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X-linked mental retardation is a very common condition that affects approximately 1 in 600 males. Despite recent progress, in most cases the molecular defects underlying this disorder remain unknown. Recently, a study using the candidate gene approach demonstrated the presence of mutations in PAK3 (p21-activating kinase) associated with nonspecific mental retardation. PAK3 is a member of the larger family of PAK genes. PAK proteins have been implicated as critical downstream effectors that link Rho-GTPases to the actin cytoskeleton and to MAP kinase cascades, including the c-Jun amino-terminal kinase (JNK) and p38. We screened 12 MRX pedigrees that map to a large region overlying Xq21-q24. Mutation screening of the whole coding region of the PAK3 gene was performed by using a combination of denaturing gradient gel electrophoresis and direct sequencing. We have identified a novel missense mutation in exon 2 of PAK3 gene (R67C) in MRX47. This confirms the involvement of PAK3 in MRX following the report of a nonsense mutation recently reported in MRX30. In the MRX47 family, all affected males show moderate to severe mental retardation. No seizures, statural growth deficiency, or minor facial or other abnormal physical features were observed. This mutation R67C is located in a conserved polybasic domain (AA 66-68) of the protein that is predicted to play a major role in the GTPases binding and stimulation of Pak activity.

The fragile X syndrome is the most common inherited form of mental retardation. Its prevalence is estimated to be one in 1000-4000 males and one in 2000-6000 females, depending of the region. A large canadian population study in Quebec has shown a frequency of 1/260 carrier women. The fragile X syndrome was the first disease shown to be associated with "dynamic mutations", caused by an amplification of an unstable DNA sequence transmitted from generations to generations till a pathologic expression: mental retardation. The prevention is possible by a specific DNA analysis of patients and male and female carriers. It is possible to detect the mutation or the premutation in pregnant women and to propose a prenatal diagnosis by molecular study on chorionic villi samples or cultivated amniocytes.

In fragile X syndrome, the most common cause of inherited mental retardation, phenotypic expression has been linked to a region containing a repetitive sequence, (CGG)n, that appears to lengthen dramatically in fagile X patients and to show length variation in normal individuals. In order to investigate possible mechanisms responsible for further expansion of CGG in the normal population, we selected 31 normal unrelated X chromosomes carrying either the high-risk DX204-AC15 5 or DX196-AC 151 haplotypes, as defined by the flanking microsatellites, DXS548 and FRAXAC2. Nearly 100% of CGGs with more than 35 repeats were found on DX204-AC155 haplotypes, with a mean length significantly higher and much more variable than in normal individuals carrying other haplotypes including the high-risk haplotype DX196-AC151. These findings suggest that the transition from the normal to the abnormal range occurs by a multistep process, a primary event, such as unequal crossing-over, leading to increased size and moderate instability of the repeat, and from which DNA polymerase slippage could lead to recurrent premutations. Our results also suggest that the upper limit of the normal range is roughly 35 repeats in the fragile X gene. The 36–54 repeats range would define an intermediate allele only observed, up to now, in DX204-AC155 fragile X chromosomes.

The fragile-X mental retardation syndrome, one of the most prevalent chromosome X-linked diseases (approximately equal to 1 of 2000 newborn males), is characterized by the presence in affected males and in a portion of carrier females of a fragile site at chromosomes band Xq27. We have performed a linkage analysis in 16 families between the locus for the fragile-X syndrome, FRAXQ27, and two polymorphic DNA markers that correspond to the anonymous probe St14 and to the coagulation factor IX gene F9. Our results indicate that the order of loci is centromere-F9-FRAXQ27-St14-Xqter. The estimate of the recombination fraction for the linkage F9-FRAXQ27 is 0.12 (90% confidence limits: 0.044-0.225) and 0.10 for FRAXQ27-St14 (90% confidence limits: 0.040-0.185). Recombination between St14 and F9 does not appear to be significantly different in normal and fragile-X families. The two flanking probes were used for diagnosis of the carrier state and for detection of transmission of the disease through phenotypically normal males. They should also allow first-trimester diagnosis with a reliability of about 98% in 40% of the families. Used in conjunction with the cytogenetic analysis, the segregation studies with both probes should improve the genetic counseling for the fragile-X syndrome and should be useful for the formal genetic analysis of this unique disease.

A pericentric inversion of chromosome 9 has been detected in 10 unrelated families. The break points are identical and the inversions involved the heterochromatic segment. The effects of inversion of chromosome 9 on different aspects of reproductive failure are discussed.

Antenatal diagnosis enables certain fetal abnormalities to be detected "in utero", and in particular mongolism. This examination is often undertaken in the process of medical attention in pregnancy. This explains why interviews with pregnant women about this far from ordinary act have become so superficial. Men and women react differently to this take-over. The former take part in a scientific discussion, the latter, who are more closely involved, which is to say with their whole bodies, set themselves against both good and bad doctors and often try to resist this test. We have attempted to understand the meaning of wanting to or not wanting to know the sex of the child in this context before its birth, and what happens to the wish to have a child after this kind of medical care.

Twenty-eight HLA-A and B markers have been tested in 49 couples who had one or more triploid abortions. The antigen frequencies were compared to those of 209 couples and 591 normal individuals as controls. No significant deviations were observed. However, a non significant excess of antigens shared in common by both parents was shown in comparison with the normal couples. This could be related to a possible dispermy mechanism. On the other hand, a slight excess of A 28 may be in relation to a possible anomaly of gametogenesis.

Chorionic villi biopsy allows first trimester prenatal diagnosis of some genetic diseases. In this study the results of 163 diagnoses are presented, and among these, 59 diagnoses of autosomal recessive metabolic diseases with 8 observations of congenital adrenal hyperplasia due to 21 OH deficiency and 6 observations of Fanconi anemia.

Genetic, clinic and biologic features from three families with Xq fra syndrome are described. First, the authors give their experience for the best ways of culture in order to see the fragile site. Then, they insist upon the main points of each family: in the first, two women have a mental retardation; in the second, a prenatal diagnosis could be made; in the third, treatment with folic acid did not change the IQ but improves the behaviour of two brothers.

Four unexpected karyotypes were found in prenatal diagnosis: 47,XXX; 47,XXY; double reciprocal translocation; Yq-. Supplementary biological studies (including specific Y-DNA probes) are carried out in order to help in the parents' decision. No induced abortion was performed. The children are described after delivery.

The close genetic linkage between 21 hydroxylase deficiency and HLA loci considerably enlarges the possibilities of genetic counselling. Two 21-OH deficient complex families are reported, illustrating several aspects of this genetic counselling: detection of carriers, determination of the actual risk to related couples, suspicion of 21-OH deficiency by an HLA specificity association, and prenatal diagnosis.

The request for prenatal diagnosis of cystic fibrosis has been evaluated by an interview during a visit at a cystic fibrosis clinic among 32 couples whose one or several children are affected. Six couples resorted to the procedure between June 1984 and October 1985. In all the cases, in these families the only child (or children) alive was affected. The diagnosis of the disease in the first affected child reduces the number of children planned by the family. The significant use of the test, since its availability points to the existence of a real demand from the parents.

In cases of artificial insemination for genetic indication, it may be useful to determine that in fact the foetus is the result of AID. Chromosome markers may or may not provide an answer, when HLA typing of amniotic fluid cells can.

A dose genetic linkage exist between the HLA complex (especially HLA-B), and the 21 hydroxylase deficiency form of adrenal hyperplasia. By their polymorphisms HLA antigens can be used as "markers" to follow the segregation of 21-OH deficiency in families, to diagnose the heterozygous offspring and eventually to offer a prenatal diagnosis to couples at risk. In late onset forms of 21-OH deficiency the same genetic linkage has been demonstrated with a high frequency of HLA-B14 antigen.

Etiological and epidemiological studies of triploid and hydatidiform molar conceptuses were done using HLA polymorphism. The segregation of HLA markers allowed to know the etiology of 25 triploidies and 19 hydatidiform moles. Five other moles and a post molar choriocarcinoma were also studied by molecular hybridization. This confirms that triploidies in about 3/4 of the cases involved two sets of paternal chromosomes mainly by di-sperm. Hydatidiform moles from Algeria, France and Senegal were all of androgenic origin excepted for one case. DNA analysis of the choriocarcinoma demonstrated the presence of a paternal marker suggesting for this case a direct cellular lineage from the mole. Positive associations with HLA A 28 and B 7 were found which could be related to gametogenesis-fecundation dysfunction. A slight excess of antigens shared by parents of triploidies was shown. This was not observed for parents of hydatidiform moles but when they shared HLA antigens a preferential inheritance in the mole of the shared specificities was observed. This relative compatibility of the molar conceptus with the mother may be an element of the process that prevent its early rejection.

A series of 226 antenatal diagnoses of chromosome structural re-arrangements in 181 couples has shown the usefulness of such diagnosis for couples including a genitor carrying a balanced anomaly. Analysis of the data has elicited major variations in the incidence of unbalanced anomalies in foetal cells and has provided information which can usefully be applied to genetic counselling.

A pericentric inversion of chromosome 2 has been detected in 4 unrelated families. The break points are identical in band 2p11 and band 2q13. Reproductive history of these couples is analyzed. The pathology of these particular regions of chromosome 2 is discussed.

A prenatal diagnosis of fragile X fra(X)(q28) has been performed in a pregnant woman obligate carrier of fra(X) by analysis of amniotic fluid cells taken by amniocentesis. The fra(X) has been observed in 30% (8/26) of the metaphases of the male fetus. These results were obtained within 10 days after amniocentesis using the in situ technique on cells grown first in Ham Medium supplemented with newborn calf serum and a serum substitute and changed for the last 19 hours with Tc 199 medium with 5% newborn calf serum and methotrexate (10 mg/l). This technique showed that fra(X) is not a clonal phenomenon and that its expression is related to the cell types and the origin of the studied cells.

Carrier diagnosis and prenatal diagnosis of Duchenne's muscular dystrophy (DMD) and Becker's muscular dystrophy (BMD) has become possible using some twenty RFLPs detected by more than a dozen Xp21 probes that are either intragenic or flanking the disease locus. Results from familial studies on 88 DMD and BM families stress important considerations concerning a priori and final risks, individuals necessary for the identification of the phase, and the different strategies that can be applied, regardless of whether the study concerns an on-going pregnancy or a carrier-status determination, and whether the patient is at high or low risk. Finally, multiple sources of difficulties in interpreting the results depend on a) the occurrence of new mutations that must be traced; b) the existence of meiotic recombination; c) the necessity, in some instances, of relying upon the sole identification of the paternal X. These considerations emphasize the characteristics and the important limitations of this type of methodology.

This article, which is the second installment of a study of the psychological aspects of antenatal diagnosis, presents the analysis of interviews with women (and with some of their partners) who were examined because of their age. The characteristics of these "late" pregnancies seem to be the following: 1. The question of a abnormality shifts the emphasis from the child to the pregnancy itself, which is often lived through as something abnormal; 2. knowing the sex of the child before its birth emphasizes the abnormality of the pregnancy and therefore draws attention to the problem of the age of the mother; 3. this last chance of pregnancy emphasizes the question, which is near in time for these women, of the menopause, of getting old and of death; 4. it also emphasizes in a most emphatic way the question of mourning, of loss, of the place of the future child in the history of the woman and in a more general way the question of the desire to have a baby.

In man, a malformation that recalls some of the defects associated with T/t mutants in the mouse is sacral agenesis. We report on a family with a high incidence of sacral malformation, ranging from a complete absence of the sacrum (SA), with or without spina bifida aperta, to a spina bifida occulta (SBO) that could only be detected by x-ray. The condition appeared in a man with four children who were all affect, and thereafter, to varying degrees, in 17 of his 28 descendants. Segregation analysis has been performed in this family, using the Elston and Stewart transmission probability model [1971]. The two traits (SA and SBO) were first studied separated and then together. A fully penetrant major dominant gene is show to cause SA. When the phenotypes SA and SBO are considered together, Mendelian transmission is rejected. This could be explained genetically by two alternative hypotheses: genetic heterogeneity or a dominant major gene transmitted in excess by heterozygotes (tau Aa A = 0.896), suggesting a segregation distortion property of an allele at a T-like locus.