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.

Homologous T and B cells immortalized in vitro by the Epstein-Barr virus exhibit differential genetical and functional features.

After in vitro EBV infection of peripheral blood lymphocytes (PBL), we previously obtained IL-2-independent T-cell lines expressing EBNA1 and LMP1 viral latent genes. One tumorigenic clone, NC5, was further characterized for chromosomal abnormalities, rearrangement and expression of oncogenes, and constitutive or induced activation of cellular transduction pathways. NC5 as well as TC cells derived from an NC5-induced tumor exhibited the same few chromosomal abnormalities absent in normal PBL and B-cell lines (LCLs) from the same donor. No rearrangement or altered expression of C-MYC, BCL-2 and NF-KB2 oncogenes could be detected. In contrast, we found high levels of BCL-X and thioredoxin (TRX), as markers of EBV infection or T-cell activation/transformation status. No constitutive activation of NF-kappa B or STAT transcriptional complexes was observed in these cells. For NF-kappa B, this was in apparent contradiction with its reported inducibility mediated by LMP1, taking into account that NF-kappa B was still inducible by TNF alpha or PMA and ionomycin. Our results highlight independence of EBV protein-mediated transformation towards classical cellular pathways in T-lymphocytes.

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.

[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.

[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.

[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.

Synaptonemal complexes in a subfertile man with a pericentric inversion in chromosome 21. Heterosynapsis without previous homosynapsis.

Analysis of surface-spread synaptonemal complexes of zygotene and pachytene spermatocytes was carried out on a human male carrier of a pericentric inversion of chromosome 21 ascertained after four miscarriages. The synaptic behavior of the bivalent, which could be unambiguously identified by its nonaligned kinetochores, was analyzed. All zygotene and pachytene spermatocytes had 22 linearly paired autosomal bivalents, with apparently normal synaptonemal complexes, and no evidence of a loop configuration in the 50 cells analyzed. According to the XY type (classification of Solari), the cells were distributed across zygotene and pachytene stages, not exclusively in the late pachytene to which adjustment is conventionally thought to be confined. It is suggested that inverted segments heterosynapse at early pachytene, without previous homosynapsis. It is expected that this meiotic process leads to failure of crossing-over, reduces the production of unbalanced gametes, and the risk of recombinant offspring, but can increase the incidence of aneuploidy as a result of nondisjunction during meiosis I (a frequent cause of pregnancy wastage).

Reproductive failure and pericentric inversion in man.

Pachytene analysis was carried out on an infertile man heterozygous for a pericentric inversion of chromosome 6. The synaptic behavior of the bivalent 6 inversion was analyzed using electron microscopy in silver stained surface microspread of the inversion-bearing spermatocytes. Possible mechanisms of the sterilizing effect caused by the autosomal inversion are discussed.

[Oncologic complications and cytogenetic features of ataxia telangiectasia]. / Complications oncologiques et particularités cytogénétiques de l'ataxie-télangiectasie.

A very high incidence of cancers (10%) is recorded in patients homozygous for ataxia telangiectasia (AT). From 1970 to 1987, 35 children were investigated in the department of pediatric neurology in Lille. Three developed a malignancy (one hepatic tumor, one Hodgkin's disease and one non Hodgkin's lymphoma). Constitutional chromosome fragility and immune deficiency are the main features of AT. The first one is probably linked to the pathogenesis of malignancies. Moreover, cancer therapy has to take these features into account.