Beta amyloid gene duplication in Alzheimer's disease and karyotypically normal Down syndrome.

With the recently cloned complementary DNA probe, lambda Am4 for the chromosome 21 gene encoding brain amyloid polypeptide (beta amyloid protein) of Alzheimer's disease, leukocyte DNA from three patients with sporadic Alzheimer's disease and two patients with karyotypically normal Down syndrome was found to contain three copies of this gene. Because a small region of chromosome 21 containing the ets-2 gene is duplicated in patients with Alzheimer's disease, as well as in karyotypically normal Down syndrome, duplication of a subsection of the critical segment of chromosome 21 that is duplicated in Down syndrome may be the genetic defect in Alzheimer's disease.

Aniridia, male pseudohermaphroditism, gonadoblastoma, mental retardation, and del 11p13.

A 20-month-old male patient was referred because of severe growth and mental retardation, bilateral glaucoma, hypospadias, and cryptorchidism. Karyotyping revealed a de novo complex three-chromosome rearrangement as well as deletion of band 11p13:46,XY,t(4;7;15)(q212;p14;q26),del(11) (p13p14). Trabeculectomia revealed bilateral aniridia. Surgery on the genitalia revealed male pseudohermaphroditism and bilateral gonadoblastoma. The kidneys were normal. A deficiency in catalase (CAT) activity allowed the regional assignment of the CAT gene to band 11p13.

Rett phenotype with X/autosome translocation: possible mapping to the short arm of chromosome X.

Rett syndrome (RS) was diagnosed in a girl with a t(X;22) (p11.22;p11). This translocation was also present in her unaffected mother and her sister affected by a neurological disorder compatible with a "forme fruste" of RS. Different etiological mechanisms are considered: gene disruption, X inactivation disturbance, metabolic interference. Whatever this may be, the localization of a RS related gene to the short arm of chromosome X is likely.

Molecular detection of constitutional deletions in patients with retinoblastoma.

The recent cloning of the retinoblastoma (RB) gene as well as the identification of intragenic polymorphisms afford the necessary tools for the analysis of rearrangements using molecular hybridization. We searched for constitutional deletions by Southern blotting in 67 independent patients with normal karyotype comprising 15 familial and 52 sporadic cases. Among the latter, 33 were bilaterally and 19 unilaterally affected. We detected 6 deletions using cDNA probes covering almost all of the RB gene, as well as a genomic probe of the 5' part of the gene. With this approach, the incidence of detectable deletions was around 10%. No hot spots for deletion breakpoints were found. Asymptomatic carriers were detected in 2 families. The effectiveness of genetic counselling was largely improved by this approach.

Multibranched chromosomes in the ICF syndrome: immunodeficiency, centromeric instability, and facial anomalies.

A new patient with the rare ICF syndrome (immunodeficiency, centromeric heterochromatin instability, and facial anomalies) is reported. The six patients previously reported in the literature are reviewed. The main clinical and cytogenetic characteristics of the syndrome are discussed.

Retinoblastoma, deletion 13q14, and esterase D: application of gene dosage effect to prenatal diagnosis.

Esterase D (ESD) gene dosage studies were performed on amniotic cells from a fetus at risk for del 13q14. The mother was a balanced carrier of an insertion in chromosome #20: 46,XXins(20;13)(p12;q1307q14.3). She had already given birth to a monosomic child with retinoblastoma (Rb) and to a phenotypically normal child trisomic for the same 13q14 segment. Both sibs displayed the expected proportionate gene dosage effects for ESD. A 153% value of ESD activity was found in the amniotic cells indicating unambiguously that the fetus was not monosomic for segment 13q14 and therefore not at increased risk for Rb. The mother delivered a phenotypically normal child who was confirmed to be trisomic for segment 13q14 by cytogenetic analysis and by gene dosage studies for ESD in cord blood cells and in lymphoblastoid cells.

Catalase determination in various etiologic forms of Wilms' tumor and gonadoblastoma.

We have previously mapped the gene coding for catalase to 11p13 by gene dosage analysis. Deletion of this chromosomal region causes aniridia, mental retardation, and predisposition to Wilms' tumor (WT). In the present study, 22 patients with various etiologic forms of WT and/or aniridia were investigated. The catalase (CAT) level and karyotype were examined in order to determine the linkage and the gene ordering on chromosome number 11 of the different loci involved. The CAT concentration was normal in the 19 cases without detectable chromosomal abnormalities.

Cytogenetic forms of retinoblastoma: their incidence in a survey of 66 patients.

Sixty-six retinoblastoma patients were investigated using high resolution banding techniques, sister chromatid exchange (SCE) studies, and esterase-D phenotype determination and dosage. Seven patients (in six families) were found to be carriers of a rearrangement of band 13q14 due to de novo deletions, apparently balanced de novo translocations, or parental insertions. The possible role of submicroscopic parental insertions is suggested to explain transmission of nonchromosomal forms through unaffected carriers.

The human gene map: a review.

Genes are mapped to human chromosomes using many different methods: by somatic cell hybridization (by far the most fruitful method until now), by taking advantage of gene dosage effect in cases of chromosomal imbalance, and more recently by molecular hybridization which consists of techniques with great potential values. Some 350 autosomal loci have been assigned. They include genetic markers (blood groups), gene clusters such as the Ig, Hb, HLA genes, enzymatic markers, hereditary diseases (the morbid anatomy of the genome), and the recently discovered "micro-deletions" responsible, for instance, of certain types of childhood malignancies. The X- and Y-linked genes are also discussed.

Cytogenetic investigation in 413 couples with spontaneous abortions.

413 couples with one or more spontaneous miscarriages were karyotyped. Observed chromosomal rearrangements were classified as major rearrangements, i.e. Robertsonian and reciprocal translocations, pericentric and paracentric inversions, supernumerary small metacentrics, and minor rearrangements, i.e. pericentric inversions of chromosome 9, and constitutional fragility of particular chromosome sites. 2.30% of the individuals were carriers of a major rearrangement, which represents a ten-fold increase when compared to the general population. The contribution of each type of rearrangement is unequal, the most important being pericentric inversions (36 times more frequent than in the general population). Contrary to data from the literature, the probability of finding a rearrangement does not seem to increase with the number of miscarriages.

[Genetics and genetic counseling: the retinoblastoma case]. / Génétique et conseil génétique: le cas du rétinoblastome.

Forty-percent of retinoblastomas are due to a mutation inherited as an autosomal dominant trait with a high penetrance. Cytogenetic forms of retinoblastoma have led to the location of the gene, to the identification of numerous chromosome 13 specific DNA polymorphisms, and to the cloning of the gene. Intragenic DNA polymorphisms are now known. Using Southern blot hybridization, study of the mutation is possible either by direct analysis or by an indirect approach using linkage with polymorphic genetic markers. The majority of cases cannot be examined by these techniques. Their value and limits are discussed.

[Chromosome abnormalities in male sterility]. / Les remaniements chromosomiques dans la stérilité masculine

A study of the caryotype in 281 cases of male secretory sterility. Chromosomal anomalies were found in 81 cases, i.e. 78 cases, of azoospermia, 3 cases of oligospermia. Barr bodies were found in 66 cases of Klinefelter syndrome or one of its varieties. In the remaining 15 cases, there was no Barr chromatin: 7 of them bore gonosomal abnormalities with or without mosaicism. In 8 cases reciprocal translocations were found: in 2 of them a sexual chromosome was involved. The high rate of chromosomal anomalies should be stressed: every male secretory sterility, especially with azoospermia, warrants a chromosomal study. In the group of translocations, FSH and LH rates are not elevated in spite of the existence of azoospermia, whereas they are consistently increased in all the other chromosomal abnormalities: this so far undescribed phenomenon has no present explanation. The role played by translocations in male secretory sterility, although difficult to understand, is well documented, since translocations occur ten times more frequently in male sterility than in the general population.

Autosomal mendelian disorders and microcytogenetics.

The development of cytogenetic high resolution banding techniques has allowed the observation of specific chromosome rearrangements--i.e. microdeletions, translocations--in patients with morbid conditions suspected to have a genetic component but for which a precise etiology had not, or rarely, been recognized. The most striking examples are retinoblastoma, the WAGR complex, Beckwith-Wiedemann syndrome, Langer-Giedion syndrome, Prader-Willi syndrome, Miller-Dieker syndrome and others, which thus could be mapped to the genome. Molecular technology further allowed in a number of cases cloning of the genes proper or of linked DNA polymorphisms permitting genetic counseling.