NOTE The report of the Committee without its annexes appears as Official Records of the General Assembly, Sixty-third Session, Supplement No. 46. The designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. The country names used in this document are, in most cases, those that were in use at the time the data were collected or the text prepared. In other cases, however, the names have been updated, where this was possible and appropriate, to reflect political changes. Scientific Annexes Annex A. Medical radiation exposures Annex B. Exposures of the public and workers from various sources of radiation INTROdUCTION 1. In the course of the research and development for and the application of atomic energy and nuclear technologies, a number of radiation accidents have occurred. Some of these accidents have resulted in significant health effects and occasionally in fatal outcomes. The application of technologies that make use of radiation is increasingly widespread around the world. Millions of people have occupations related to the use of radiation, and hundreds of millions of individuals benefit from these uses. Facilities using intense radiation sources for energy production and for purposes such as radiotherapy, sterilization of products, preservation of foodstuffs and gamma radiography require special care in the design and operation of equipment to avoid radiation injury to workers or to the public. Experience has shown that such technology is generally used safely, but on occasion controls have been circumvented and serious radiation accidents have ensued. 2. Reviews of radiation exposures from accidents have been presented in previous UNSCEAR reports. The last report containing an exclusive chapter on exposures from accidents was the UNSCEAR 1993 Report [U6]. 3. This annex is aimed at providing a sound basis for conclusions regarding the number of significant radiation accidents that have occurred, the corresponding levels of radiation exposures and numbers of deaths and injuries, and the general trends for various practices. Its conclusions are to be seen in the context of the Committee's overall evaluations of the levels and effects of exposure to ionizing radiation. 4. The Committee's evaluations of public, occupational and medical diagnostic exposures are mostly concerned with chronic exposures of …

sources and effects of ionizing radiation

The work of Mary Lyon made us aware that half the human population is functionally mosaic with regard to their X chromosome (Lyon 1961). Normal women are made up of clones of cells, some with an active paternal X chromosome and others in which the maternal X is active. Perhaps it has been living with that reality for the past 27 years, without any apparent ill effect, that has made me comfortable with the concept that we may all be mosaic in other ways as well. Since the number of cells in the human body (1014) greatly exceeds the denominator of the mutation rate for almost all genetic disorders so far recognized, it seems likely that during the course of embryonic, fetal, and extrauterine life, virtually the entire repertoire of known mutations must occur within all normal individuals, giving rise to areas of somatic mosaicism that result from the clonal expansion of the mutated viable cells that arise during preor postnatal life. The mosaicism may result from chromosomal abnormalities (missing or extra chromosomes or parts of chromosomes), from single-gene mutations, or possibly from the incorporation of extrachromosomal DNA. This kind of change may occur as a postzygotic event in a single cell and then be passed on to daughter cells at any time during the development or lifetime of the individual (although a mutation leading to mosaicism could also occur at the half-chromatid stage, before fertilization [Gartler and Francke 1975; Lenz 1975]). The expected effects of somatic mosaicism would depend on a number of factors, including (1) the type of mutation (deletion, point mutation, etc.) that occurs, (2) the type of gene (housekeeping, structural, regulatory, etc.) in which it occurs, (3) the locus (or loci) at which the change occurs, (4) whether the mutation has led to het-

Review and hypotheses: somatic mosaicism: observations related to clinical genetics.

Small supernumerary marker chromosomes (sSMC), defined as additional centric chromosome fragments too small to be identified or characterized unambiguously by banding cytogenetics alone, are present in 0.043% of newborn children. Several attempts have been made to correlate certain sSMC with a specific clinical picture, resulting in the description of several syndromes such as the i(18p)-, der(22)-, i(12p)- (Pallister Killian syndrome) and inv dup(22)- (cat-eye) syndromes. However, most of the remaining sSMC including minute-, ring-, inverted-duplication- as well as complex-rearranged chromosomes, have not yet been correlated with clinical syndromes, mostly due to problems in their comprehensive characterization. Here we present an overview of sSMC, including the first attempt to address problems of nomenclature and their modes of formation, problems connected with mosaicism plus familial occurrence. The review also discusses the frequency of sSMC in prenatal, postnatal, and clinical cases, their chromosomal origin and their association with uniparental disomy. A short review of the up-to-date approaches available for sSMC characterization is included. Clinically relevant correlations concerning the presence of a specific sSMC and its phenotypic consequences should become available soon.

Small supernumerary marker chromosomes (sSMC) in humans.

The advent of microarray-based comparative genomic hybridization (array CGH) promises to revolutionize clinical cytogenetics because of its ability to rapidly screen the genome at an unprecedented resolution. Yet, the ability of array CGH to detect and evaluate low-level mosaicism is not known. Our laboratory has analyzed over 3,600 clinical cases with the SignatureChip which we developed for the detection of microdeletions, microduplications, aneuploidy, unbalanced translocations, and subtelomeric and pericentromeric copy number alterations. Here, we report 18 cases of mosaicism detected by array CGH in a routine diagnostic setting, 14 of which were not known to us at the time of the analysis. These 14 cases represent approximately 8% of all abnormal cases identified in our laboratory. For each case, fluorescence in situ hybridization (FISH) analysis was performed on PHA-stimulated cultures after mosaic chromosome abnormalities were suspected by array CGH. In all cases, FISH confirmed the mosaic chromosome abnormalities which included a variety of marker chromosomes, autosomal trisomies, terminal and interstitial deletions, and derivative chromosomes. Interestingly, confirmatory FISH analyses on direct blood smears indicated that the percentage of abnormal cells in unstimulated cultures was in some cases different than that found in PHA-stimulated cells. We also report the detection of a previously unsuspected case of an isochromosome 12p (associated with Pallister-Killian syndrome) by array CGH using genomic DNA extracted from peripheral blood. These results support a growing body of data that suggests that stimulated peripheral blood cultures likely distort the percentage of abnormal cells and may, for some chromosome abnormalities, make their detection unlikely by conventional analysis. Thus, array CGH, which is based on genomic DNA extracted directly from uncultured peripheral blood, may be more likely to detect low-level mosaicism for unbalanced chromosome abnormalities than traditional cytogenetic techniques.

Detection of low-level mosaicism by array CGH in routine diagnostic specimens.

Congenital diaphragmatic hernia (CDH) is a relatively common birth defect associated with high mortality and morbidity. Although the exact etiology of most cases of CDH remains unknown, there is a growing body of evidence that genetic factors play an important role in the development of CDH. In this review, we examine key findings that are likely to form the basis for future research in this field. Specific topics include a short overview of normal and abnormal diaphragm development, a discussion of syndromic forms of CDH, a detailed review of chromosomal regions recurrently altered in CDH, a description of the retinoid hypothesis of CDH, and evidence of the roles of specific genes in the development of CDH.

Genetic factors in congenital diaphragmatic hernia

Pallister-Killian syndrome is a dysmorphic syndrome characterized by a tissue-limited mosaicism: a majority of fibroblasts have 47 chromosomes with an extra small metacentric chromosome, whereas the karyotype of lymphocytes is normal. In this study, the interpretation of the extra chromosome as composed of two short arms of chromosome 12 is confirmed, using molecular methods. Furthermore, restriction fragment length polymorphisms indicate that the two arms are identical, which is compatible with the hypothesis of an isochromosome 12p. A new feature which may be important in understanding the mechanism of origin of the abnormality is described: the proportion of abnormal mitoses falls dramatically during long-term culture of fibroblasts.

Pallister-Killian syndrome: cytogenetic and molecular studies.

The Pallister-Killian syndrome (PKS) is characterized by tissue limited chromosomal mosaicism, i.e. the presence of a supernumerary metacentric chromosome [i(12p)] often confined to skin fibroblasts while the karyotype of cultured lymphocytes is normal. In the present study, chromosome painting by chromosomal in situ suppression (CISS) hybridization and interphase cytogenetic procedures employing biotinylated or digoxigenin labelled probes was carried out. These probes comprised a chromosome 12 specific library (LA 12NSO1) and chromosome 12 centromere specific α-satellite (pSP12-1). They were used to analyse and quantify the presence of i(12p) in lymphocytes, granulocytes/monocytes, skin fibroblasts and buccal mucosal cells from five patients and one aborted fetus with PKS, and ten normal donors. CISS hybridization on mitotic skin fibroblasts reliably indicated the presence of i(12p) cells, even when metaphases of poor quality were included in the analysis. Two of the five patients showed i(12p) in a small proportion (≤0.5%) of the cultured lymphocytes too. The interphase cytogenetics procedure did not reveal the isochromosome in lymphocytes or granulocytes/monocytes in any of the patients. Two of the six patients had a twofold increase in the number of buccal mucosal cells with three hybridization signals over control values. However, for mucosal cells, methodological improvements are required. For cytogenetic diagnosis of PKS, cultured fibroblasts subjected to chromosome painting by CISS hybridization with a chromosome 12 specific library probe are recommended.

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A. Ritvanen

Papers

Pallister-Killian syndrome: cytogenetic and molecular studies.

Molecular cytogenetic study of patients with Pallister-Killian syndrome