Abstract: In the present study we examined cells from several patients clinically diagnosed as having ataxia-telangiectasia (AT), for the capacity of their cells to inhibit DNA synthesis following exposure to gamma irradiation, and for the rate of spontaneous or blcomycin-induced chromosomal aberrations. Cells from two patients showed normal inhibition of DNA synthesis and levels of induced chromosomal aberrations intermediate between normal and AT cells. These two patients had only minimal immunologic impairment. These findings appear to define one distinct subset of AT.

Abstract: It is considered axiomatic in human genetics that the study of relatively rare disorders may yield far more in dividends than might be anticipated based on the incidence of the condition in question. This has clearly been demonstrated in studies of human steroid sulfatase deficiency and the steroid sulfatase system during the past few years. Investigations of this infrequent human variation have led to expanded studies of sulfated steroid metabolism, the physiological control of epidermal keratinization, estrogen biosynthesis in pregnancy, testosterone biosynthesis, and the molecular mechanism of X-chromosome inactivation and the escape of inactivation of certain portions of the human X. In addition, the availability of a readily scoreable marker for the distal human short arm provides the potential basis for a number of observations regarding X/Y interchange involving this portion of the X and has raised a number of evolutionary issues as well. Further studies may help clarify several of these questions and substantially add to our understanding of a variety of human X-chromosome disorders, such as X aneuploid states, XX males, and true hermaphrodites.

Abstract: Techniques in molecular biology and genetics have made it possible to systematically study gene effects in human disease. The number of gene clusters specifically encoding human brain structure and function is probably about 1,600 or half of all clusters. Evolutionary effects such as linkage disequilibrium and conservation of exons (DNA encoding structural proteins) as well as the fact that there are a tractable number of gene clusters involved, tend to make it quite likely that DNA pathology or DNA variation (polymorphism) predisposing to mental illness can be detected. Genes involved in mental illness can be detected either by studying DNA obtained from blood samples (genomic DNA) directly or by the analysis of mRNA and proteins from suitable cell or tissue preparations. The study of gene expression in the human brain is still in its infancy, nevertheless there are some hints that non-poly-adenylated mRNAs may be important in brain development and certain transcribed sequences may have a specific role in gene expression of the brain. The advantage of studying genomic DNA by the use of linkage and association analysis in multiply affected families is that it will, in the end, almost certainly yield a positive result for a disease with a substantial genetic input. Analysis of gene products from tissues such as brain could in theory detect specific disease genes but the approach will also identify genes secondarily affected by the disease process. Differentiation of genes that are primarily causing mental illness from those that are secondarily affected can be carried out by using such candidate genes as linkage markers in multiply affected families.

Abstract: Within the last decade linkage analysis has become one of the most useful tools in the human genetics arsenal and is beginning to make substantial contributions in all areas of medicine. Its increasing popularity is a direct result of the burgeoning number of polymorphic markers that are now mapped to specific chromosomal locations. Within the near future the entire human genome is likely to be saturated. This paper is intended as an introduction to linkage analysis for non-geneticists. Basic methodological approaches, along with their strengths, weaknesses and assumptions are reviewed. A subsequent paper will critically review methodological difficulties in the application of linkage analysis to the psychiatric disorders.

Abstract: Cytogenetic studies have been performed in over 4,000 couples with antecedent spontaneous foetal loss (1068 couples reported by Fryns et al. 1984; 3,500 couples in 55 studies summarised by Schwartz and Palmer 1983) and no complex chromosome re-arrangements (CCR) involving three or more chromosomes were reported. Our case was a phenotypically normal twice married female aged 28 years, who had sustained five first tr imester spontaneous abortions, one second trimester abortion, and one stillbirth. There were no living children. Rout ine endocrine investigations were normal; gynaecological tests showed an ovarian cyst. Cytogenetic analysis revealed a CCR which was apparently balanced involving chromosomes 3, 5, and 11--46,XX,t(3;5;11)(3q13;5q35; 11q14) shown in Fig. 1. Both parents had a normal karyotype and the family history was unremarkable . Kleczkowska et al. (1982) reviewed the literature on 39 CCR and the most frequent cause for referral was a child with multiple congenital malformations. We could find only one case report of a CCR detected through a proband presenting with a history of repeated abort ion (Meer et al. 1981) and in this case the CCR was familial. Ours appears to be the second such case and is de novo. We would be interested to hear of any similar cases in abortion.

Abstract: The origin of the small extra chromosome in the cat eye syndrome (CES) has been repeatedly disputed (Feldman and Sparkes 1978; Guanti 1981; Schinzel et al. 1981a,b). Nevertheless, most authors have assumed that it is derived from a chromosome 22. Most valuable evidence for its origin came from cases with partial trisomy due to familial translocation. In 1972 two cases of atypical CES (lacking coloboma in both, and anal atresia in one) with partial trisomy 22 due to a familial rearrangement were reported (Biihler et al. 1972). This report was the first one presenting evidence for familial partial trisomy 22, thus almost every paper discussing the subject afterwards referred to it. Since the cytogenetic investigation of this family was performed at the beginning of the banding era, the elucidation of the chromosomal rearrangement was not possible. Recently, we had the opportunity to reexamine the index patient and her mother, the latter with high resolution banding. We think it is useful for the further discussion of the \"cat eye story\" to present our observation. As shown in Fig. 1 the mother has a balanced reciprocal translocation between chromosomes 10 and 22. Breaks have occurred in band q12, probably in subband q12.1 (or 2) of chromosome 22 and in subband q26.2 of chromosome 10, resulting in a karyotype: 46,XX,t(10;22)(q26.2;q12.1). The proposita inherited from her mother, in addition to the normal chromosome 10 and the normal chromosome 22, the derivative chromosome 22 resulting in partial trisomy 22 (pter--~q12.1) and partial trisomy 10 (q26.2--~qter). Out of the 81 metaphases examined 72 had 47 chromosomes including the der(22) while the remaining nine cells had 46 chromosomes, one of the chromosomes 22 being replaced by the der(22). The patient is now, at the age of 151/12 years, a mentally retarded girl with an IQ of 65. Her height is 158 cm and her weight is 52 kg. In addition to the anomalies reported in the original paper (Btihler et al. 1972), she now has thoracic kyphosis as well as pulmonary hypertension. Unfortunately, we could not examine the mother's brother, the second patient reported in the original paper, II-3 in the pedigree. According to the present cytogenetic examination with prometaphase banding, the index patient showing many features of CES but lacking ocular coloboma and anal atresia is trisomic for chromosome 22pter--~q12.1, viz. for a longer piece of 22 than was assumed previously (pter--->qll), and for chromosome 10q26.2--~qter. Restudying other cases with high

Abstract: The RT1.B/D region-associated molecules were isolated and characterized by immunochemical means, utilizing three different rat monoclonal alloantibodies (HOK7, HOK12, and HOK33). The inbred rats employed in these experiments and their respective RT1 .B and RT1.D haplotypes are described in Table 1. Inbred rats were obtained from the Institute for Animal Experiment, Hokkaido University School of Medicine. The recombinant rats, WRC, were obtained from the Department of Pathology, University of Pittsburgh School of Medicine. (WKAH x WRC) F2 homozygous rats (K.WRC, RT1 rt2) were bred in our institute. Three cytotoxic monoclonal antibodies (MoAbs), HOK7 (IgG2b), HOK12 (IgM), and HOK33 (IgG2b), were obtained from hybridomas created by fusing mouse myeloma cells, P3-X63-Ag8, with splenocytes from ACI (RT1 a) rats which had been immunized using cells from WKAH (RT1 k) rats. Antibody HOK7 has already been described by Natori and co-workers (1983). Immunoglobulins were isolated from the hybridoma culture supernatant and were coupled to cyanogen bromide-activated Sepharose 4B (Pharmacia Fine Chemicals, Uppsala, Sweden) at a gel concentration of 3-5 mg/ml. Partially purified Ia-like glycoproteins, described fully in the report by Natori and co-workers (1983), were used in the experiment. NP40-solubilized, concanavalin A (Con-A)-bound glycoprotein fractions of KNL14 cells (a rat B-cell leukemia line carrying RT1.AkB/D k antigens) were subjected to further chroma-

Abstract: We describe clinical features and laboratory findings in a physically and mentally retarded male with under-developed testes, a seemingly monocentric isochromosome of Yq but the presence of a Yp-specific DNA sequence at a single dose of unknown genomic localisation, and the presence of H-Y antigen at normal male titer. Our data contribute to the fine mapping of the human Y chromosome by correlating phenotypic features with results from karyotypic, immunologic, and molecular hybridisation analyses.

Abstract: Vidgoff (1984) in a short communicat ion to your journal, suggested that the excess of paternal meiot ic errors in human Turner individuals, the approximate 3 :1 ratio of x M o to x P o (Race and Sanger 1975), could be predicted f rom bias of ascertainment favouring detection of paternal meiot ic error. Sanger et al. (1971), whose results are quoted in full by Race and Sanger (1975), were aware of this bias and applied the formula of Fraser (1963) to 234 X O families giving the answer of about 77% x M o and 23% x P o ; the same as the percentages when calculated after analysing a further 72 X O families (San-

Abstract: The pattern of inheritance of several X polymorphic markers is studied in the pedigree of a 46,XX true hermaphrodite. The results of the Xga, 12E7, and G6PD segregation analysis favour the hypothesis of a preferential inactivation of the paternally derived X chromosome.

Abstract: A cytogenetic study of Khanty from the lower Ob river in West Siberia has detected a high frequency of the Y chromosome heterochromatin subtotal deletion—del(Y) (q12). This morphologically identical deletion was found in 32 of 154 males examined (20.8%). The carriers had 10 different surnames. Taking into account the small size, isolation by distance, and historical pecularities of the surname formation of the population, it has been concluded that the high frequency of the del(Y)(q12) results from the genetic drift of the marker chromosome.

Abstract: From the study of two cases of 13qter-Y translocations (Pfeiffer et al. 1982) and additional observations of various structural aberrations of chromosome 13 (Ott and Pfeiffer 1984), we conclude that clotting factors VII and X are coded by closely linked genes located at 13(q34). This finding was confirmed by de Grouchy et al. (1984). We report its diagnostic use. The patient (SG 800216) is the only child of healthy unrelated parents. Paternal age was 28 years; maternal age was 23 years. Pregnancy was uneventful. Birth weight at term was 2650 g; length was 48 cm; HC was 33 cm. At the age of 7 months the patient was examined because of microcephaly and psychomotor retardation. Computed tomography of the brain showed mild dilatation of the subarachnoid spaces, particularly over the frontotemporal parts. When she was first seen at the age of 3.3 years, craniofacial dysmorphy suggested 13qsyndrome but routine cytogenetics failed to support this diagnosis. Coagulation studies, however, showed a significant decrease of factor VII and X activities. Acute lymphoblastic leukemia (CALL) was noted. During remission reduction of factor VII and X activities was again noticed (Table 1). Meanwhile RBG banding of late proFig. 1

Abstract: The report by Wahlstr6m et al. (1985) represents the first in vivo observation of intraindividual Y-chromosome heteromorphism in man. Since in their observation the paternal Y chromosome was not commensurate in length with either of the two Y-chromosome types in the proband, the authors invoke a somatic event, involving unequal sister chromatid exchange, in an early postzygotic division as the explanation of their findings. Although this hypothesis cannot be proven, the concept of intraindividual Y-chromosome heteromorphism arising from unequal mitotic exchange is supported by two kinds of additional evidence from in vitro studies: The first of these concerns the induction, via mitomycin C treatments, of intra-individual Y-chromosome heteromorphism in human diploid fibroblast cultures (Hoehn and Martin 1973). A number of clones arising after 24 h exposures to the bifunctional alkylating agent displayed de novo heteromorphisms of constitutive heterochromatin, including examples of Y-chromosome heterochromatin amplification. The second line of evidence, as yet unpublished, concerns observations made during the course of an investigation of Bloom syndrome fibroblast clones (Hoehn and Salk 1984). Of 100 colonies (covering an estimated 850 mitotic divisions) there were three independent clones in which all metaphases showed substantial diminution of Y-chromosome heterochromatin. These findings are illustrated in Fig. 1 which depicts partial karyotypes of the original (a) Bloom syndrome strain GM 1492 (having a rather large Y chromosome), and an example each (b-d) of the clones showing distinctly altered Ychromosome lengths, evidently resulting from heterochromatin diminution. Since Bloom syndrome cells are known to exhibit intrinsically elevated levels of mitotic exchange, the high frequency of de novo heteromorphisms observed in these clonal derivatives of the Bloom strain is not unexpected. Both the in vivo data reported by Wahlstr6m et al. (1985) and the in vitro data summarized in this letter support the hypothesis that unequal mitotic exchanges engender the variant distribution of constitutive heterochromatin encountered in our species (Kurnit 1979; Miklos and John 1979).

Abstract: The significance of germ-line and somatic genetic changes to the etiology of cancer has been a subject of continuing interest for cancer cell biologists Recognition of certain basic principles of cancer cell genetics such as the clonal nature of tumors and their dynamic genetic systems were the early results of these studies, which mainly related to chromosomes in tumor cells Recent advances in techniques of chromosome analysis and the integration of tumor cytogenetics with immunology and molecular genetics have permitted extraordinary insights into the nature of the perturbations that gene structure and function undergo in cancer cells These developments have been reviewed here in so far as they address the central issue of cancer genetics, namely, the role of somatic and gerrn-line chromosome change in the origin and evolution of neopolastic cells