Clinical features and mental development of a child with a prenatally identified 45,XX,der(5)t(5;18) (p15;q11.2),-18 karyotype.

We present the clinical features and growth and development of a child with a 45,XX,der(5)t(5;18) (p15;q11.2),-18 karyotype. She had microcephaly, prominent, posteriorly rotated ears, short palpebral fissures with an upward slant, a wide nasal bridge, a thin upper lip, and a short neck. In addition, she had complex congenital heart disease. Although there has been delay in growth and development, she has shown progress in both areas.

Ethnic intermarriage and its consequences for cystic fibrosis carrier screening.

Cystic fibrosis gene mutations can vary in frequency between different ethnic populations. However, there is a rising trend of ethnic intermarriage in the United States, a situation suggesting that differences in specific mutation frequencies currently apparent in Europe may not persist for long in this country. Therefore, limited mutation screens targeted at specific ethnic groups and risk calculations based on data from more homogeneous European populations may not be appropriate in the United States. The genetic consequences of ethnic admixture are also likely to extend to other recessive diseases (e.g., Tay-Sachs, thalassemia), which, in the past, have been limited largely to particular ethnic, racial, or religious subgroups, with implications for public health agencies overseeing newborn screening programs for genetic diseases and for clinical genetics programs offering population-based carrier-detection programs, carrier risk assessment, and counseling.

Transfection of normal human and Chinese hamster DNA corrects diepoxybutane-induced chromosomal hypersensitivity of Fanconi anemia fibroblasts.

Cultured cells from individuals affected with Fanconi anemia (FA) exhibit spontaneous chromosome breakage and hypersensitivity to the cell killing and clastogenic effects of the difunctional alkylating agent diepoxybutane (DEB). We report here the correction of both of these DEB-hypersensitivity phenotypes of FA cells achieved by cotransfection of normal placental or Chinese hamster lung cell DNA and the plasmid pSV2-neo-SVgpt. Transfectants were selected for clonogenic survival after treatment with DEB at a dose of 5 micrograms/ml. At this dose of DEB, the clonogenicity of normal fibroblasts was reduced to 50% and that of FA fibroblasts was reduced to zero. DEB-resistant (DEBr) colonies selected in this system exhibited a normal response to DEB-induced chromosome breakage and resistance to repeated DEB treatment. The neo and gpt sequences were detected by Southern blot analysis of DNA from one of four DEBr colonies independently derived from transfection of human DNA and one of three DEBr colonies independently derived from transfection of Chinese hamster DNA. In addition, Alu-equivalent hamster sequences were detected in three of seven additional independently derived colonies from transfection of Chinese hamster DNA. The DEBr phenotype of these colonies was stably maintained over several subcultures. Our results demonstrate that DNA sequences that complement the two hallmark cellular phenotypes (cellular and chromosomal hypersensitivity to alkylating agents) of FA are present in human as well as Chinese hamster DNA. The cloning of these genes using transfection strategies can be expected to enable molecular characterization of FA.

Chromosome breakage in Fanconi's anemia and normal cells following in vitro and in vivo cocultivation.

Studies of Fanconi's anemia (FA) have been in conflict as to the existence of a clastogenic factor. Two male FA patients who received bone marrow transplants were studied. One FA patient received a transplant from his normal sister whose engrafted lymphocytes showed spontaneous, as well as diepoxybutane (DEB)-induced chromosome breakage in the normal range. The second FA patient received a transplant from his obligate heterozygous mother whose engrafted lymphocytes exhibited increased spontaneous chromosome breakage but not in response to DEB treatment. In vitro cocultivation of FA and FA heterozygous lymphocytes and of FA and normal lymphocytes showed chromosome breakage levels consistent with their genotypes. These results suggest that no detectable clastogenic factor is produced by FA cells.

Transformation of chromosome breakage syndrome fibroblasts by SV40 DNA transfection.

SV40 DNA was transfected into three Fanconi's anemia, two classical ataxia-telangiectasia, two variant ataxia-telangiectasia, three Bloom's syndrome, and three normal fibroblast cultures in order to study T-antigen expression, growth transformation, and survival of the crisis phase. Although Fanconi's anemia cells exhibited an initially higher frequency of uptake of transfected DNA compared with all the other cell strains studied, they did not acquire the transformed phenotype any faster than the others. Classical ataxia-telangiectasia fibroblasts, on the other hand, showed approximately the same rate of initial uptake of SV40, but were significantly slower than all other cell strains in expressing the transformed phenotype. The uptake and growth transformation properties of Bloom's syndrome and variant ataxia-telangiectasia cells were similar to those of normals. Serial subculturing of transfected cells was found to accelerate the appearance of growth-transformed cells. Although a number of transformed sublines of Fanconi's anemia, classical and variant ataxia-telangiectasia, and Bloom's syndrome strains apparently survived the crisis phase, no immortalized strains emerged from them.

Increased level of bleomycin-induced chromosome breakage in ataxia telangiectasia skin fibroblasts.

Ataxia telangiectasia (AT) is an autosomal recessive disorder in which increased level of chromosome breakage and specific sensitivity to radiation and carcinogens have been reported. The effect of the radiomimetic drug bleomycin on chromosome breakage has been tested in skin fibroblasts of three patients with AT, two AT obligate heterozygotes, two normal human controls, and one normal amniotic fluid cell culture. Bleomycin in two concentrations (1 and 5 micrograms/ml) was added for 1 hr and cultures were harvested 4 hr later. A significant increase in chromosome damage was found in AT fibroblasts: a higher number of total breaks per cell, affected cells, and breaks per affected cell was found. The heterozygotes did not differ significantly from the controls. Chromosome breakage in skin fibroblasts of AT patients after bleomycin treatment has not been reported before.

Prenatal diagnosis of Fanconi anemia.

Prenatal diagnosis was performed on a fetus at risk for Fanconi anemia. A high spontaneous (0.30 breaks/cell) and diepoxybutane-induced (0.69 breaks/cell) chromosome breakage rate indicated an affected fetus and the pregnancy was terminated. The anatomic findings in the aborted fetus together with cytogenetic findings in cultured fetal skin fibroblasts confirmed the prenatal diagnosis.

A diffusable clastogenic factor in ataxia telangiectasia.

Cocultivation of plasma and lymphocytes from ataxia telangiectasia (AT) patients with those of normal individuals resulted in a significant increase in chromosomal damage in the normal cells. Tissue culture medium used to cultivate AT skin fibroblasts also significantly increased chromosome breakage in PHA-stimulated normal lymphocytes. This clastogenic effect was maximal when the "conditioned medium" was 8-9 days old. A similar effect was not observed with medium derived from normal skin fibroblasts. These observations suggest the presence of a clastogenic factor in the plasma of AT patients which may also be produced by AT skin fibroblasts in culture.

Small marker chromosome mosaicism confirmed in two cases ascertained prenatally.

Two cases of chromosomal mosaicism were prenatally diagnosed and confirmed in tissues cultured from subsequently aborted fetuses. In both cases a small marker chromosome was observed which proved de novo in origin, since parental chromosomes were normal. The implications and interpretation of such findings in counselling families undergoing amniocenteses is discussed. Mosaicism for small marker chromosomes may be more frequent than hitherto suggested.

Cytogenetic evaluation of 500 Jerusalem newborn infants.

Cytogenetic investigations were carried out on cord blood lymphocytes of 500 normal healthy newborns. This population was divided into seven geoethnic groups according to the birthplace of the four grandparents of the infant. No numerical chromosomal aberrations were observed, but 10% of the individuals manifested cytogenetic variants. Six inherited structural abnormalities (four inversions and two deletions) were observed, while the remainder were classified as "minor variants." The chromosomal variants were randomly distributed among the population, and no particular variant was characteristic of a given subgroup.

Cytogenetic investigations in families with ataxia-telangiectasia.

Chromosomal studies were performed on peripheral blood lymphocytes and cultured skin fibroblasts from five Israeli-Moroccan families with ataxia-telangiectasia. A total of 24 individuals, including seven propositi, was investigated. Among the probands, significantly elevated rates of chromosome damage were observed in both blood and skin. Skin fibroblasts of affected individuals showed several orders of magnitude more chromosome breakage than lymphocytes. Increased rates of chromosome damage were also observed in the fibroblasts of some phenotypically normal family members (obligate heterozygotes and sibs) when compared to normal controls. An apparent abnormal clone of cells, possessing a large acrocentric marker chromosome (14q+), was observed in varying proportions among cells of all the propositi (2-5% of lymphocytes; 1-9% of fibroblasts).

Camphor plasmid-mediated chromosomal transfer in Pseudomonas putida.

Camphor-utilizing strains of Pseudomonas putida have been shown to carry the genetic information required for camphor degradation on a plasmid. The plasmid-carrying strains can serve as donors of both plasmid-borne and chromosomal genes. As recipients, plasmid-deleted strains are much superior to those carrying the camphor pathway genes. The transfer frequency of chromosomal, but not plasmid-borne, genes is markedly enhanced if the donor cells are irradiated with ultraviolet light followed by 3-h of growth on a rich medium in the dark. Recombinants selected for prototrophy are stable and most acquire the camphor (CAM) plasmid concomitantly; only a few of the Cam(+) recombinants inherit the donor's ability to transfer chromosomal genes at a high frequency. Transfer-defective mutations occur on the CAM plasmid, affecting both CAM and chromosomal gene transfer.