Statistical analysis of clone formation in cultures of human stem cells.

We performed a statistical analysis of clone formation from aneuploid cells (chromosomes 6, 8, 11, X) in cultures of bone marrow-derived human multipotent mesenchymal stromal cells by spontaneous level of aneuploidy at different terms of culturing (from 2 to 19 cell cycles). It was found that the duration of cell cycle increased from 65.6 h at passages 2-3 to 164.5 h at passage 12. The expected ratio of aneuploid cells was calculated using modeled 5, 10, 20 and 30% selective preference in reproduction. The size of samples for detecting 10, 25, and 50% increased level of aneuploidy was calculated. The presented principles for evaluation of aneuploid clone formation may be used to distinguish clones of any abnormal cells.

[Genetic safety of cellular therapy].

This paper presents the main results of the study on chromosome and genome variability of mesenchymal stem cell cultures from bone marrow and adipose tissue carried out in the Laboratory of Mutagenesis, Research Centre for Medical Genetics, over the last three years. Genome stability was assessed from DNA damage using the DNA comet assay, karyotyping and registration of aneuploidy by the FISH method. We found that DNA damage rate in MSC cultures from bone marrow was 3.9% and 3.8% at the early (2-5) passages and the late (10-15) passages respectively. The cultures were characterized by high dispersion of individual values. Karyotyping showed mosaicism in both types of MSC cultures at the early and late stages of cultivation. The fraction of abnormal cells in some cultures amounted to 80-90%. Evaluation of aneuploidy in interphase cells revealed 1.34% of aneuploid cells (on the average) per one "conventional" chromosome; their overall frequency in the genome amounted to 20-40%. The frequency of aneuploid cells was similar at the early and late passages. Cultures with clones of trisomic and monosomic cells were revealed. The probability of occurrence of abnormal cells may increase by virtue of de novo mutations in the culture and as a result of positive selection of the cells existing in the organism that exhibit a higher reproduction rate in culture. Based on the experimental data on mutational process, selection of mutant cells and clone formation, it is concluded that cytogenetic control of stem cells is necessary to ensure the safety of cellular therapy.

Methodological guidelines for genetic safety testing of cell transplants.

A combination of karyotyping and aneuploidy analysis by interphase fluorescent in situ hybridization is a sensitive method for evaluation of genetic stability of stem cell cultures. The methodology and specific features of preparing and analyzing the cytogenetic preparations are described as exemplified by human multipotent mesenchymal stromal cells.

Spontaneous aneuploidy and clone formation in adipose tissue stem cells during different periods of culturing.

Cytogenetic analysis of 13 mesenchymal stem cell cultures isolated from normal human adipose tissue was carried out at different stages of culturing. The incidence of chromosomes 6, 8, 11, and X aneuploidy and polyploidy was studied by fluorescent in situ hybridization. During the early passages, monosomal cells were more often detected than trisomal ones. A clone with chromosome 6 monosomy was detected in three cultures during late passages.

Cytogenetic analysis of peripheral lymphocytes in workers occupationally exposed to epichlorohydrin.

Peripheral lymphocytes of 3 groups of adult subject (28 workers occupationally exposed for 4 years to epichlorohydrin [ECHH], 34 matching controls and 21 subjects of the general population (control group) were cytogenetically analysed. In total, 11 806 metaphases were scored. The following frequencies of aberrant cells (bearing mostly chromatid and chromosome breaks) were detected in individual groups: ECHH-exposed group 3.12%; matching controls 2.06%; general population control group 1.33%. The results seem to indicate that even the concentration of 1 mg ECHH/m3 was capable of increasing the frequency of aberrant cells in the occupationally exposed group of workers.

System for the evaluation of the risk from chemical mutagens for man: basic principles and practical recommendations.

A testing system is recommended that permits (1) reduction in cost and time requirements, (2) analysis of gene and chromosome mutations in germ and somatic cells, (3) evaluation of mutagenic effects of a chemical substance and its metabolites, (4) guarantee of the minimal variability between separate experiments and (5) evaluation of the dose--effect relationship. The testing scheme has two parts, a screening system and a complete test system. The screening system consists of two tests: (a) test on microorganisms with a metabolic activation in vitro (or test on Drosophila) and (b) cytogenetic analysis of mammalian bone marrow. The complete test system includes 4 tests: (a) test on microorganisms with a metabolic activation in vitro and in vivo (or test on Drosophila), (b) dominant-lethal test on mammals, (c) cytogenetic analysis of mammalian bone marrow and (d) cytogenetic analysis of the culture of human lymphocytes. The decision whether the selected chemical substance is to be tested according to the screening or complete test system is based on: its occurrence in the population, its economic (or medical) significance, and on information concerning its mutagenic, carcinogenic or teratogenic effects. The group of chemicals to be tested according to the screening system involves: industrial chemicals, organophosphate insecticides, drugs used by a limited group of patients. The group of chemicals to be tested according to the complete test system consists of pesticides, food additives, drugs in general use as well as chemicals of the former group, if at least one of the screening system tests detected some genetic effect. Genetic risk estimation should be governed by the following considerations. A positive effect identified in any test of the testing system must have a direct bearing on man. Quantitative evaluation of mutagenic risk from a chemical substance can be determined by the increased level of spontaneous mutations in the most sensitive test on the basis of an average dose of, and exposure to, the given chemical substance in the human population. Chemicals showing a mutagenic activity in any of recommended tests are subject to the quantitative evaluation, they are usually widespread and because of their social or economic value they cannot be replaced or excluded. Genetic aspects require that any substance with a mutagenic activity be considered dangerous and its use should be prohibited or it should be replaced by another non-mutagenic chemical, or at least the contact with it should be limited to persons of non-reproductive age. From the hygienic aspect it is recommended, as a temporary measure, to evaluate a chemical mutagen and to prohibit or limit its use if its average population dose produces a 0.1% or greater increase in the spontaneous level of mutations.

[Chromosome aberrations in premature infant lymphocytes]. / Khromosomnye aberratsii v limfotsitakh nedonoshennykh detei

A cytogenetic investigation of a group of prematurely born babies was carried out during the first months of their life (at ages of 0 days, 5-7 days, 2-4 weeks), as well as of a group of infants born in proper time and having a normal weight. As it was shown by the analysis of chromosome aberrations, frequencies of aberrant cells in babies at ages of 0 days, 5-7 days, 2-4 weeks and in those that have endured some bacterial or viral infection were 1,96% (0.22 aberrations per cell), 3,38% (0,037 aberrations per cell), 4,92% (0,053 aberrations per cell) and 6,73% respectively. The role of infection of drugs in the increase of the frequency of aberrant cells is also indicated by the investigation of babies born in proper time and having normal weight, that have endured an acute respiratory disease. In this group of children the frequency of aberrant cells was 5,3%. However, it is impossible to assess the role of each of these factors separately, since their effect on the organism of prematurely born babies is simultaneous from the very moment of birth.

[Frequency of chromosome variants in human populations]. / Chastota khromosomnykh variantov v populiatsiiakh cheloveka.

Chromosome variants were analyzed in the course of the population chromosome investigation of 6000 newborns and clinical cytogenetic studies of 403 married couples with recurrent spontaneous abortions, stillbirths or offsprings having congenital malformations or Down's syndrome. The following variants were determined: 1) Igh+, 9gh+, 16gh+ - the enlargement of the secondary constrictions of the size, more than 1/4 of the long arm of the chromosome; 2) Dp+ or Gp+ - the enlargement of the short arms of acrocentrics, their size being more than the short arm of the chromosome 18; 3) Ds+ or Gs - large satellites of the acrocentrics which are equal or more than the thickness of the chromatids of the long arms; 4) Es+ - satellites on the short arms of the chromosomes 17 or 18; 5) Dss of Gss - double satellites; 6) Yq+ - the enlargement of the long arm of Y chromosome, the size of which being more than G chromosome; 7) Yq- - deletion of the long arm of Y chromosome, the size of the long arm being less than chromosomes 21--22. The total frequency of variants in newborns was 12.8/1000 births. The incidence of different types of variants per 1000 births was as follows: Igh+ - 0.33; 9gh+ - 0.17; 16gh+ - 0.50; Ds+ - 2.33; Dp+ - 1.50; Dp- - 0.17; Gs+ - 0.83; Gp+ - 2.17; Yq+ - 6.91/1000 males; Yg- - 0.99/1000 males; double variants - 0.33; other variants - 0.33. 4.0% of married couples with recurrent spontaneous abortions had major chromosome aberrations, 14.6% - extreme variants of chromosomes. Among 113 couples with the history of congenital malformations in their offsprings major chromosome abnormalities were found in 4.4%, chromosome variants - 13.3%. The frequency of chromosome variants among 139 patients with Down's syndrome was 7.2%. In one case Robertsonian translocation t(DqGa) was determined. The most frequent types of variant chromosomes were Ds+, Dp+, Es+, Yq+.

[Spontaneous and induced chromosome instability in patients with fragile X syndrome]. / Spontannaia i indutsirovannaia nestabil'nost' khromosom u bol'nykh s sindrom lomkosti X-khromosomy.

Spontaneous and degranol- and dimatiph-induced chromosomal instability in the lymphocyte culture of patients with fra-X syndrome was investigated. The cultures contained TC 199 and 5% FC serum. It was found that the frequency of spontaneous chromosomal aberrations (CA) was 7.3% in cells from patients with fra(X), 3.9% in patients with MR of unknown origin, and 1.3% in normal individuals. Spontaneous break-points in the patients with fra(X) were localized in 1p, 2q, 3p, 6q, 7q, 16 q more often than in normal individuals. No significant difference was found in SCEs. The cells of patients with fra(X) were not sensitive to the induction of CA by degranol. It was found that chromosomal telomeric changes (CTC) were mutagen-independent, remaining at the spontaneous level: in the patients with fra(X) CTC were 10.5% (9.5% fra-Xq27, and 1% autosomal telomeric changes); in normal individuals CTC were 0.1%.

[Individual variations in the frequency of chromosome aberrations following exposure to chemical mutagens. II. Interindividual variation in the frequency of chromosome aberrations in the presence of different mutagen concentrations]. / Individual'nye variatsii chastoty khromosomnykh aberratsii pri deistvii khimicheskikh mutagenov. Soobshchenie II. Mezhindividual'nye variatsii chastoty khromosomnykh aberratsii pri raznykh kontsentratsiiakh mutagena.

The object of this investigation was the distribution of human periferal blood cultured obtained from different donors with respect to their sensitivity to different concentrations of thiophosphamide (10, 20 and 30 mcg/ml for 1 hour). Two test characteristics were studied, "the proportion of aberrant metaphases" and "the number of chromosome breaks per 100 cells". It is shown that the distribution of individuals does not depend on the mutagen concentration, being normal in all the series of experiments. The same results were obtained when two different statistical methods were used, viz. the method of four moments and the chi-square test. Since the former method is less labour-consuming, the authors recommend it for fitting the normal distribution in cytogenetic investigations. The variances of the test-characteristics studies ("percent aberrant metaphases" and "total number of breaks per 100 cells") increased with the increase of the mean values. Therefore, before the analysis of variance and the regression analysis the cytogenetic data should be preliminary transformed for the purpose of stabilization of variances.

[Anomalies in the karyotypes of premature children]. / Anomalii kariotipa u nedonoshennykh detei

A cytogenetic investigation of two groups of prematurely born babies was carried out on the basis of the specialized department for prematurely born children in Moscow and in the Moscow Region. The material for this investigation was the culture of lymphocytes. In the first group comprising 607 prematurely born babies without any perceptible developmental defects abnormalities of the karyotype were observed in 15 probands (2.5%) which is 3.5 times higher than the frequency of karyotypic abnormalities among newborn babies from the same population born in proper time. In the second group comprising 70 prematurely born babies with various congenital malformations various karyotypic abnormalities were observed in 13 probands (18,6%), which is 8 times the frequency among babies from the same population born in proper time. The main type of abnormalities observed were those affecting the system of sex chromosomes and the cases of trisomy of the 21st pair of autosomes and structural abnormalities. The high proportion of X- and 21-trisomies among the chromosome abnormalities observed suggests their important role in the etiology of premature births and postnatal death-rate of mutant organisms having D- and E-trisomies and structurally unbalanced chromosomal aberrations.

[Chromosomal instability parameters in the population affected by nuclear explosions at the Semipalatinsk nuclear test site]. / Pokazateli nestabil'nosti khromosomnogo apparata u naseleniia, postradavshego v rezul'tate iadernykh vzryvov na Semipalatinskom poligone.

A population genetic survey of 149 persons who were born and have permanently lived in the contaminated zones of the Semipalatinsk region has been performed. A cytogenetic study has demonstrated that the frequency of aberrant cells is 1.7-3 times higher than control parameters. The total frequencies of chromosome aberrations are 3.43 +/- 0.48, 3.1 +/- 0.3, 1.8 +/- 0.2, and 1.15 +/- 0.17 aberrations per 100 cells in the populations of the extreme radiation risk (ERR), maximum radiation risk (MaxRR), minimum radiation risk (MinRR), and control zones, respectively. The high chromosome aberration rate in all three zones of radiation risk has been detected mainly due to radiation-induced chromosome markers, including paired fragments (1.2 +/- 0.2, 0.94 +/- 0.13, and 0.43 +/- 0.06 per 100 cells, respectively), dicentric and ring chromosomes (0.44 +/- 0.04, 0.45 +/- 0.07, and 0.11 +/- 0.02 per 100 cells, respectively), and stable chromosome aberrations (0.74 +/- 0.16, 0.8 +/- 0.1, and 0.63 +/- 0.13 per 100 cells, respectively). The qualitative spectra of the cytogenetic lesions observed in these groups indicate a mutagenic effect of ionizing radiation on chromosomes in the populations studied.

[Medico-genetic study of isolates in Uzbekistan. IV. Clinico-biochemical diagnosis of hereditary diseases]. / Mediko-geneticheskoe izuchenie izoliatov v Uzbekistane. Soobshchenie IV. Kliniko-biokhimicheskaia diagnostika nasledstvennykh boleznei

An exhaustive clinico-biochemical examination of the population of two kishlaks of the Samarkand Region, viz. Karakent (210 persons) and Ishan (248 persons) was carried out. The program of this examination permitted to exclude over 160 forms of hereditary pathology. A total of 45 persons affected with diseases belonging to 12 nosological forms were revealed in the course of the examination. Among the diseases observed only 5 are hereditary sensu stricto, viz. myoclonus-epilepsy, Bonevi-Ulrich's syndrome, imperfect osteogenesis, pigment choreoretinite and Down's syndrome, others belong to diseases with a pronounced hereditary predisposition. The main part of this group comprises neuro-psychic diseases, such as non-differentiated olygophreny (5.0%), epilepsy (1.3%), schizophreny; many of these cases have a familial character, particularly in Karakent. Besides the persons suffering from diseases, 20 heterozygous carriers of beta-thalassemia and 17 heterozygous carriers of G6PD-deficiency were discovered in the kishlaks examined. On the whole the frequency of the diseases revealed did not exceed the level in the general population. Despite the different degree of isolation of the kishlaks examined (Karakent is isolated on a religious basis, F = 0.0064; while Ishan is a desintagrated isolate, F = = 0.0014), no substantial differences between them in the distribution of pathological phenomena were observed. On the basis of the experience of this expedition recomendations are proposed concerning the origination and accomplishment of medico-genetic expeditions. A scheme is proposed for the performance of medico-genetic examination through several stages. The first stage in the composition of tentative maps of the distribution of hereditary diseases within a region on the basis of the information obtained from the medical personnel and from the examination of the documents of district and regional hospitals. Subsequently the primary information is specified, the regions to be examined are determined, as well as concrete tasks and the staff of the expedition. The conclusive stage is the medico-genetic examination proper, including clinical, biochemical, immunological and cytogenetic diagnoses of hereditary pathological phenomena. The place of the disposition is a village or a district hospital. More complicated laboratory studies should be performed on the basis of the institution by which the expedition is formed. The results obtained by such expeditions would be important for the investigation of the problems of genogeography, for the discovery of new forms of mutant alleles, for the investigation of the causes and the conditions of the formation of the definite populational structure, of clinical polymorphism of human hereditary diseases.

[A system for assessment of chemical substances on mutagenicity in man: general priniciples, practical recommendations and further elaboration]. / Sistema otsenki khimicheskikh veshchestv na mutagennost' dlia cheloveka: obshchie printsipy, prakticheskie rekomendatsii i del'neishie razrabotki

As a basis of the suggested test-system, the following conditions are observed: 1) the economy of fulfilment in a short time; 2) the analysis of gene and chromosome mutations in germ and somatic cells; 3) the evaluation of mutagenic effects of not only substance, but also of the products of its metabolism; 4) including in the system only the tests which give the minimal variability between separate experiments; 5) the evaluation of dose-effect relationship. The practical scheme of testing is divided into two parts: a screening and a complete one. The screening programme consists of two tests: a) a test on microorganisms with a metabolic activation in vitro; b) a cytogenetic analysis of bone marrow of mammals. The complete programme of testing includes 4 tests: a) a test on microorganisms with a metabolic activation in vitro and in vivo; b) a test of dominant lethal mutations on mammals; c) a cytogenetic analysis of bone marrow of mammals; d) a cytogenetic analysis in the culture of human lymphocytes. There are good reasons for the principles of selection of substance for testing according to the screening and complete programme: population occurence, economic (or medical) significance, information about relative chemicals showing mutagenic, carcinogenic and teratogenic effect. In the group of chemicals which are to be tested according to the screening programme, such ones can be included: industrial chemicals, phosphoorganic insecticides, drugs which are taken by a limited group of patients. The group of chemicals which are to be tested according to the complete programme consists of the following ones: pesticides, food additices, widespread drugs, the chemicals of the group 1, if during one of the tests of the screening programme a genetic effect is detected. At the genetic risk estimation it is advisable to keep to the following rule: a positive effect, identified in any object of the system must in the direct meaning extrapolate on men. The quantitative evaluation of the mutagenic danger of a chemical can be determined by the increase of the spontaneous level of mutations in the test-object on the basis of an average dose and exposition of the given chemical in the human population. Those chemicals are subject to the quantitative evaluation, which have shown a mutagenic activity during any of the test-objects; they are also widespread and because of their social or economic value can not be replaced or excluded from taking. From the point of view of genetics any substance with a mutagenic activity is dangerous and must be prohibited from using or replaced by any other non-mutagenic chemical, or limited by the contact of persons of non-reproductive age. As a temporary measure from a hygienic point of view, it is recommended to evaluate this chemical as especially mutagenic and prohibit or limit its using, when its average population dose produces 1/10 or more increase of the spontaneous level of mutations.

[A medico-genetic study of isolates in Uzbekistan. III. Results of a cytogenetic study]. / Mediko-geneticheskoe izuchenie izoliatov v Uzbekistane. III. Rezul'taty tsitogeneticheskogo obsledovaniia

The cytogenetic examination of the population of the villages of Karakent and Ishan consisted of two directions: the study on the frequency of chromosome aberrations in the culture of lymphocytes and the diagnostics of anomalies and variants of karyotype. The frequency of chromosome aberrations of 40 individuals was studied. It is shown that the frequency of cells with chromosome aberrations of the individuals in different villages does not differ and on the average is 1,4%. The distribution of lymphocyte culture according to the number of aberrations corresponds to that of theoretical Puassonian. Chromatide breaks are the main type of the aberrations. Among 250 karyotypically examined individuals no evident structure reformations were found. In the caryotype of a 7-year old girl trisomia of the 21st autosome was detected. On the basis of differential staining of chromosomes by Hiemse's dye 18 individuals (7,2%) were diagnosed to have insignificant changes in morphology of some chromosomes, considered as variants of caryotype. In the majority of cases these changes were of a family nature. On the medical examination mnay individuals were diagnosed to have different pathological features, though we did not succeed in revealing any correlation between a certain microanomaly of chromosomes and a pathological feature.

[Medicogenetic study of isolates in Uzbekistan. I. Statement of the problem and characteristics of the groups studied]. / Mediko-geneticheskoe izuchenie izoliatov v Uzbekistane. Soobshchenie I. Postanovka problemy i kharakteristika obsledovannykh grupp

The paper comprises results of studying some demographic and populaton characteristics of the inhabitans of the Samarkand region as a whole and two villages, Karakent and Ishan, inhabited with Uzbeks-Khoja, a special religious-social caste in the past. It is shown that 87.4% of marriages in the Samarkand region are of international character (the information has been obtained on 7995 married couples). The frequency of consanguineous marriages is 11.6%, and among them 40.5% are first-cousin marriages and 39.1% are marriages of remote relatives. The coefficients of inbreeding are rather high among the Jewish, Tajik and Uzbek communities. The coefficient of inbreeding as a whole is F=0.0042 in this region and approaches to the maximal level, characterizing a panmix population. The average size of a family in the villages of Karakent and Ishan is approximately 4.0 persons. The values of reproductive performance, the nature of termination of pregnancies do not differ from those of panmix population. The percentage of intravillage and consanguineous marriages are 56% and 12.5% for the first village, and 25% and 2% for the second one respectively. The coefficient of inbreeding for karakent is F=0.0064, for Ishan--F=0.0014. Taking into consideration the historical development of the two villages and the cumulative data, the conclusion is drawn that Karakent is an isolate on a religious ground whereas Ishan is a disintegrated isolate.

[Frequency of chromosome anomalies in children dying in the perinatal period]. / Chastota khromosomnykh anomalii u detei, umershikh v perinatal'nyi period

348 different tissues were sampled for cultivation from 300 infants perinatally, died: a) from 118 fetuses, died at the antenatal period, 143 samples of four types of tissues were taken (kidney type -27, skin type-10, gonad type-74, blood type -32); b) 72 samples of blood and 13 samples of gonad were taken from 75 fetuses died at the intranatal period; c) 120 samples (blood type -86, gonad type -86) were taken from 97 newborn infants, died at the early neonatal period. Positive results of the growth of cultures were found in 46% (15.4% -from antenatally dead fetuses, 71.8% -intranatal deaths of infants, 64.2% -early mortality of the newborn). Among the 22 antenatally dead infants 3 appeared to have chromosome anomalies (13.6%); 1) 47, XY, +22; 2) 69, XXX; 3) 46, XX/46, XY. Among 61 intranatally dead infants 3 were found to have karyotype anomalies (4.9%): 1) 47, XX, +18; 2) 47, XY, +21;3) 46, XX/46, XY. 5 (6.5%) of the 77 newborn, dead in the first days after parturition, had the anomalies of the following types: 1) 45, XO; 2) 47, XYY; 3) 47, XY; +13; 4) 47, XY, +21; 5) 46, XX, 13q-. The total frequency of chromosome anomalies among 160 perinatally dead infants was 6.9%.

[Chromosomal abnormalities in lymphocytes from a patient with Werner's syndrome in intact culture and after treatment with halogenated analogs of thymidine]. / Khromosomnye anomalii u bol'nogo sindromom Vernera v intaktnoi kul'ture limfotsitov i posle vozdeistviia galogenovykh analogov timidina.

Four balanced chromosomal translocation, deletion of chromosome 15, and a break in chromosome 11 were detected in 100 G-banded metaphases of cultured lymphocytes of a patient with Werner's syndrome. We observed aneuploidy that included both trisomies and monosomies for various chromosomes. Halogenated analogs of thymidine in low doses increased significantly the incidence of chromosome aberrations accompanied by fragments. 5-Iododeoxyuridine induced lesions in centromeric regions of B-group chromosomes in 44.4% of all the cases of breaks. A hypothesis is proposed about the existence of a special mechanism for genetic control in changes in the cell nucleus and mitotic chromosome transformation. This mechanism can be manifested after the application of halogenated analogs of thymidine. The mutation involved in Werner's syndrome is presumably related to this mode of genetic control.

[Phenotype and "critical segments" of chromosomes during partial aneuploidy for chromosome 4 in man]. / Fenotip i "kriticheskie segmenty" khromosom pri chastichnykh aneuploidiiakh po khromosome 4 u cheloveka.

Computerized analysis of sparse matrix, based on the list of involved organs, body parts, extremities, function etc. (total item number about 600) was performed for different cytogenetically identified anomalies of human chromosome 4 (35 cases of 4p-, 32 cases of 4p+, 39 cases of 4q-, 39 cases of 4q+; both published and original data were used). For each of the four types of partial aneusomy, 4 specific enough groups of traits were revealed which had been found in 50% of respective patients, at least. Such "nuclei" of traits were highly similar to those given in comprehensive modern manuals. However, 4p- and 4q- could only be classified as strictly enough delineated chromosomal syndromes. The 4(p14-pter) region was found to be the most likely crucial segment for the Wolf-Hirschhorn syndrome.

[Langer-Giedion syndrome and deletion in the long arm of chromosome 8]. / Sindrom Langera-Gidiona i deletsiia dlinnogo plecha khromosomy 8.

Del(8) (q24.11-q24.13) were detected in 3 patients with typical Langer-Giedion syndrome (LGS) and studied by high-resolution methods. Analysis of the literature strongly suggests the chromosomal ethiology of the LGS, because in all patients examined in detail a deletion of the segment 8(q24.11-q24.13) was revealed, which is critical for the LGS. Interrelationships between the LGS and two monogenic conditions-tricho-rhino-phalangeal syndrome type I and multiple exostoses are discussed. The possible role of c-myc oncogene in exostoses' (including those in LGS) origin is anticipated.