Abnormal expression of the KLF8 (ZNF741) gene in a female patient with an X;autosome translocation t(X;21)(p11.2;q22.3) and non-syndromic mental retardation.

Non-syndromic X linked mental retardation (MRX) is a heterogeneous group of conditions in which all patients have mental retardation as the only constant phenotypic feature. We have identified a female patient with mental retardation and a balanced translocation involving chromosomes X and 21, t(X;21)(p11.2;q22.3). Physical mapping of the translocation breakpoint on the human X chromosome was performed using fluorescence in situ hybridisation. We have mapped the X chromosome breakpoint to a 21 kb DNA fragment upstream of the first exon of the KLF8 (ZNF741) gene in Xp11.21. We have subsequently shown that the KLF8 transcript is no longer detected in cells from the patient, although KLF8 expression is otherwise normally present in control lymphoblasts. Mutation screening of probands from 20 unrelated XLMR families linked to the proximal short arm of the human X chromosome failed to show any mutation in the coding region of the KLF8 gene.

Clinical heterogeneity in 16 patients with inv dup 15 chromosome: cytogenetic and molecular studies, search for an imprinting effect.

We report on clinical, cytogenetic and molecular analyses of 16 patients with inv dup (15) chromosome. We define the content of the inv dup (15) markers, their meiotic origin and the methylation status of the chromosome region involved. Precise phenotype-karyotype-genotype correlations allowed the identification of five different types of marker and demonstrated that even when the molecular content of the inv dup (15) chromosome clearly contributes to the severity of the phenotype, it does not appear to be the only relevant factor. All the markers were of maternal origin with an identical methylation profile, and neither imprinting nor methylation can explain the phenotypic variability. We suggest that the degree of phenotypic severity may be correlated with the severity of epilepsy.

Three families with high expression of a fragile site at Xq27.3, lack of anomalies at the FMR-1 CpG island, and no clear phenotypic association.

We report on 3 families where the presence and segregation at high frequency of a fragile Xq27.3 site is not associated with the mutations and methylation anomalies typically seen in the fragile X [Fra(X)] syndrome. In one family, a folate insensitive fragile site was associated with Robin sequence in the propositus. In a second family a fra(X) negative mother has two fra(X) positive sons (one mentally retarded and the other newborn). The third family presents very high expression of a folate sensitive site, unlinked to mental retardation, and was described previously by Voelckel et al. [1989]. The fragile sites in these or similar families recently described must be different from the one associated with the fra(X) syndrome. Their association with a clinical phenotype or with mental retardation is certainly not consistent, and may represent an ascertainment bias. However, the relatively high frequency with which they have been found among previously diagnosed fra(X) families suggests that, at least in some cases, the association with mental impairment may be significant. In two families reported up to now, a male with high expression of such variant fra(X) site failed to transmit it to his daughter, which may reflect an imprinting effect. Previously diagnosed families should be reinvestigated before direct DNA analysis is used for prenatal or carrier diagnosis of the fra(X) syndrome.

Identification and molecular characterization of a small 11q23.3 de novo duplication in a patient with Rett syndrome manifestations.

We report on an interstitial duplication of the long arm of chromosome 11 [46XX,dup(11) (q23.3)] in a girl with atypical Rett syndrome (RS). This case was discovered during a systematic cytogenetic study of RS. Fluorescent in situ hybridization including total chromosome painting and use of regional specific YAC, cosmid and plasmid probes, was used to confirm the chromosome 11q involvement and to identify the landmarks of the smallest 11q duplication reported to date. The findings are compared to cases of trisomy 11q reported previously, all of which have a larger duplication and different clinical manifestations. Surprisingly, mental retardation and behavior disorders are less severe in these cases.

Genotype-phenotype relationship in female carriers of the premutation and full mutation of FMR-1.

The present French-German cooperative study focuses on the genotype-phenotype relationship of mutations of the FMR-1 gene and psychiatric conditions in mothers with a full mutation in the FMR-1 gene of fra-X children (n=13), mothers with a premutation in the FMR-1 gene of fra-X children (n=61), as well as premutated siblings of these mothers without affected children (n=17) and two non-mutated control groups: (1) siblings of these mothers with normal CGG repeat (n=18); and (2) mothers of non-fra-X autistic children (n=42). Mothers with a full mutation in the FMR-1 gene and mothers with a premutation in the FMR-1 gene did not differ in the frequency of any axis I disorder; however, both groups were diagnosed with social phobia more often than the control group of mothers of autistic children. Moreover, mothers with a premutation in the FMR-1 gene of fra-X children and their siblings with the premutation (without affected offspring) revealed a similar frequency of social phobia. Furthermore avoidant personality disorder was more common in groups of carriers of the full premutation than in siblings without mutation or than the control group of mothers with autistic children. On the basis of our data, we therefore suggest that social avoidance (expressed as social phobia or avoidant personality disorder) has been underestimated in previous studies of carriers with the FMR-1 full mutation or premutation. Comorbidity of axis I and axis II psychiatric diagnoses was mainly restricted to the group of carriers of the full mutation and carriers of the premutation of FMR-1. Correlations between size of CGG repeat and IQ as well as CGG and age of onset of axis I diagnosis were non-significant. IQ of subjects had no impact on presence or absence of axis I and/or axis II diagnoses.

[Smith-Magenis syndrome]. / Le syndrome de Smith-Magenis.

Smith-Magenis syndrome is caused by a 17p11.2 deletion. It associates mental retardation, facial dysmorphism and brachydactyly; aberrant behavior and major sleep problems are present in 70% of the cases. It is probably under-diagnosed because the facial abnormalities are mild and the behavioral problems with hyperactivity and self-injuries are dominant, leading to the diagnosis of psychiatric pathology. However these behavioral problems are sufficiently characterized to allow the diagnosis of the syndrome and look for a 17p11.2 microdeletion. Otorhinolaryngologic, ophthalmologic, cardiac and renal abnormalities can be associated and their evaluation is necessary. Smith-Magenis syndrome is considered as a contiguous gene syndrome. Genes have been mapped and isolated to the critical region, but their participation in the pathogenesis of the syndrome remains unclear.

[Fragile X syndrome is still unrecognized: efficacy of molecular diagnosis in mentally retarded probands]. / Le syndrome X fragile est encore méconnu: efficacité du diagnostic moléculaire chez les proposants avec retard mental.

BACKGROUND: The fragile X mental retardation syndrome is the most common cause of inherited mental retardation. Identification of the unstable mutation responsible for the disease has allowed the design of a fully reliable molecular test for the diagnosis of the disease and for genetic counselling (identification of clinically normal carriers and prenatal diagnosis). We started in July 1991 to search for the mutation in mentally retarded probands, with no known cause for their phenotype. We present the results of a 42-month experience. POPULATION AND METHODS: One thousand and one hundred fourty-nine probands were analysed. In case of a positive diagnosis, an extension of the molecular study to relatives was proposed. DNA samples were studied by Southern blot following EcoRI or EcoRI + EagI digestion. Clinical data were collected from referring clinicians. RESULTS: Seventy-three carriers of a full mutation were identified, belonging to 52 families. The mean age of the fragile X probands was 16 +/- 14 years, which is very surprising for a disease that causes significant manifestations by the age of 2 to 3 years. This indicates an insufficient knowledge about this disease in France. Most of the demands for the test were from clinical geneticists. This diagnosis is of major importance for genetic counselling, as illustrated by the following study of 108 women at risk in these families. CONCLUSIONS: The importance of an early diagnosis followed by an extended family study, for carrier screening and prevention of this severe disease, justifies molecular testing on any child with mental retardation or significant language delay of unknown cause, in the absence of clinical signs formally excluding a fragile X diagnosis.

[Major malformation syndrome and apparently balanced chromosomal abnormality: holoprosencephaly and 5p; 12q translocation]. / Syndrome malformatif majeur et anomalie chromosomique apparemment équilibrée: holoprosencéphalie et translocation 5p; 12q.

Observation of holoprosencephaly associated to chromosomic aberration (balanced translocation 5p; 12q); genetic council may be difficult in case of familial translocation.

[A difficult cytogenetic diagnosis of 4p monosomy]. / Un diagnostic cytogénétique difficile de monosomie 4p.

Monosomy 4p is rare; cytogenetic diagnosis is difficult when it is not oriented by clinical signs such as severe hypotonia, profound encephalopathy and dysmorphism ("casque de guerrier grec"). Parenteral karyotype is indispensable in case of translocation.

[Chromosome anomalies in rheumatoid polyarthritis. Breakage level and study of the breaking factor]. / Anomalies chromosomiques au cours de la polyarthrite rhumatoïde. Taux de cassure et recherche du facteur cassant. A propos de 78 observations.

This current study confirms the significant elevation of the rate of chromosomal abnormalities (18.32 p. cent in 90.62 p. cent of cases) and the presence of a breaking capacity of the serum in a series of 78 rheumatoid polyarthritis compared with a control group. Chromosomal gaps and breaks represent the most frequently encountered lesions. These lesions are observed from the onset of the disease but are not specific of this disease. Chromosomal abnormalities do not seem to be randomly distributed on the chromosomes. They are not correlated with clinical or biological parameters in a statistically significant fashion. The cytogenetic study only represents a non specific biological test of rheumatoid disease. The advantage could apply, in practice, to beginning or atypical forms of rheumatoid polyarthritis in order to identify them within the group of auto-immune diseases.

New data on clonal anomalies of chromosome 14 in ataxia telangiectasia: tct(14;14) and inv(14).

From a series of 53 patients with ataxia telangiectasia, two large clones with a t tan or tct(14;14) and two with an inv(14) were observed among phytohaemagglutinin (PHA)-stimulated lymphocytes. Smaller clones with the same inv(14) were observed in two other cases. Similar breakpoints may exist, both for t(14;14) and inv(14): q11.1/q11.2 and q32, and it is postulated that the rearrangements are related to a recombination of the alpha-chain of the T-cell receptor and IgH clusters of genes.

XY-quadrivalent association and sterility in a man carrier of a reciprocal autosomal translocation involving the whole arm of an acrocentric chromosome t(2;15)(q21.3;cen).

Meiotic and synaptonemal complex studies using electron microscopy were carried out on an infertile man with a 46,XY t(2q;15p). Synaptonemal complex analysis showed terminal asynapsis in the totality of quadrivalents and a high and significant frequency of association with the XY vesicle (80%), possibly related to the high amount of satellite DNA of the acrocentric chromosome 15. In this translocation carrier, the XY quadrivalent association at pachytene stage is positively correlated with the degree of spermatogenic breakdown after pachytene stage. Whether association with the non-paired segment represents the causative factor or only a secondary effect has still to be clarified.

[Lethal polymalformative syndrome with 13q deletion secondary to a maternal X; 13 translocation]. / Syndrome polymalformatif léthal avec délétion 13q secondaire à une translocation maternelle X; 13.

The authors report the case of a newborn full term delivered by cesarean section for evolutive hydrocephalus, in the last month of pregnancy. This hydrocephalus was confirmed by echography after birth. This also having ambiguous genitalia and atresia ani, he died a few hours later. No evidence of infectious or toxic embryofetopathy was found out as an etiologic factor, but the karyotype of the baby showed a 13 q deletion and that of the mother a non reciprocal Xqter; 13q31.3 translocation. The study of inactivation of X indicated that the inactivated X chromosome in each cell was normal. On this occasion, the authors try to bring together the main points of "13q-syndrome" and discuss on the practical approach of antenatal diagnosis which they could propose to the couple.

Identification of the gene-richest bands in human prometaphase chromosomes.

The human genome is a mosaic of long, compositionally homogeneous DNA segments, the isochores, that can be partitioned into five families, two GC-poor families (L1 and L2), representing 63% of the genome, and three GC-rich families (H1, H2 and H3), representing 24%, 7.5% and 4-5% of the genome, respectively. Gene concentration increases with increasing GC levels, reaching a level 20-fold higher in H3 compared with L isochores. In-situ hybridization of DNA from different isochore families provides, therefore, information on the chromosomal distribution of genes. Using this approach, three subsets of reverse or Giemsa-negative bands, H3+, H3* and H3-, containing large, moderate, and no detectable amounts, respectively, of the gene-richest H3 isochores were identified at a resolution of 400 bands. H3+ bands largely coincide with the most heat-denaturation-resistant bands, the chromomycin-A3-positive, DAPI-negative bands, the bands with the highest CpG island concentrations, and the earliest replicating bands. Here, we have defined the H3+ bands at a 850-band resolution, and have thus identified the human genome regions, having an average size of 4 Mb, that are endowed with the highest gene density.