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C Moutou

Publications and source records attributed to C Moutou.

At least 19 recordsLinked to original sources
PubMed2006

ESHRE PGD Consortium data collection VI: cycles from January to December 2003 with pregnancy follow-up to October 2004.

The sixth report of the ESHRE PGD Consortium is presented, relating to cycles collected for the calendar year 2003 and follow-up of the pregnancies and babies born up to October 2004. Since the beginning of the data collections, there has been a steady rise in the number of cycles, pregnancies and babies reported. For this report, 50 centres participated, reporting on 2984 cycles, 501 pregnancies and 373 babies born. Five hundred and twenty-nine cycles were reported for chromosomal abnormalities, 516 cycles were reported for monogenic diseases, 137 cycles were reported for sexing for X-linked diseases, 1722 cycles were reported for preimplantation genetic screening (PGS) and 80 cycles were reported for social sexing. Data VI is compared to the cumulative data for data collections I-V.

Abortion, Spontaneous↗
PubMed2006

Strategies and outcomes of PGD of familial adenomatous polyposis.

Owing to adult onset of hereditary cancer, prenatal diagnosis (PND) raises numerous ethical issues on the acceptability to terminate an affected pregnancy (TOP). PND for these disorders is often considered as unacceptable by couples as well as geneticists and legal or ethical authorities, but preimplantation genetic diagnosis (PGD), even if subject to controversy, seems to be a more acceptable option. Therefore, many couples, who do not want to transmit their cancer to their children, consider PGD as their only reproductive option. This article describes our experience of PGD for familial adenomatous polyposis (FAP). Twelve couples were referred between 2000 and 2005. We developed PGD tests to detect the mutation alone, but we rapidly set up multiplex PCR combining mutation detection and indirect diagnosis. Finally, we set up duplex and triplex indirect diagnoses to be able to offer a PGD, whatever mutation was involved in familial cases. PGD strategies were based on (i) a new double allele-specific PCR approach (D-ARMS) allowing the detection of the wild-type and mutated allele; (ii) PCR fragments sizing and (iii) restriction length polymorphisms. For the 12 referrals, we developed eight tests, and 11 cycles have been performed for four couples, resulting in eight embryo transfers and five pregnancies, with the birth of one healthy boy and two ongoing pregnancies. We are now able to propose PGD to most couples at risk of transmitting FAP to their offspring, whether the mutation is familial or occurred de novo.

Adenomatous Polyposis Coli↗
PubMed2005

ESHRE PGD Consortium data collection V: cycles from January to December 2002 with pregnancy follow-up to October 2003.

The fifth report of the ESHRE PGD Consortium is presented (data collection V). For the first time, the cycle data were collected for one calendar year (2002) in the following October, so that data collection was complete for pregnancies and babies. The data were collected using a Filemaker Pro database and divided into referrals, cycles, pregnancies and babies. There are currently 66 active centres registered with the consortium; however, the data presented here were obtained from 43 centres and included 1603 referrals, 2219 cycles, 485 pregnancies and 382 babies born. The cycle data were divided into preimplantation genetic diagnosis (PGD) for inherited disorders (including chromosome abnormalities, sexing for X-linked disease and monogenic disorders), aneuploidy screening (PGS) and the use of PGD for social sexing. Data collection V is compared with the previous cumulative data collection (I-IV), which comprised 4058 PGD/PGS cycles that reached oocyte retrieval.

Aneuploidy↗
PubMed2004

ESHRE PGD Consortium data collection IV: May-December 2001.

The ESHRE PGD Consortium was formed in 1997 to survey the practice of preimplantation genetic diagnosis (PGD). Since then, three reports have been published giving an overview on PGD from an ever-increasing number of centres and reporting on an increasing number of PGD cycles and pregnancies and babies born after PGD. After these initial influential publications, important shortcomings were identified primarily on the method of data collection, i.e. with Excel spreadsheets, and in the timing of the collection (cycles were collected in a different time frame from pregnancies and babies, making the follow-up of cycles very difficult). This is why the Steering Committee has made a major investment in developing and implementing a new database in FileMaker Pro 6. It was also decided that cycles would be collected from one calendar year, as well as the pregnancies and babies ensuing from that particular calendar year. This gave us the opportunity to take a closer look at the data collected earlier, and to attempt to improve their quality. This is a report on the corrected data from the first three data collections (I-III) as well as the result of the last data collection (IV) that was completely carried out using the new database.

Data Collection↗
PubMed2004

ESHRE PGD Consortium 'Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)'.

Among the many educational materials produced by the European Society of Human Reproduction and Embryology (ESHRE) are guidelines. ESHRE guidelines may be developed for many reasons but their intent is always to promote best quality practices in reproductive medicine. In an era in which preimplantation genetic diagnosis (PGD) has become a reality, we must strive to maintain its efficacy and credibility by offering the safest and most effective treatment available. The dominant motivators for the development of current comprehensive guidelines for best PGD practice were (i) the absence of guidelines and/or regulation for PGD in many countries and (ii) the observation that no consensus exists on many of the clinical and technical aspects of PGD. As a consequence, the ESHRE PGD Consortium undertook to draw up guidelines aimed at giving information, support and guidance to potential, fledgling and established PGD centres. The success of a PGD treatment cycle is the result of great attention to detail. We have strived to provide a similar level of detail in this document and hope that it will assist staff in achieving the best clinical outcome for their patients.

Biopsy↗
PubMed2001

Allele-specific amplification for preimplantation genetic diagnosis (PGD) of spinal muscular atrophy.

We have developed a new allele-specific amplification method for the preimplantation genetic diagnosis (PGD) of spinal muscular atrophy (SMA; Werdnig-Hoffmann disease) from a single cell. This method is based on the detection of the deletion of exon 7 of the telomeric copy of the survival motor neurone (SMN(t)) gene. An oligonucleotide was designed to be specific to the SMN(t) nucleotidic sequence with exonic mismatch G (for SMN(t))-->A (for SMN(c)) at its 3' end. This test produces reliable PCR products in 95% of single lymphoblasts (85/88) tested as well as in 16/16 blastomeres from normal controls. Specificity analysis showed that we were able to detect homozygous deletion of the SMN(t) gene in 99% of single lymphoblasts (103/104) from a SMA patient. No contamination was detected in 68 blanks tested. Multiple cell and DNA dilution analysis revealed that the test is accurate and specific up to 100 pg DNA and should thus also be suitable for PGD at the blastocyst stage. This rapid procedure requires a single round of fluorescent PCR and no restriction digestion, while previously described single cell methods include nested PCR followed by restriction enzyme digestion. Two PGD cycles for SMA using this procedure were performed in our centre.

Adult↗
PubMed2001

[Twin birth after preimplantation diagnosis for cystic fibrosis].

OBJECTIVE: Cystic fibrosis is a common autosomal recessive disease most often caused by a deletion (delta F508) in the CFTR gene. It is the most common indication for preimplantaion genetic diagnosis which allows genetic analysis of embryos obtained after in vitro fertilization and transfer of unaffected embryos into the patient's uterus. PATIENTS AND METHODS: We report the first preimplantation genetic diagnosis performed in Strasbourg for a couple at risk of having a child affected by severe cystic fibrosis due to a homozygous delta F508 mutation. Three days after fertilisation, embryos obtained after intra-cytoplasmic testiculare sperm injection were biopsied and analysed. PCR amplification of the genomic fragment containing the delta F508 locus allowed detection of the delta F508 mutation and transfer only of the unaffected embryos. RESULTS: Three embryos were transferred after this preimplantation genetic diagnosis. A twin pregnancy was obtained and the babies born from this cycle are both exempt from the mutation. CONCLUSIONS: Preimplantation genetic diagnosis for the cystic fibrosis delta F508 mutation is now available in our centre. In this report, we could resolve both the problem of infertility and the risk of transmission of a severe form of cystic fibrosis. Preimplantation genetic diagnosis is also available for other mutations involved in cystic fibrosis and also for other genetic diseases.

Adult↗
PubMed2000

A clinical and genetic study of a manifesting heterozygote with X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM) characteristically causes severe or fatal muscle weakness in male infants. Mutations in the gene MTM1, encoding the protein myotubularin, can be identified in most families. Prior to this report, XLMTM was thought not to cause symptomatic manifestations in female carriers. We describe an adult female from a large family with typical XLMTM. The patient had progressive disabling muscle weakness of later onset and lesser severity than that observed in affected males. The distribution of weakness resembled typical XLMTM with facial weakness, marked limb-girdle weakness, respiratory muscle involvement and dysphagia. Analysis of the MTM1 gene identified a heterozygous missense mutation (G378R) within the highly conserved tyrosine phosphatase site of myotubularin. We did not identify significantly skewed X-inactivation. We conclude that XLMTM is capable of causing significant disability in heterozygotes.

Female↗
PubMed1999

Identification of novel mutations in the MTM1 gene causing severe and mild forms of X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM) is a congenital muscular disease characterized by severe hypotonia and generalized muscle weakness, leading in most cases to early postnatal death. The gene responsible for the disease, MTM1, encodes a dual specificity phosphatase, named myotubularin, which is highly conserved throughout evolution. To date, 139 MTM1 mutations in independent patients have been reported, corresponding to 93 different mutations. In this report we describe the identification of 21 mutations (14 novel) in XLMTM patients. Seventeen mutations are associated with a severe phenotype in males, with death occurring mainly before the first year of life. However, four mutations-three missense (R241C, I225T, and novel mutation P179S) and one single-amino acid deletion (G294del)-were found in patients with a much milder phenotype. These patients, while having a severe hypotonia at birth, are still alive at the age of 4, 7, 13, and 15 years, respectively, and display mild to moderate muscle weakness.

Adolescent↗
PubMed1997

Evolution of the Friedreich's ataxia trinucleotide repeat expansion: founder effect and premutations.

Friedreich's ataxia, the most frequent inherited ataxia, is caused, in the vast majority of cases, by large GAA repeat expansions in the first intron of the frataxin gene. The normal sequence corresponds to a moderately polymorphic trinucleotide repeat with bimodal size distribution. Small normal alleles have approximately eight to nine repeats whereas a more heterogeneous mode of large normal alleles ranges from 16 to 34 GAA. The latter class accounts for approximately 17% of normal alleles. To identify the origin of the expansion mutation, we analyzed linkage disequilibrium between expansion mutations or normal alleles and a haplotype of five polymorphic markers within or close to the frataxin gene; 51% of the expansions were associated with a single haplotype, and the other expansions were associated with haplotypes that could be related to the major one by mutation at a polymorphic marker or by ancient recombination. Of interest, the major haplotype associated with expansion is also the major haplotype associated with the larger alleles in the normal size range and was almost never found associated with the smaller normal alleles. The results indicate that most if not all large normal alleles derive from a single founder chromosome and that they represent a reservoir for larger expansion events, possibly through "premutation" intermediates. Indeed, we found two such alleles (42 and 60 GAA) that underwent cataclysmic expansion to pathological range in a single generation. This stepwise evolution to large trinucleotide expansions already was suggested for myotonic dystrophy and fragile X syndrome and may relate to a common mutational mechanism, despite sequence motif differences.

Alleles↗
PubMed1997

[Fragile X syndrome is still unrecognized: efficacy of molecular diagnosis in mentally retarded probands].

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.

Adolescent↗
PubMed1997

Transition from premutation to full mutation in fragile X syndrome is likely to be prezygotic.

In the fragile X syndrome, the transition from unmethylated moderate expansions of the CGG repeat (premutations) to methylated large expansions (full mutations) occurs only through maternal transmission. The risk of such transition is highly correlated with the size of the maternal premutation (PM), being very low for small PM alleles (approximately 60 repeats), to 100% for alleles above 100 repeats. The timing of this transition was the object of much speculation. A postzygotic transition was proposed as a preferred model, based on the observation that males with full mutation (FM) have PM in sperm. Analysis of tissues from affected fetuses, including additional data reported here, indicate that such a putative postzygotic transition would have to occur very early in embryogenesis and most likely before determination of germ cell lineage. At least 15% of carriers of a FM show a significant proportion of white blood cells carrying a PM (mutation mosaics). We performed a simulation study showing that, if transition to FM is postzygotic, one should observe a much higher proportion of such mosaics in offspring of mothers with small PMs. This was compared with the actual pattern observed in 212 mutated offspring of 112 PM carrier mothers. We found no effect of maternal PM size on incidence of mosaicism in leucocytes. We propose that this is strong, albeit indirect evidence against a postzygotic transition to FM. A transition at an early morula stage (before day 3) cannot, however, be formally excluded.

Child↗
PubMed1996

Genetic transmission of susceptibility to cancer in families of children with soft tissue sarcomas.

BACKGROUND: This article presents analysis of clinical and family data for 239 patients with childhood soft tissue sarcoma (STS) treated at the Institut Gustave Roussy in Villejuif. METHODS: A molecular study was performed to detect germline p53 mutations in the 44 families in which at least 1 relative developed cancer before the age of 46 or in which the proband had a second neoplasm. Mutations were found in five families. Standardized incidence ratio calculation and segregation analysis were used to study cancer occurrence in 4448 relatives, including first- and second-degree relatives and first cousins. RESULTS: An excess of brain tumors was observed in all relatives, and of breast carcinoma and STS in first-degree relatives of patients with STS. An excess of breast carcinoma was observed only in young mothers of patients with rhabdomyosarcoma. This excess might be mostly linked to the presence of a germline p53 mutation because it was no more significant when excluding families in which such a mutation existed. No association between breast carcinoma in the mother and rhabdomyosarcoma of the genitourinary tract in the proband was observed. This should be kept in mind when developing a screening strategy for breast carcinoma in mothers of patients with STS. Segregation analysis showed evidence for transmission of an autosomal dominant gene with complete penetrance by the age of 84. The genetic component was explained primarily by p53 germline mutations. CONCLUSIONS: These results show that most relatives of patients with STS are at the same risk for cancer as the general population.

Adult↗
PubMed1996

Cancers in relatives of children with non-Hodgkin's lymphoma.

We undertook a family study of children treated at the Institute Gustave-Roussy in France to investigate a familial aggregation of cancer in the families of children with non-Hodgkin's lymphoma (NHL). We obtained family dat for 284 children with NHL. Using the Standardized Incidence Ratio, we compared the observed and expected number of families with at least one proband relative affected by cancer at a young age (before 46 years). We found a small but non-significant excess of all tumors in first-degree relatives (SIR = 1.3, 95% CI = 0.7-2.3) explained by a small but non-significant excess of hematological malignancies (SIR = 1.5, 95% CI = 0.2-5.5), particularly Hodgkin's disease and leukemia, and of osteosarcoma (SIR = 7.5, 95% CI = 0.1-41.4). This is probably a lower bound of the SIR, because the expected number of families was estimated from cancer incidence in France between 1978 and 1982, whereas most cancers occurred before this period. Other tumors were not in excess in first-degree relatives.

Adolescent↗
PubMed1995

ARCAD: a method for estimating age-dependent disease risk associated with mutation carrier status from family data.

We present ARCAD, a method to estimate the disease risk associated with mutation carrier status using data on families ascertained by affected individuals, in which a germline mutation has been detected. Because the event of interest, the age of onset, is a censored variable, the method uses the survival analysis approach to formulate the likelihood. Provided that selection criteria are clearly defined, the ascertainment bias is removed by including a correction term in the likelihood computation. We simulated family data and selected those with a proband affected before age 17, and at least one or at least two relatives affected before age 46. We show that including the correction for the ascertainment provides reliable estimates of the risk, even when many individuals are not tested for the mutation. An application to cancer risk and germline p53 mutations is presented. We routinely investigate the p53 status for all the children treated in the Department of Pediatric Oncology at the Institute Gustave Roussy, whose family displays at least one relative affected by cancer before age 46. We identified 5 families with an inherited germline p53 mutation. The risk for any cancer for a mutation carrier estimated by ARCAD was 42% within the age class 0-16 years, 38% within the age class 17-45 years, and 63% after 45 years, with a lifetime risk of 85%. These risks are almost entirely explained by the occurrence of the six most frequent cancers encountered in the Li-Fraumeni syndrome.

Adolescent↗
PubMed1994

The French Wilms' tumour study: no clear evidence for cancer prone families.

Wilms' tumour of the kidney is known to occur in Beckwith-Wiedemann syndrome. It has also been described in four cancer prone families displaying Li-Fraumeni syndrome but it is not usually considered to be part of this syndrome. In order to detect particular familial cancer aggregations associated with this tumour, we studied the cancer incidence and mortality among relatives of the 501 Wilms' tumour patients in the French Wilms' Tumour Study. We found no familial association with breast cancer or soft tissue sarcomas which are the most common cancers in the Li-Fraumeni syndrome. However, we found two significant familial associations of Wilms' tumour with bone cancers on the one hand and with brain tumours on the other hand. These associations could reflect a small proportion of families segregating for some susceptibility gene. This should then be confirmed at the molecular level.

Adolescent↗