[Cancer genetics: estimation of the needs of the population in France for the next ten years]. / Oncogénétique : estimation des besoins de la population en France pour les dix ans à venir.

Organised since 1990 in France, cancer genetics has been strengthened since 2003 by the programme "Plan Cancer" which resulted in an improvement of the organisation of activities. The aim of this review is to present an update of the estimation of the needs of the population in this field for the next ten years, provided by a group of experts mandated by the French National Cancer Institute. Identification and management of major hereditary predispositions to cancer have a major impact on decrease in mortality and incidence. Sensitivity of criteria for the detection of BRCA1/2 mutations could be substantially improved by enlarging the indication for genetic testing to isolated cases of ovarian cancer occurring before 70 years and to familial cases occurring after this age limit. In the Lynch syndrome, the present criteria would have an excellent sensitivity for the detection of mutations in the mismatch repair (MMR) genes if the pre-screening of tumours on microsatellite instability (MSI) phenotype was effective, but these criteria are actually poorly applied. However, genetic testing should not be proposed to all the patients affected by tumours belonging to the spectrum of major predispositions and a fortiori to unaffected persons unless an affected relative has been identified as a carrier. The prescription of tests should continue to be strictly controlled and organised, in patients as well as in at-risk relatives. The enlargement of criteria and the improvement in the spreading of recommendations should result in an increase of genetic counselling activity and of the prescriptions of tests by a factor 2 to 4, and to a lesser extent in the clinical management of at risk persons. In a near future, it appears important to mandate experts on specific issues such as the determinants of the lack of effective application of tumour screening for MSI phenotype, the recommendations for the identification and the management of MYH-associated polyposis, or the predictive value of tumour characteristics for the identification of BRCA1/2 mutations. The expected increase in cancer genetics activity will need an optimal organisation to increase the throughput. Such measures will help in facing up to new predispositions that will probably be identified in common cancers.

[Value of karyotyping women patients of couples referred for sterility]. / Place du caryotype féminin en assistance médicale à la procréation (AMP).

It has been known for some 25 years that there is a causal relation between chromosomal aberrations and male infertility and that the major indication for karyotyping an infertile man is still usually an abnormal sperm analysis. The value of karyotyping women in the routine work-up of couples referred for sterility has long been debated. A French recent cytogenetic study found an overall increased frequency of chromosomal aberrations in the female and confirmed that in some cases of poor reproductive outcome there may be a contribution of maternal chromosome aberrations. Indeed, the existence of a chromosome abnormality in the female partner was associated with the group of infertile men in which there was no apparent cause of infertility. These results emphasise the need for thorough genetic work-up in couples referred for sterility. This work-up should include karyotyping of the female for some indications explained in this work.

Cerebro-costo-mandibular syndrome in a father and a female fetus: early prenatal ultrasonographic diagnosis and autosomal dominant transmission.

Ultrasonography in a female fetus revealed cystic cervical hygroma, severe micrognathia, and vertebral and upper limb anomalies suggestive of cerebro-costo-mandibular syndrome (CCMS) which was diagnosed ultrasonographically at 16 weeks' gestation. The father is affected and presents with a Pierre Robin sequence, short stature and typical costovertebral anomalies. CCMS is a rare and severe disorder. The high frequency of sporadic cases, vertical transmission, and the excess of sibs affected via horizontal transmission suggest dominant autosomal mutation with possible germinal mosaicism. The vertical familial case detailed in the present report is a reminder of the high risk when one parent or one sibling is affected and the extreme variability of phenotype and costal ossification. Early prenatal ultrasound diagnosis is possible in a severely affected fetus.

[X-linked recessive chondrodysplasia punctata. Cytogenetic study and role of molecular biology]. / Chondrodysplasie ponctuée récessive liée à l'X. Etude cytogénétique et place de la biologie moléculaire.

UNLABELLED: Among the many acquired or constitutional causes of chondrodysplasia punctata, the X-linked recessive form is well individualized. CASE REPORT: A male newborn presented a dysmorphic syndrome with a marked nasal hypoplasia, a macroglossia and a short neck. The diagnosis of chondrodysplasia punctata was made by radiography whereas the chromosomal chart revealed the existence of an additional Y fragment in Xpter, effectuating a partial disomy Yp and a monosomy Xpter. Molecular biology showed a deletion of very small size, isolated and located between the gene missing aryl sulfatase E and the microsatellite DXS 1233, sping gene MRX2 (non-specific gene of mental retardation), and making it possible to give the reassuring elements as regards the psychomotor prognosis, sometimes compromised in this disorder. CONCLUSION: In case of chondrodysplasia punctata with dysmorphy, it is important to execute a chromosomal chart in the search for a chromosomal reorganization on the X and a study in molecular biology.

Chromosomal factors of infertility in candidate couples for ICSI: an equal risk of constitutional aberrations in women and men.

To assess the frequency of chromosomal aberrations in French candidates for intracytoplasmic sperm injection (ICSI), and to explore the existence of a female chromosomal factor in some cases of couple infertility, a collaborative retrospective clinical and cytogenetic study was performed, launched by the Association des Cytogénéticiens de Langue Franciaise (ACLF). The karyotypes of 3208 patients [2196 men (68.4%), 1012 (31.6%) women] included in ICSI programmes over a 3-year period in France were collected. A total of 183 aberrant karyotypes was diagnosed, corresponding to an abnormality frequency of 6.1% (134/2196) for men and 4.84% (49/1012) for women. The following frequencies of abnormalities were observed respectively for men and women: 1.23% (n = 27) and 0.69% (n = 7) for reciprocal translocations, 0.82% (n = 18) and 0.69% (n = 7) for Robertsonian translocations, 0.13% (n = 3) and 0.69% (n = 7) for inversions, 3.32% (n = 73) and 2.77% (n = 28) for numerical sex chromosome aberrations, and 0.59% (n = 13) and 0% for other structural aberrations. Among the male patients of this latter group, 0.40% (n = 9) had a Y chromosome abnormality. Among the male patients with numerical sex chromosome abnormalities, 2.23% (n = 49) were 47,XXY, 0.32% (n = 7) were 47,XYY, and 0.77% (n = 17) had a mosaicism for numerical sex chromosome anomalies. All the female patients with sex chromosome abnormalities (2.77%, n = 28) had mosaicism for numerical sex chromosome anomalies. Even if these cases-the significance of which was sometimes questioned-were disregarded in the analysis, 2.08% (21/1012) of abnormal karyotypes remained in women. An overall increased frequency of chromosomal aberrations was found, and this confirmed that in some cases of poor reproductive outcome there may be a contribution of maternal chromosome aberrations. Indeed, the existence of a chromosome abnormality in the female partner was associated with the group of infertile men in which there was no apparent cause of infertility.

[1998 french results on medically assisted reproduction with gamete cryopreservation and donation. French Federation of CECOS]. / Bilan français 1998 de l'assistance médicale à la procréation avec tiers donneur et de l'autoconservation. Fédération Française des CECOS.

During the year 1998, the French Federation of CECOS recorded the results of the 23 CECOS centers and IFRAERES in Toulouse. 1,573 first demands of procreation with sperm donors were registed (versus 1,620 in 1997). From 9,339 cycles (AID or IVFD), 1351 pregnancies were obtained, scoring the identical amount in terms of pregnancies as in 1997 but with less 9% in terms of cycles. Ovulation monitoring and IVFD are more and more used. The analysis of the 1,169 deliveries of the 1997 pregnancies shows a malformation rate of 1.8%. 658 male volunteers came forward as semen donors (51% more than in 1997). In gamete autocryopreservation, the number of semen preservation is globaly increasing (16% more than in 1997), mainly due to the capacity of a better reutilisation with ICSI. At the end of 1998, 15 Centres was looking after 21,222 cryopreserved embryos, 25% in the aim of a near future use.

[Results of oocyte donation in France (Study Group on Oocyte Donation)]. / Bilan du don d'ovocytes en France (GEDO).

The French study group on oocyte donation, named GEDO, reports the results concerning the oocyte donation activity in France during 1998, including information from all the centers in effective operation except one. These data describe the recipients' and donors' situation and give the analysis of the results obtained.

Informed consent to serum screening for Down syndrome: are women given adequate information?

To assess the information given to women during a maternal serum screening (MSS) programme, we prospectively applied a questionnaire to 504 pregnant women attending for amniocentesis after a screen-positive result. The survey based on 200 usable questionnaires (39.7 per cent of our study population) showed that MSS was imposed as mandatory by 41.5 per cent of providers and done without their patients' agreement by 16 per cent. After release of the test results, 6.5 per cent of women believed that they were carrying a Down syndrome-affected fetus and 21.5 per cent thought the risk was about 50-50. A total of 38.5 per cent of the pregnant women were not informed of the risk of miscarriage after amniocentesis and 67.5 per cent believed that there was no possibility of a false-negative result with MSS. Information given over the telephone was particularly poorly understood compared with information provided during an outcome visit, since women who learned of their test result during such a visit scored significantly higher (69 per cent) when questioned about the risk of carrying a Down syndrome-affected fetus, compared with women informed of their test results by telephone (38.7 per cent) or by letter (47 per cent). We therefore suggest routine consultation with an antenatal care professional before testing to enable pregnant women to give their informed consent to MSS.

[1997 results of medical assisted procreation with third party donations and autopreservation. CECOS French Federation]. / Bilan 1997 de l'assistance médicale à la procréation avec tiers donneur et de l'autoconservation. Fédération Française des CECOS.

During the year 1997, the French Federation of CECOS recorded the results of the 23 CECOS centers and IFRAERES in Toulouse. 1620 first demands of procreation with sperm donors were registed (versus 1,690 in 1996) but only 3,235 patients received at least one donation in the year, 22% less than 1996. From 10,935 cycles (AID or IVFD), 1,333 pregnancies were obtained, scoring the identical amount in terms of pregnancies as in 1996 but with less 30% in terms of cycles. The analysis of the 1,298 deliveries of the 1996 pregnancies show a malformation rate of 1.9%. 419 male volunteers came forward as sperm donors (5% more than 1996). In gamete autocryopreservation, the number of semen preservation is globally increasing (11.2% more than 1996), mainly because the capacity of a better reutilization with ICSI.

[Results of oocyte donation in France (GEDO)]. / Bilan du don d'ovocytes en France (GEDO).

The French study group on oocyte donation, named GEDO, reports the results concerning the oocyte donation activity in France from 1994 to 1997, with the informations of all the centers, in effective operation. These data describe the recipients' and donors' situation and give the analysis of the results obtained.

Multicentre approaches to donor insemination in the French CECOS Federation: nationwide evaluation, donor matching, screening for genetic diseases and consanguinity. Centre d'Etudes et de Conservation des Oeufs et du Sperme humain.

The French CECOS Federation collates the results of its 22 sperm banks and provides annual reports on their activity. These records allow studies on many different aspects; annual nationwide evaluation, matching of donors and recipients, follow-up of pregnancies, research into artificial procreation, and natural fertility. Risk of transmitted hereditary disease is minimised by genetic screening which establishes the genealogy of donor candidates and includes karyotyping and other biological investigations when a particular risk is suspected. The real risk of consanguinity is very small. Limiting the number of children born from a given sperm donor can be defined at the local level.

Pregnancy outcome after artificial insemination or IVF with frozen semen donor: a collaborative study of the French CECOS Federation on 21,597 pregnancies.

OBJECTIVE: To assess pregnancies and conceptus after artificial insemination (AID) or IVF with frozen semen donor (IVF-D) on sufficiently large study population in order to distinguished minor variations. STUDY DESIGN: From 1987 to 1994, all pregnancies obtained after AID or IVF-D were registered prospectively in the French CECOS Federation data base. Different factors were recorded for this study: first menarche age of the recipient women, cycle length, insemination date in the conception cycle, maternal age at delivery, hormonal treatments, donor age, sperm conservation length and follow up of the pregnancy: miscarriage, tubal pregnancy, time at delivery, sex of the foetus, weight, malformation. RESULTS: 21,597 pregnancies obtained after AID and 3381 after IVF-D were registered. 2% were lost to follow up. Foetal loss rate is 18% after AID and 21.5% after IVF-D (p < 0.001). The tubal pregnancy rate is 0.9% after AID and 1.7% after IVF-D (p < 0.0001). 18,128 children were born after AID and 3313 after IVF-D. After AID, the twin pregnancy rate is 6.9% and the multiple pregnancy (> or = 3 foetus) rate is 0.7%. After IVF-D, these rates are 24.8% and 4.2% respectively (p < 0.0001). After AID the mean weight at delivery, sex ratio, premature rate, intra uterine growth retardation rate are not different from national rates published in 1995. The foetus malformation rate (including medical abortions) is 1.9% after AID and 2.7% after IVF-D (p < 0.009). After AID the trisomy 21 rate increases with the mother age but also with the donors age if the maternal age is equal. The birth defects rate is not different from those registered in Paris, Strasbourg and Marseille. The birth defects rate observed after IVF-D is not different from the rate observed after IVF with husband semen. (2.74% versus 2.99%; p = 0.16). CONCLUSION: After AID the miscarriage and tubal pregnancy rate, the children's weight, the premature rate is not different from that of the general French population. Sex ratio is normal as is the global malformation rate. The multiple pregnancy rate (x 7 for twin and by 10 for multiple pregnancies more than 3 foetus) is high, showing the influence of ovulation induction treatment. The birth chromosomal abnormalities rate is normal and correlated not only to the mother's age but also to the donor's age. This result without clear biological explanation will require further verification in a greater population. Practically speaking, these observations encourages lowering the age limit for semen donors less than 45 years. IVF-D practice instead of AID doubles the tubal pregnancy rate (0.9% versus 1.7% and increases the twin pregnancy rate by 2.5% and the multiple pregnancy (> or = 3 fetus) rate by 3. It is necessary to promote good practice for AID for which the pregnancy rate is very different from one centre to another within the centres with AID low results a too high rate of IVF-D. Finally we can say that pregnancies from IVF-D or IVF with husband semen are not significantly different. In other words pregnancy outcome is not changed after sperm cryopreservation.

Collaborative study of mosaic tetrasomy 12p or Pallister-Killian syndrome (nineteen fetuses or children).

The difficulties in the diagnosis of Pallister-Killian syndrome are illustrated in this study of nineteen fetuses and children. Diagnosis based on clinical appearance alone is often difficult due to the broad spectrum of clinical anomalies not specific to this syndrome. Due to mosaicism, it is altogether necessary to examine several tissues for the presence of tetrasomy 12p, including circulating lymphocytes in which mosaicism can be as low as 1-3%, amniocytes, chorionic cells and skin fibro-blasts in which mosaicism ranges from 6-100%. When highly suspected on ultrasound examination, the diagnosis recommends prenatal cytogenetic studies because survivors are severely mentally retarded. All the cases are sporadic with only a single preliminary report of recurrence. The cytogenetic diagnosis is therefore helpful in order to reassure family members in regard to genetic counseling.

Incidence of birth defects after artificial insemination with frozen donor spermatozoa: a collaborative study of the French CECOS Federation on 11,535 pregnancies.

Artificial insemination using cryogenically preserved spermatozoa has been widely used in human reproduction for several decades. No evaluation of the resulting pregnancies and conceptions has been undertaken in sufficiently large study populations for minor variations to be distinguished. This study involves 11,535 pregnancies conceived by artificial insemination using donor spermatozoa and followed from the time that pregnancy was diagnosed. The pregnancies followed a normal course with, in particular, no excessive fetal losses. While the global incidence of birth defects was similar to that of natural conception, our observations raise doubts concerning trisomy 21. The frequency of trisomy 12 was somewhat elevated when compared with French malformation registries. A recruitment bias could, in part, explain this discrepancy, but donor age cannot be excluded as an influencing factor.

Analysis of germline variation at the FMR1 CGG repeat shows variation in the normal-premutated borderline range.

In order to characterize the dynamics of CGG repeat instability at the fragile X syndrome locus (FMR1 gene), we have used small pool PCR to estimate the mutation rate within germline (sperm) and somatic tissue (leukocytes) of two normal males, one carrying the most common 29 CGG repeats allele, the other carrying a borderline normal-premutated allele of 55 repeats. Large contractions and moderate expansions of the repeat were found in sperm and blood for the 55 repeat allele while almost no variation was found in sperm or blood with the 29 repeat allele. Somatic blood DNA exhibited fewer expansions and contractions than sperm. Contractions were more frequent than expansions, and all the expansions were found in the +4 to +10 repeats range, while most of the contractions were found in the -10 to -30 range, suggesting that a subset of contractions results from a distinct mechanism. These results also suggest that the dynamics of the CGG repeat could be partly due to germline instability within the high normal or premutated ranges.

Maternal serum screening for fetal Down's syndrome, a retrospective study.

A retrospective study of the different biochemical markers used in screening for Down's syndrome was carried out on serum from 18,600 women between their 15th and 18th week of pregnancy. Thirty-two sera were from women with fetal Down's syndrome. The retrospective study of these 32 sera involves: (a) the screening of the maternal serum concentrations of human chorionic gonadotropin (hCG) and of alpha-fetoprotein (AFP); (b) the evaluation of the risk of Down's syndrome when screening maternal serum concentrations of hCG alone, then the combination of the two markers and finally the maternal serum concentrations of unconjugated estriol (uE3). The mean of MOM (multiples of the median) for the pathological sera were calculated for hCG (1.91), for AFP (0.63), for the ratio hCG over AFP (3.02) and for uE3 (0.72). With the use of hCG alone we estimated a 41% detection rate for an amniocentesis rate of 5.3%, whereas when hCG was combined with AFP the detection rate approached 65% for an amniocentesis rate of 5.5% at a risk cut-off of 1:300. The results of the uE3 determination confirm the validity of this marker. The comparison of these results with other retrospective studies shows the incidence of different factors in the detection rate such as the choice of markers, the age group studied, the modes of calculating the risk and the actual cut-off chosen.

Molecular analysis of a ring chromosome X in a family with fragile X syndrome.

The phenotypically normal sister of a patient affected by fragile X syndrome was referred for genetic counselling and was found to carry a mosaic karyotype 46,X,r(X)/45,X. Because the probability of the simultaneous chance occurrence of fragile X syndrome and a ring chromosome X in the same family is very low, we postulated that the breakpoint of the ring chromosome X originated in the cytogenetic break in Xq27.3 responsible for fragile X syndrome. In order to determine the relative positions of the breakpoint on the ring chromosome X and the (CGG)n unstable sequence responsible for the fragile X mutation, we used molecular markers to analyse the telomeric regions of chromosome X in this family. The results showed that the ring chromosome X was the maternal fragile X chromosome and that the telomeric deletion on the long arm encompassed the (CGG)n sequence. This suggests that the cytogenetic break in Xq27.3 is distinct from the unstable (CGG)n sequence, or that the break followed by the end-to-end fusion creating the ring chromosome was not completely conservative. Analysis of DNA markers on the short arm of chromosome X evidenced a deletion of a large part of the pseudoautosomal region, allowing us to position the genes involved in stature and in some syndromes associated with telomeric deletions of Xp on the proximal side of the pseudoautosomal region.

[Paternal age and pregnancy issues. The CECOS experience]. / Age paternel et issues de grossesses. Expérience des CECOS.

From a collaborative study of the French "Federation des CECOS" who collected the follow up of 11,535 pregnancies, the effect of parental age on the offspring is studied. A significant influence of the donor's age is demonstrated for the occurrence of trisomy 21 (37.4 +/- 7.8 vs 34.5 +/- 6.0; p < 0.05).

[Contribution of applied cytogenetics to medically assisted procreation]. / Apports de la cytogénétique appliquée aux procréations médicalement assistées.

The cytogenetic studies of gametes and embryos reveal the incidence of chromosomic abnormalities in medically assisted pregnancies. When extended to natural fecundation, these data enable a better comprehension of the place and the role of the selection in the quality of the conceptus.