Search

The genetic load and diversity of monogenic hereditary diseases (HD) in the Russian population of Karachay-Cherkess Republic (KCHR), living in 10 administrative and municipal divisions, were studied. The total size of the population surveyed was 410,367 people, including 134,756 Russians. In total, 385 patients from 281 families were registered among Russians of KCHR. Genetic load of AD, AR, and X-linked diseases (3.01 ± 0.32, 1.98 ± 0.26, and 1.23 ± 0.29, respectively) are more than twice higher in cities and municipal centers than in corresponding rural regions (1.00 ± 0.10, 0.89 ± 0.09, and 0.42 ± 0.09, respectively). The diversity of HD was 96 nosological forms: 56 diseases with AD type of inheritance (193 patients from 126 families), 28 clinical forms with AR (152 patients out of 124 families) and 12 diseases with the X-linked type of inheritance (40 affected from 31 families). A comparative analysis of the diversity of AD and AR HD with the previously studied populations and ethnic groups of the European part of Russia (Russians of 7 regions, 5 peoples of the Volga-Ural region, and 5 populations of the North Caucasus) was conducted, showing that Russians in the KCHR preserved genetic load with other Russian populations and its difference from the same mutation pool of Karachays and Circassians., Competing Interests: None.

Oculodentodigital dysplasia (ODDD) is a rare autosomal dominant disorder caused by mutations in connexin 43 gene GJA1. Typical features are syndactyly of IV-V or III-V fingers with/without feet syndactyly, anomalies of eyes, teeth, hair and nose. In about 30% of patients neurological disorders appear later in life: progressive spastic paraparesis, neurogenic bladder/bowel, ataxia, white matter lesions on MRI. First Russian DNA-confirmed ODDD cases are presented: 4 unrelated families with 5 affected women age 10-59 yrs. In addition to typical congenital anomalies all patients had neurological symptoms (mainly spastic paraparesis) with different age of onset. In three cases, preliminary diagnoses were hereditary neurodegenerations, only in one patient ODDD was recognized earlier. In GJA1 gene three novel mutations were detected: c.400_402delAAG (in two families), с.461C>T (p.Thr154Ile) and с.94T>G (p.Phe32Val). De novo origin of mutations in three sporadic cases was proved by parent DNA testing; in the familial case, the mutation in elder patient also obviously occurred de novo.

Congenital aniridia is a severe autosomal dominant congenital panocular disorder, mainly associated with pathogenic variants in the PAX6 gene. The objective of the study was to investigate the mutational and clinical spectra of congenital aniridia in a cohort of 117 patients from Russia. Each patient underwent detailed ophthalmological examination. From 91 unrelated families, 110 patients were diagnosed with congenital aniridia and 7 with WAGR syndrome (Wilms tumor, Aniridia, Genitourinary anomalies, and mental Retardation syndrome). The clinical presentation in aniridia patients varied from the complete bilateral absence of the iris (75.5%) to partial aniridia or iris hypoplasia (24.5%). Additional ocular abnormalities were consistent with previous reports. In our cohort, we saw a previously not described high percentage of patients (45%) who showed non-ocular phenotypes. Prevalence of deletions coherent with WAGR syndrome appeared to be 19.4% out of sporadic patients. Among the other aniridia cases, PAX6 deletions were identified in 18 probands, and small intragenic changes were detected in 58 probands with 27 of these mutations being novel and 21 previously reported. In 3 families mosaic mutation was transmitted from a subtly affected parent. Therefore, PAX6 mutations explained 96.7% of aniridia phenotypes in this study with only 3 of 91 probands lacking pathogenic variants in the gene., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The diversity of monogenic hereditary diseases (HDs) (autosomal dominant (AD), autosomal recessive (AR), and X-linked diseases) has been studied in five districts of Bashkortostan Republic: Burzyanskii, Abzelilovskii, Baimak, Salavatskii, and Arkhangel'skoe raions. The spectrum of HDs comprised 144 diseases, including 83, 48, and 13 Ad, AR, and X-linked diseases. Most of them were found earlier during studies in ten other regions of Russia (Kirov, Kostroma, Tver', Bryansk, and Rostov oblasts, and Krasnodar krai, and the republics of Adygea, Marii El, Udmurtia, and Chuvashia). Foci of local accumulation of some AD, AR, and X-linked diseases have been found in individual districts. Data on the gene frequencies for the HDs have been used for cluster analysis, which has shown the gene geographic position of Bashkirs among nine ethnic populations of Russia: Russians (Kostroma, Kirov, and Rostov oblasts and Krasnodar krai), Chuvashes (Chuvashia), Adygeans (Adygea), Maris (Marii El), Udmurts (Udmurtia), and Bashkirs (Bashkortostan).

Analysis of the diversity of monogenic hereditary diseases in eight raions (districts) of Rostov oblast (region) of Russia (Tsimlyansk, Volgodonskoi, Tselina, Egorlykskaya, Millerovo, Tarasovskaya, Rodionovo-Nesvetaiskaya, and Matveevo-Kurgan raions) has been summarized. The total sample size was 320925 subjects. The spectrum of hereditary diseases detected in the eight districts comprises 187 diseases, including 99 autosomal dominant (AD), 72 autosomal recessive (AR), and 16 X-linked diseases. The mean prevalence rate of each disease in the total population has been calculated. Accumulation of individual diseases in different regions of Rostov oblast has been calculated; the disease accumulation has been compared with that in some populations of Russia examined earlier. Cluster analysis using the data on the frequencies of genes of hereditary diseases has shown the gene geographic position of the Rostov oblast population among the following ethnic populations of Russia: Russians (Kostroma, Kirov, and Rostov oblasts and Krasnodar krai), Chuvashes (Chuvashia), Adygeans (Adygea), Maris (Marii El), and Udmurts (Udmurtia).

Here we present the data obtained during medical genetic examination of the population of five districts of Bashkortostan Republic (Burzyanskii, Baimakskii, Abzelilovskii, Salavatskii, and Arkhangelskii) populated with 168050 persons including 135748 Bashkirs. The study involved all the population of the districts including each ethnic group and was conducted according to standard protocol developed in the Laboratory of Genetic Epidemiology, Medical Genetic Research Center, Russian Academy of Medical Sciences. Based on segregation analysis, the values of prevalence rates of the major types of Mendelian pathology (AD, AR, and X- linked diseases) was calculated in five regions of the Republic as well as for Bashkirs alone. Significant differences in the prevalence rates of AD and AR pathologies between individual districts, in particular upon division in rural and urban population, was observed. The prevalence rates comparison of monogenic hereditary pathology among Bashkirs compared to other previously examined populations have shown that the patterns of the hereditary disease load in the inspected districts of Bashkortostan were similar to that observed in the population of some districts in Udmurtia, Marii El and Chuvashiya. Russian European populations have shown significantly lower load of hereditary diseases. Correlation analysis of local inbreeding, endogamy and prevalence rates of AD and AR pathologies has shown that development of hereditary diseases load is significantly affected by gene drift.

The efficiency of retinalamin was studied in 33 patients, aged 4 to 7, with 5 types of retinal abiotrophy. The experimental group comprised children with retinal abiotrophy of Franceschetti type (36%) and mixed type (39%). The pathological process was stabilized during 18 months in all cases of developed disease. The visual acuity improved in 82% of patients after treatment by retinalamin; visual fields enlarged and central scotomas reduced in 54% of cases. Parameters of elctroretinography improved in 37% of cases.

Comprehensive population genetic and medical genetic studies were performed in three raions (districts) of Chuvashia. The population of these districts is more than 90% Chuvash. About 70% of the families that completed reproduction had two or three children. The proportion of families with four or more children was 18%. The duration of generation was 27.6 years. The differential fertility and differential mortality indices in the Chuvash population were estimated at 0.33 and 0.076, respectively. The total index of differential selection was 0.403, which is typical of modern urbanized populations. Mean values of local inbreeding calculated from Malecot's model of isolation by distance were 0.00124 and 0.00377 for the urban and rural populations, respectively, of the districts studied. The prevalence rates of autosomal dominant (AD), autosomal recessive (AR), and X-linked diseases were found to be 0.47, 0.52, and 0.35 per 1000, respectively, in the urban population and 1.62, 1.14, and 0.31 per 1000, respectively, in the rural population. Significant correlation between the local inbreeding and prevalence rates of AD and AR diseases was found. A total of 43 AD and 43 AR diseases were identified. Some of them were not found in previous studies on other populations.

A summary of the medical genetic studies of the Marii El population is presented. A total of 276,900 people, 110,894 and 166,006 urban and rural inhabitants, respectively, were examined. Regarding the ethnic composition, the studied population was mostly Mari (61.96%) and Russian (32.04%). Medical genetic examination revealed 480 subjects from 260 families with autosomal dominant (AD) diseases, 234 subjects from 184 families with autosomal recessive (AR) diseases, and 49 subjects from 41 families with x-linked diseases. Segregation analysis revealed a good agreement between the expected and observed segregation frequencies for families with AR and AD diseases and allowed the frequency of hereditary diseases in the urban and rural, as well as the Russian and Mari, populations, to be estimated. The total frequency of AD diseases in Maris was approximately twice as high as in Russians (1.99 and 0.97%, respectively); substantial differences between district populations were found. The total frequency of AR diseases was also two times higher in Maris than in Russians (1.00 and 0.54%, respectively). The frequencies of AR and AD diseases in different districts were correlated with the levels of random and local inbreeding, population size, and the index of maximum selection.

The diversity of Mendelian hereditary pathology was studied in Marii El Republic. In total, 276,900 subjects, including 171,151 Maris and 88,714 Russians, living in seven raions (districts) were studied. Fifty-five autosomal dominant disease entities were found, with more than ten diseases having a frequency of 1:50,000 people or higher. In Maris, autosomal recessive hypotrichosis was observed at a relatively high frequency (1:15,337); this disease was not revealed in the Russian population studied earlier. Conversely, no phenylketonuria (PKU) was found in Maris, while it was a relatively common autosomal recessive disease in Russians. Regarding autosomal dominant pathology, 76 disease entities were revealed, with 21 diseases being observed at a frequency of at least 1:50,000. Ten X-linked diseases were found. The numbers of both autosomal recessive and autosomal dominant diseases exhibited a linear relationship with the number of subjects examined. The genetic structure of the Mari population was studied on the basis of data on the genes of recessive diseases. A matrix of Nei's genetic distances was calculated from the frequencies of 45 recessive diseases found in the seven districts studied. The average genetic distance calculated for the 45 loci of autosomal recessive diseases was 0.006175 x 10(-3). Similarly, matrix of genetic distances for five Mari populations was obtained (Medvedevskii and Zvenigovskii raions were not included) based on a total of 32 allelic frequencies for ten polymorphic immune and biochemical loci. The average genetic distance calculated from the ten polymorphic loci was 0.001930, i.e., 2.5 orders of magnitude greater than the average genetic distance for recessive diseases. The matrices of genetic distances for the five Mari populations calculated from the gene frequencies for recessive diseases and for the ten polymorphic systems were largely similar to each other. Thus, the main elements of the genetic structure of the Mari population can be estimated on the basis of gene frequencies for hereditary diseases. In this case, the characteristics of individual populations, which are more or less isolated, and of their interaction are the same as in the case of studying genetic structure with the use of polymorphic biological markers.

A medical genetic study of Orshanskii, Morkinskii, Sovetskii, and Semurskii raions (districts) of the Marii El Republic was performed. The total number of subjects examined was 115,743. Meadow Maris and Russians accounted for the most part of the populations of the districts studied. A total of 147 families with presumably autosomal dominant (AD) pathology and 150 families with presumably autosomal recessive (AR) or X-linked pathology (270 and 169 affected persons, respectively) were revealed. Segregation analysis demonstrated a good agreement between the observed and expected segregation frequencies for both AR and AD diseases, as well as a considerable number of sporadic cases of presumably AD diseases. The incidence of hereditary diseases was estimated separately for different population groups. Significant differences in this incidence were revealed between the urban and rural, as well as between the Russian and Mari populations; the average incidence was 2.33 affected subjects per 1000 people. The incidence of AR diseases was significantly higher in Maris than in Russians (1.34 x 10(-3) and 0.82 x 10(-3), respectively). The populations studied exhibited a significant, high correlation between the incidence of AR diseases and the levels of random and local inbreeding. The incidence of X-linked recessive diseases was approximately the same as in Russian populations studied earlier. Its average value was 0.5 per 1000 men; the incidence in the Mari and Russian populations did not differ significantly. The higher AD incidence in the total population studied and the higher AR incidence in the Meadow Mari population compared to the populations studied earlier are discussed.

The population of Gornomariiskii raion, Marii El Republic, primarily made up of mountain Marii, was subjected to medical genetic examination. The size of the entire population is 54853. Estimates of hereditary pathology in urban and rural populations of the raion were obtained. They were 0.68 and 1.11, respectively, for autosomal dominant pathology (AD); 0.55 and 0.81 for autosomal recessive pathology (AR); and 0.45 and 0.20 for X-linked pathology. Twenty-two, 25, and six nosologic forms of autosomal dominant, autosomal recessive, and X-linked diseases were revealed, respectively. We attempted to compare the sample under consideration with previously studied Russian and Finnish populations for rare pathologic recessive genes.

The main purpose of this report is to present the nosological spectrum of hereditary diseases in 9 Districts of Kirov Province and to compare it with that studies earlier in other Russian populations. This comparison is undertaken in an attempt to define a "nucleus" of hereditary diseases in the Russian population studied. During this study 343 families with 546 affected were registered. The spectrum covered 55 different autosomal dominant, 14 autosomal recessive and 11 X-linked recessive hereditary disorders in the population under study. Some of these forms could be considered as common forms for the whole Russian population, because they were met in all Russian populations which were analysed. This conclusion is proved by the cluster analysis of genetic distances calculated on the basis of gene frequencies for autosomal recessive hereditary disorders.

Medical-genetic study was carried out in the population of Kirov Province (population size about 120.000). 203 families with 334 affected with hereditary disorders were registered. The correctness of pathology classification for the inheritance type was confirmed by segregational analysis. The load of hereditary diseases in the population was: 1.25 +/- 0.06 for autosomal dominant, 1.37 +/- 0.07 for autosomal recessive and 0.22 +/- 0.06 for X-linked recessive disorders. It is suggested that variability in the values of the load of autosomal recessive disorders is determined to the large extent by genetic structure of the population.

This report is one of the series of communications dedicated to medico-genetical description of the Adyg population in the autonomous national district. The peculiarities have been considered of the forms of hereditary diseases both in the Adyg and Russian populations neighbouring each other in the Adyg national district territory. It was inferred that the minimal distance between Adyg and Russian populations consists in the level of aggregation and variety of autosomal-recessive forms which depended on subdivision and the level of inbreeding in the populations studied.

Comparative analysis of the loads of hereditary diseases in two ethnically different populations coexisting in the Adyg national district was performed. The modes of inheritance of diseases studied were tested by segregational analysis. The results obtained demonstrated that the load of autosomal-recessive diseases in the populations of the Adyg national district is higher than that in Russian population, while the load of autosomal-dominant diseases is similar in two populations. This difference in the level of the loads appear to be connected with genetic structure of the populations studied. Regressional analysis of relations between loads and the level of inbreeding in the Adyg population showed the explicit interrelation between the load of autosomal-dominant diseases and the Fst correlation coefficient being 0.89.

Medical-genetic study of the population of Kostroma (the total size of the population analysed approx. 250,000) was carried on. The load of hereditary diseases in the population (per 1000) was 0.75 for autosomal dominant, 0.49 for autosomal recessive and 0.17 for X-linked recessive disorders. Significant differences in the prevalence of autosomal recessive hereditary disorders between rural populations and the population of Kostroma were observed. The dependence of the load of autosomal recessive pathology on random inbreeding was shown for the whole Kostroma province.

The diversity of hereditary pathology in 5 regions of Kostroma district was studied. 32 nosological forms of autosomal dominant, 30 autosomal recessive and 7 X-linked recessive disorders were found. The most frequent autosomal dominant disorders were: neurofibromatosis, pigmentary degeneration of retina, hypochondroplasia, ichtiosis, idiopathic scoliosis. The most frequent among the autosomal recessive disorders were: oligophrenia, pigmentary degeneration of retina, muscular atrophy of juvenile Kugelberg--Welander type, congenital cataract. The most frequent X-linked disorders were: muscular Duchenne type dystrophy and hemophilia A. Analysis of mutant gene distribution over the territory by the study of birthplaces of probands and their parents was carried out.

Data on the prevalence of hereditary diseases in five regions of the Kostroma province were obtained and analysed. 28 autosomal recessive, 25 autosomal dominant and 4 X-linked recessive disorders were found. Segregation analysis proved the rightness of the material subdivision, according to the type of inheritance. The load of hereditary diseases in five regions was: 0.86 +/- 0.09 X 10(3) for autosomal recessive, 0.97 +/- 0.1 X 10(3) for autosomal dominant and 0.36 +/- 0.09 X 10(3) for X-linked recessive disorders. The problems of prevalence of hereditary diseases connected with population structure is discussed.

Data on the prevalence of hereditary diseases in five regions of the Kostroma province were obtained and analysed. It was shown that the ascertainment was close to the truncate selection for the rural population and to the single selection for the urban population. Segregational analysis proved the rightness of the material subdivision, according to the type of inheritance. The load of hereditary diseases (for the registered forms) in the population was: 0.78 +/- 0.08 X 10(-3) for autosomal dominant, 0.75 +/- 0.08 X 10(-3) for autosomal-recessive and 0.54 +/- 0.1 X 10(-3) for X-linked recessive disorders. The dynamics of the load of hereditary diseases in the populations with different structure is discussed.

The diversity of hereditary pathology in Kostroma was studied. An attempt was made to classify all isolated cases by genetic and clinical analysis. 57 nosological forms of autosomal dominants, 41 autosomal recessive and 14 X-linked recessive disorders were found. The analysis of marriage distances in the whole population and in the families of the probands was carried out. The spectra of hereditary pathology in Kostroma and Kostroma Province were compared. The sources of the load of hereditary pathology in Kostroma are discussed.