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A cytogenetic survey of 475 patients in an institution for the mentally retarded is reported. The chromosomes of all patients were studied using both a non-banding and a G-banding technique in order to estimate the relative efficiency of the two techniques in detecting structural rearrangements of the chromosomes. A total of 57 patients was found to have a chromosome abnormality, including five with a balanced structural rearrangement. The contribution of chromosome aberrations to the etiology of mental retardation is discussed with special emphasis on the contribution of balanced structural rearrangements.

A cytogenetic survey of a population of 274 mentally retarded males on community placement is described. Thirty-five had an aneuploid chromosome constitution and five had the mar(X) syndrome. The range of clinical variation among the mar(X) probands and their affected relatives is described. Family studies were possible for four of the five mar(X) probands and in two families the mar(X) gene was apparently transmitted through a clinically normal male, suggesting that this type of male transmission may be a not uncommon phenomenon.

Cytogenetic abnormalities were discovered in more than half of 16 lymphoblastoid cell lines established from fragile X individuals and their relatives upon routine cytogenetic analysis of early passage cultures. Subsequently, a second series of lymphoblastoid lines was analyzed to determine if the aneuploidy was (1) a characteristic of lymphoblastoid cell lines derived from fragile X families or (2) a result of the use of cyclosporin A in the establishment of these lines. In the second series of 33 lymphoblastoid cultures, no aneuploid clones were found in the fragile X group, while two were detected in the control cultures, one in a line initiated with cyclosporin A and the other in a line established without cyclosporin A. We conclude that the abnormal clones in our preliminary series were not a characteristic of lines derived from fragile X families and probably not due to the use of cyclosporin A. However, the finding of chromosome abnormalities in a large proportion of lines during the first 3 mo of culture contrasts with previous reports of chromosome stability for the first 12–18 mo of cultivation and indicates that the chromosomes of lymphoblastoid lines should be monitored in any experiment in which a normal diploid complement is critical.

Eighty-one probands from an initial population of 223 school-aged retarded individuals were assessed by history, clinical examination and, where appropriate, cytogenetic analysis. In 51 individuals, the retardation occurred as an isolated event within the family, whereas 30 patients had a family history of retardation. In 39 of the isolated individuals, the retardation was either related to environmental factors or associated with a major neurological abnormality. The remaining 12 patients were phenotypically normal with no cytogenetic abnormality. Of the 30 probands from 15 families with a history of retardation, 3 families had X-linked syndromes. One, with 4 proband daughters, had the mar(X) syndrome and two families were considered to have the phenotypically similar syndrome but without demonstrating the mar(X). In an additional 5 families, the distribution and clinical features of the affected individuals were compatible with nonspecific X-linked mental retardation.

We performed chromosomal analysis of a primary testicular tumor from an individual who, on subsequent analysis of peripheral blood, was found to have a balanced (13q14q) translocation. Histologically, the tumor was a mixed germ cell neoplasm, predominantly embryonal carcinoma, with some teratomatous elements. The modal chromosome count of the tumor cells was 62, with most counts ranging from 54 to 66. In addition to a t(13q14q) chromosome (of constitutional origin), nine nonrandomly acquired chromosomal abnormalities were identified, including an abnormal chromosome #1 and a probable i(12p). These findings are further discussed and compared with cytogenetic data on human testicular neoplasms from the literature. This case is also discussed with regard to the possible association of a constitutional t(13q14q) and various malignancies and related disorders.

We report an oriental family with sex-linked mental retardation, macroorchidism, and a marker or fragile site on the X chromosome--mar(X)(q28). The three affected males resemble clinically most previously reported affected Caucasians. The marker was present in four female 40-70 years old, including one with normal intelligence. Transmission of the disorder appears to have taken place through a clinically normal male to his grandson.

Sixteen patients with unusual heteromorphisms involving alterations of the length and/or position of centromeric heterochromatin are described. Family studies showed that the heteromorphisms were present in other relatives and segregated in the expected 1:1 ratio. There was a significantly greater frequency of unusual heteromorphisms among Orientals than in other races studied.

Three populations of retarded individuals were surveyed and the frequency of the fra (X) was found to be 1.9% in males and 0.3% in females.

Heteromorphisms of chromosomes 3, 4, 13-15, 21-22, and Y were studied in a population of 374 mentally retarded patients from diverse ethnic groups. A significant variation in the size of the Y chromosome was found among different racial groups, those of the Orientals and Filipinos being larger than those of the Caucasians or Polynesians. No other significant variation was found among the different racial groups, although suggestive differences were seen in bands 3 cen, 13p3, and 14p3. Band 13 cen/pl was significantly larger in the category of socio-familial retardation than in the other two categories. However, as the significance was at the 0.05% level and as this was the only heteromorphism whose distribution was different among the three categories of mental retardation, we assign little importance to this observation.

Seven families with X-linked mental retardation (MR) have been studied clinically and cytogenetically. All affected males in six of the families were found to have a fragile site on Xq in a number of their peripheral lymphocytes. The fragile site was not seen in any of the affected males in the seventh family. The affected males in the six families with the fragile X had a syndrome characterized by a variable degree of MR, macro-orchidism, a characteristic repetitive, jocular speech, normal body proportions, and large jaws and ears. The fragile X chromosome could only be detected in a proportion of female carriers and its frequency in females was found to be correlated with their mental status to be inversely correlated with their age.

Caffeine has been reported to enhance the expression of the fragile X [fra(X)] and common fragile sites in peripheral blood lymphocyte cultures (PBLC) treated with 5-fluorodeoxyuridine (FUdR). One of the effects of caffeine on replicating cells is inhibition of DNA repair suggesting that fragile sites may be regions of DNA with a high rate of misreplication under the conditions of thymidylate stress induced by FUdR. We have studied the effect of caffeine on the expression of the fra(X) and common folate-dependent fragile sites in PBLC from two fra(X) expressing individuals and in five lymphoblastoid cell lines (LCL) established from individuals in families in which the fra(X) is segregating. Caffeine did not enhance the expression of the fra(X) in the PBLC or in the three LCL from fra(X) expressing individuals nor did it elicit fra(X) expression in LCL from a non-expressing obligate-carrier female and a transmitting male. However, in all cultures there was a marked increase of common fragile site expression due to caffeine treatment. These data suggest that the mechanism of expression of the common fragile sites and the fra(X) may be quite different.