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Mutations in the methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome, a severe neurodevelopmental disorder occurring predominantly in females. Male patients with Rett syndrome are extremely rare, as the Rett-causing mutations in the MECP2 gene are usually lethal in hemizygous males. However, different mutations in the same gene were reported to cause mental retardation, both in sporadic non-syndromic males as well as in syndromic families with disease manifestation in carrier females. The majority of the reported MECP2 mutations in mentally retarded patients cause amino acid substitutions and, especially in isolated cases, discrimination between a disease-causing mutation and a rare polymorphism is not obvious and the significance of each individual variation should be verified. We mapped a new non-syndromic X-linked family (MRX79) to the chromosomal region Xq27.3-Xq28 and identified an A140V mutation in the MEPC2 gene in all patients with the disease haplotype. In addition to data published by others, this suggests that A140V is a recurrent mutation (and not a polymorphism) found in patients with X-linked mental retardation., (Copyright 2002 Wiley-Liss, Inc.)

Created in 1987, the department of medical genetics finds its origins in molecular endocrinology research which had developed from the seventies at the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM) of the Faculty of Medicine. After its fusion with the Center of Human Genetics of the ULB, in 1992, the department is composed of three units: the lab of molecular genetics and oncology, the lab of cytogenetics and a clinical genetics unit. One thousand consultations of genetic counseling and more than 15,000 molecular or cytogenetic diagnostic procedures are performed annually. The development of the clinical activities was paralleled by a very active research activity, resulting in a series of "firsts". Amongst the main results are: the identification of the first mutations responsible for congenital hypothyroidism; the molecular cloning of the TSH receptor and of a series of "orphan" G protein-coupled receptors; the identification of a novel neuropeptide, nociceptin, by the first example of "reverse pharmacology"; the identification of olfactory receptors on the sperm of mammals, including man; the identification in molecular terms of the mechanisms responsible for acquired and hereditary hyperthyroidisms; the identification of the chemokine receptor CCR5 as the major coreceptor of HIV-1, and of the prevalent mutation of CCR5 conferring resistance to HIV to about 1% of the European population.

The 3 affected children from 2 different wedlocks of the mother have been previously described (11). Search by FISH analysis in the mother revealed she is a carrier of balanced translocation of clear terminal G bands of equal sizes of the long arms of chromosomes 10 and 14. Chromosomal slides of the last child (Patient 3) could be analysed by fish and revealed that he did inherit the derivative chromosome 10. He had a partial trisomy 14 and a partial deletion of the long arm of chromosome 10. The clinical pictures correspondence to the possibly abnormal karyotypes will be discussed.

In the literature dealing with the impact of genetic counsel in the reproduction decision, two aspects are discussed: 1. memorization and appraisal of the recurrence risk, chosen options for family planning, appraisal of genetic counsel by the patients 2. mechanisms of decision making and psychological impact of genetic counsel.

1000 cases of genetic counseling have been reviewed. Most patients are sent to the genetic center by gynecologists (68.4%), mostly because of a personal or previous familial history (64%). This previous history concerns mainly congenital malformations (44%, 283/640) and mental retardation (24%, 154/640). Generally, the patients consult outside a pregnancy, nevertheless one fourth comes after conception and this occurs more often when the proband is a family member (38% versus 19% when the proband is a spouse and 20% when the proband is a child). Ten percent of the patients knowing they could be at risk because spouse or child is affected consult after having already had a child or having had another child. The mode of inheritance of the diseases for which patients with previous family history consult is as follows: mendelian inheritance (36%), multifactorial inheritance (19%), chromosomal defect (18%), non genetic (5%), variable inheritance (2%), unknown (15%) and insufficient information (5%). The majority of patients coming for previous familial history could be tranquilized, the recurrence risk was either small or minimal. In 2.6% of the cases, a high recurrence risk has been given and the risk could not be evaluated in 7% of the cases. The importance of genetic counseling is stressed by the fact that antenatal diagnosis could be proposed to half of the patients with a recurrence risk equal or higher than 1%.

The authors report the results of chromosomal analyses performed on 6235 amniocenteses and 559 choriocenteses. Whereas the frequencies of chromosomal anomalies observed respectively on amniocenteses and choriocenteses did not differ significantly, the comparison of the types of aberrations found revealed, in chorion villi, a relatively high proportion of lethal anomalies, never encountered in amniocyte cultures. Furthermore, chromosomal mosaicism was observed 10 times more frequently on chorion villi than on amniotic cells. These results are globally comparable to those reported in other surveys. In view of literature reports of discordances between fetal chorionic karyotypes, never found in amniocenteses, rapid karyotyping from chorion villi is not as reliable as from amniotic cells. Taking into account the risk of cytogenetic discordance specific to choriocentesis, it is recommended that this method be strictly limited to pregnancies with high genetic risk.

The authors tried to determine a dose-effect relation between the concentration of Bleomycin and the number of chromosomal aberrations "in vitro" in human lymphocytes during 48 h cultures. Concentrations of 1 gamma/ml, 2 gamma/ml, 10 gamma/ml and 20 gamma/ml were used. The number of normal cells seems to decrease according an exponential function; at a concentration of 20 gamma/ml, 15 p. 100 of the cells were apparently normal and this rises the problem of chemotherapeutic agent resistance. The number of one hit and two hit damages increases according to the dose of Bleomycine but it was not possible to determine a mathematic relation of the phenomenon. Like viruses and others chemicals, Bleomycin was responsible for "pulverisation" of chromosomes in several cells.

Two siblings affected with partial trisomy 3p resulting from a maternal balanced translocation 46,XXt(3;10) (p21;q26) are reported. The clinical features of this syndrome are reviewed. The necropsy findings of the two siblings are discussed.

Three related new cases with almost complete trisomy 11p due to paternal balanced translocation 46, XY, t(7; 11) (q36.1; p11.1) are reported. The proband (Case 1) was a malformed stillborn with exomphalos, case 2 was diagnosed in the first trimester by direct chromosome preparations from chorionic villi, and confirmed on fetal products after termination of pregnancy. Case 3, a cousin to cases 1 and 2, was a 29-weeks-old fetus with omphalocele discovered at ultrasound. Literature reports of trisomy 11p are reviewed with regard to those new cases, and the possible relationship of this chromosome imbalance with the Beckwith-Wiedemann Syndrome is discussed.

Ten thousand children born consecutively in a university hospital were surveyed for the presence of major congenital malformations. About 2% (174) had a major congenital defect. Seventy-eight percent (135 of 174) of these malformations are associated with increased recurrence risk (greater than 1%), and 9% carry a high recurrence risk (greater than or equal to 10%). On the basis of the recurrence risk of 1% or higher and the feasibility of prenatal diagnosis, such a procedure should be considered in future pregnancies in 45% (79 of 174) of the mothers, especially inasmuch as 40% were primiparae younger than 36 years.

We report on two sibs with Dandy-Walker malformation and tetramelic postaxial polydactyly. We conclude that this is a new autosomal recessive syndrome.

Cytogenetic analyses performed in infertile men showed a frequency of genetic abnormalities definitely higher than in normal population. Cytogenetic analysis is perfectly justified in infertile men with normal phenotype.