social sources. Given the fact that each symptom can be typical for more than one disease and is usually typical for a group of diseases, the entire clinical picture entails identifying the highest possible number of cases of OHDs (affecting both individual systems and multiple organs). Examination of families and patients of various age groups was performed during the meeting of experts in various medical specialties, which made it possible to identify a broad range of OHDs [20–24]. The diagnoses were verified by clinical, instrumental, and laboratory methods (biochemical, cytogenetic, molecular genetic, etc.).

The size of the actually examined population of the RNO-A (2017–2023) was 543,817 people, including 145,560 (26.77%) children aged 0–18 years (tab. 1). Epidemiological analysis of OHDs in the pediatric population of the RNO-A was performed.

Considering the heterogeneity of many OHDs, we performed segregation analysis aimed to confirm certain inheritance types (autosomal dominant (AD), autosomal recessive (AR), or X-linked (XL)) showing that the resulting distribution was correct: р = 0.27 ± 0.06 (expected value 0.25) for AR inheritance and р = 0.49 ± 0.04 (expected value 0.5) for AD inheritance [25–26].

The cumulative prevalence, or genetic burden, of OHDs per 1000 examined individuals by populations was calculated using the following formula: n / (N / 1000), where n was the number of affected individuals, and N was the number of children. The standard error of the OHD genetic burden values was calculated using the formula ((n / N) × (1 – (n / N)) / N) / 0.5 × 1000, where n was the number of affected individuals, N was the number of children [25–26]. 

To analyze the OHD diversity, we compiled the list of diseases and calculated the disease prevalence (n / N) per 100,000 children. The genetic burden and prevalence of X-linked OHDs were calculated for boys. The genetic burden values were compared by the χ² method [17–26].

RESULTS

Cumulative prevalence of OHDs in pediatric population of the RNO-A

Comprehensive assessment of the population of the RNO-A resulted in the identification of 1241 patients (from 1037 families) with various nosological forms of OHDs, which accounted for 58.62% of the total number of affected individuals of various age groups identified in this region (2115 patients from 1489 families). We calculated the genetic burden of OHDs in the city of Vladikavkaz and eight rural districts of the RNO-A.  

The cumulative prevalence (per 1000 children) of the main types of OHDs (AD, AR, and XL) in the pediatric population of the RNO-A (in the city of Vladikavkaz, Ardonsky, Pravoberezhny, Kirovsky, Alagirsky, Digorsky, Irafsky, Prigorodny, and Mozdoksky districts) was calculated (tab. 2).

We revealed variability of cumulative prevalence by subpopulations between 5.48 ± 0.621 (1 : 196) in the town of Beslan and 30.91 ± 4.137 (1 : 34) in rural areas of the Irafsky District (tab. 2). The analysis of 17 subpopulations showed that the cumulative prevalence of all types of OHDs in rural areas was more than twice higher compared to that in towns and district centers (χ²AD = 54.35; χ²AR = 48.89; χ²XL = 29.46; χ²Tot. = 136.18; d.f. = 16; р < 0.05), which is typical for populations of the Russian Federation [17–20].

The average prevalence in the surveyed sample was 1 : 117 children, i.e. about 1% of children were diagnosed with OHDs.

This indicator varies widely: between 1 : 34 in rural areas of the Irafsky District (more than 2% of children) and 1 : 196 (0.5%) in the town of Beslan.

Comparative analysis of the cumulative prevalence of hereditary diseases among children in the surveyed pediatric populations of the Russian Federation

We conducted a comparative analysis of the cumulative prevalence of hereditary diseases among children in the surveyed pediatric populations of the Russian Federation, including the data reported for the RNO-A. It should be noted that the share of the total number of affected children among all the OHD patients identified was 58.62% (1241/2117, respectively), even though the share of the pediatric population in the Republic is 26.77%.

A comparison of the cumulative prevalence values reported for the AD, AR, and XL diseases in the pediatric population showed that the genetic burden of OHDs in children was higher in rural areas than in towns and district centers (tab. 3). The analysis conducted showed differentiation and revealed the differences in this indicator between the rural and urban populations. In rural populations, the highest prevalence values were reported for the RNO-A (1 : 65), Karachay-Cherkessia (1 : 69), Udmurt Republic (1 : 79), Kirov Region (1 : 85), while the average value for rural areas was 1 : 97, i.e. more than 1% of children. As for towns and district centers, the prevalence ranged between 1 : 144 in Karachay-Cherkessia and 1 : 301 in the Rostov Region [17–20].

According to tab. 3 and figure, the average values of OHDs prevalence in the pediatric population of the RNO-A obtained in our study (1 : 117) are similar to the values reported for other regions of the Russian Federation we have assessed (1 : 103 for Tatarstan, 1 : 146 for Bashkortostan, 1 : 200 for the Chuvash Republic, 1 : 173 for the Udmurt Republic, 1 : 149 for the Rostov Region, 1 : 130 for the Kirov Region, 1 : 99 for the Republic of Karachay-Cherkessia). It is important that the average prevalence among children is 1 : 130, i.e. 1% of children are diagnosed with OHDs, which has to be taken into account when developing prevention programs and treatment programs for orphan diseases.

OHD diversity in pediatric population of the RNO-A

A total of 1241 patients with various OHD forms from 1037 families were identified in the pediatric population of the RNO-A. The diversity of OHDs is made up of 241 nosological forms: 109 ones with AD inheritance, 102 ones with AR inheritance, and 30 XL diseases. The largest number of affected individuals (n = 880, 70.91%) is reported for the group of 57 (23.65%) common OHD disease entities. In contrast, the smallest number (n = 87, 7.01%) is noted for the group of 87 (36.10%) rare diseases (tab. 4).

The majority of diseases have been already found in the surveyed populations of the Russian Federation. Table tab. 5 presents the diversity of common (with the prevalence exceeding 1 : 30 000) OHDs in the RNO-A, along with the average prevalence in seven previously assessed regions of European Russia (ER) and the disease prevalence according to the data of the international Orphanet database [6, 17–20].

High prevalence (per 100,000 children) of 11 diseases is the feature of the surveyed population: childhood myotonic dystrophy — 6.87  (1 : 14.556), Duchenne muscular dystrophy — 37.10 (1 : 2696 boys), type I neurofibromatosis — 18.06 (1 : 7661), type 12 congenital myasthenia — 3.44 (1 : 29.112), congenital X-linked ichthyosis — 12.37 (1 : 8087 boys), fragile X syndrome — 9.62  (1 : 10,327 boys), Rett syndrome — 9.62 (1 : 12,130 boys), achondroplasia — 9.62 (1 : 10.397), AR deafness — 70.76 (1 : 1413), rare form of congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency — 6.18 (1 : 16.173). All patients with the above diseases were genotyped, and the locus and allelic heterogeneity were determined. The previously unreported brachydactyly E–amelogenesis–mental retardation–nanism syndrome showing high prevalence (11.28/100,000) was identified in four families. This syndrome was submitted to Orphanet, but it has not been mapped.

The prevalence of other diseases in the RNO-A was similar to that observed in other regions and aligned with the frequency reported in Europe as documented in Orphanet [6, 17–20]. However, we would like to note the high prevalence of undifferentiated intellectual developmental disorder with all types of inheritance (AD, AR, XL) in the RNO-A (13.74/100,000; 39.85/100,000 and 35.72/100,000 boys, respectively), the overall prevalence was 1 : 1400 children.

Thus, the OHD analysis conducted revealed regional specifics of the spectrum and showed the need to develop specific regional prevention programs.

DISCUSSION

In global practice, there is a limited number of studies focused on assessing the cumulative prevalence, diversity, and features of the spread of OHDs in pediatric populations [2, 7–16]. In the Russian Federation, such studies are conducted only by the team of the Research Centre for Medical Genetics. Assessment of the OHD cumulative prevalence in the pediatric population of the RNO-A revealed variability of this indicator in 17 subpopulations of the region: between 5.48 ± 0.621 (1 : 196) in the town of Beslan and 30.91 ± 4.137 (1 : 34) in rural areas of the Irafsky District. A more than 2-fold increase in genetic burden relative to the values reported for towns and district centers was found in children living in rural areas of 17 subpopulations. Such a situation is observed in all seven pediatric populations previously surveyed in the Russian Federation [17–20].

The average OHD prevalence (1 : 117) in children of the RNO-A (tab. 3 and figure) obtained in this study is similar to the data on cumulative prevalence in the previously assessed regions of the Russian Federation (the values range between 1 : 200 in the Chuvash Republic and 1 : 99 in KarachayCherkessia). It is important to note that the average prevalence among children is 1 : 130, i.e. 1% of children are diagnosed with OHDs, which is consistent with the data provided in the reports of foreign colleagues [2, 3]. It is important for scientists, practical healthcare, and the society to emphasize that it is children, who constitute the share of the total number of patients with OHDs in the population: 58.62% of all patients identified in the Republic. The same situation is observed in other regions. The average share of pediatric patients with OHDs among all the patients identified in eight surveyed constituent territories of the Russian Federation was 43.5% (from 35% in the Kirov Region to 58% in the RNO-A), although the share of children in the surveyed regions varies between 17.80% in the Kirov Region and 26.77% in the RNO-A. Such a situation is due to the high mortality rate and decreased genotype fitness associated with a number of common OHDs [2, 3, 17–20].

The diversity of OHDs is made up of 241 diseases (109 AD, 102 AR, and 30 XL ones). The largest number of affected individuals (n = 880, 70.91%) is reported for the group of common (with the prevalence exceeding 1 : 30.000) OHD disease entities: 57 (23.65%). We have analyzed the spectrum of common OHDs and their prevalence in the RNO-A (tab. 5); a comparison with the prevalence in seven previously surveyed regions of European Russia (ER) and the data deposited in the international Orphanet database has been conducted [6, 17–20].

High prevalence (per 100,000 children) of 11 diseases, three of which have not been previously reported in our studies (type 12 congenital myasthenia (GFPT1 gene) — 3.44 (1 : 29,112); the rare form found globally in 1% of patients with congenital adrenal cortex dysfunction (3-beta-hydroxysteroid dehydrogenase 2 deficiency — HSD3B2 gene) — 6.18 (1 : 16,173); brachydactyly E–amelogenesis–mental retardation–nanism syndrome — 11.28 (has not been mapped)), is the feature of the surveyed population.

We identified type 1 congenital myotonic dystrophy — 6.87 (1 : 14.556), associated with the trinucleotide repeat expansion in the DMPK gene, Duchenne muscular dystrophy — 37.10 (1 : 2696 boys), type I neurofibromatosis — 18.06 (1 : 7661), congenital X-linked ichthyosis — 12.37 (1 : 8087 boys), fragile X syndrome — 9.62 (1 : 10,327 boys), Rett syndrome — 9.62 (1 : 12,130 boys), achondroplasia — 9.62 (1 : 10,397), AR deafness — 70.76/100,000 (1 : 1413) showing high prevalence among children. All patients with the above diseases have been genotyped, the locus and allelic heterogeneity have been determined.

CONCLUSIONS

The population of the Republic of North Ossetia–Alania (RNO-A) is characterized by a specific spectrum of OHDs caused by rare mutations, some of which do not occur or are significantly less common in other populations of the world and the Russian Federation. The higher prevalence of this spectrum of diseases in rural populations attracts attention. The findings suggest the need to develop customized region-specific programs for the prevention of childhood disability. Given the fact that hereditary diseases in children are characterized by severe course and often lead to premature death, the development of methods to prevent such diseases constitutes the obligatory direction of reducing child mortality. In general, the data obtained during this study are important in practical terms; these also contribute to global science and fundamental epidemiological studies of OHDs.