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Objectives – To create a follow-up protocol for pregnant patients with Marfan syndrome.Patients and methods – We retrospectively reviewed the charts of patients who delivered in the Jeanne de Flandre University Hospital between June 1996 and June 1999. Four pregnant patients with Marfan syndrome were identified.Results – Three of these patients had Bentall procedure. One of them had vaginal delivery and the two others underwent cesarean section. One of these two patients developed aortic valve thrombus at 14 weeks of amenorrhea. The fourth patient did not have surgery and had two vaginal deliveries.Discussion – According to our results and after reviewing literature pregnant patients with Marfan syndrome were divided into two groups. The 1st group was comprised of patients who underwent Bentall procedure. The 2nd one was comprised of patients who did not undergo any surgical procedure. The possibility of vaginal delivery for patients who underwent Bentall procedure (one case) and the interest of Propanolol® and anticoagulant treatment are emphasized.Conclusion – The multivariant approach of pregnant patients with Marfan syndrome is stressed out with special reference to the potential complications of this syndrome such as aortic dissection and to the problems related to the anticoagulant treatment [ABSTRACT FROM AUTHOR]

We describe a family of seven boys affected by Lesch-Nyhan disease with various phenotypes. Further investigations revealed a mutation c.203T>C in the gene encoding HGprt of all members, with substitution of leucine to proline at residue 68 (p.Leu68Pro). Thus patients from this family display a wide variety of symptoms although sharing the same mutation. Mutant HGprt enzyme was prepared by site-directed mutagenesis and the kinetics of the enzyme revealed that the catalytic activity of the mutant was reduced, in association with marked reductions in the affinity towards phosphoribosylpyrophosphate (PRPP). Its Km for PRPP was increased 215-fold with hypoxanthine as substrate and 40-fold with guanine as substrate with associated reduced catalytic potential. Molecular modeling confirmed that the most prominent defect was the dramatically reduced affinity towards PRPP. Our studies suggest that the p.Leu68Pro mutation has a strong impact on PRPP binding and on stability of the active conformation. This suggests that factors other than HGprt activity per se may influence the phenotype of Lesch-Nyhan patients., (© 2013 Elsevier Inc. All rights reserved.)

UMD-DMD France is a knowledgebase developed through a multicenter academic effort to provide an up-to-date resource of curated information covering all identified mutations in patients with a dystrophinopathy. The current release includes 2,411 entries consisting in 2,084 independent mutational events identified in 2,046 male patients and 38 expressing females, which corresponds to an estimated number of 39 people per million with a genetic diagnosis of dystrophinopathy in France. Mutations consist in 1,404 large deletions, 215 large duplications, and 465 small rearrangements, of which 39.8% are nonsense mutations. The reading frame rule holds true for 96% of the DMD patients and 93% of the BMD patients. Quality control relies on the curation by four experts for the DMD gene and related diseases. Data on dystrophin and RNA analysis, phenotypic groups, and transmission are also available. About 24% of the mutations are de novo events. This national centralized resource will contribute to a greater understanding of prevalence of dystrophinopathies in France, and in particular, of the true frequency of BMD, which was found to be almost half (43%) that of DMD. UMD-DMD is a searchable anonymous database that includes numerous newly developed tools, which can benefit to all the scientific community interested in dystrophinopathies. Dedicated functions for genotype-based therapies allowed the prediction of a new multiexon skipping (del 45-53) potentially applicable to 53% of the deleted DMD patients. Finally, such a national database will prove to be useful to implement the international global DMD patients' registries under development.

The p11.2-p12 region of human chromosome 17 is gene rich and composed of at least two genomically unstable domains: the Smith-Magenis syndrome region (17p11.2) and the Charcot-Marie-Tooth region (17p12), both of which are flanked by several low-copy repeat sequences. Homologous recombination between these flanking repeats results in either deletion- or duplication-associated phenotypes caused by a gene dosage effect. We report on the clinical phenotype of three patients presenting with either a 17p11.2 or 17p11.2p12 duplication, revealed by chromosome analysis and confirmed by fluorescent in situ hybridization analysis, high resolution genomic analysis of the 17p region using oligonucleotide array comparative genomic hybridization, and molecular studies with microsatellite markers. Two patients carry the 17p11.2 duplication, while the third one shows a larger duplication including the 17p12 region. The facial features observed in our patients include triangular face, full cheeks, smooth philtrum, thin upper lip, dental malocclusion, irregular eyebrows, and sparse hair, all of which are consistent with the pure proximal dup 17p phenotype. The patients' other clinical features are compared with previously published cases., (Copyright 2008 Wiley-Liss, Inc.)

Benign hereditary chorea is a rare autosomal dominant disorder presenting with a childhood-onset and slowly progressive chorea. The objective of this study was to describe the clinical and genetic features of 3 patients who developed childhood-onset chorea. Three affected patients from three generations of a family with benign hereditary chorea associated with a multisystemic disorder of the basal ganglia, thyroid, lungs, salivary glands, bowels, and teeth. The TITF-1 gene was screened by microsatellite analysis, gene sequencing, and fluorescence in situ hybridization. Genetic analysis revealed a novel 0.9-Mb deletion on chromosome 14, which includes the TITF-1 and PAX9 genes. We have identified a novel deletion responsible for a new syndrome of benign hereditary chorea, including symptoms of brain-thyroid-lung syndrome associated with bowels, salivary glands, and teeth disorders. Associated signs, sometimes of slight expression, remain of high interest for the clinical and genetic diagnosis of benign hereditary chorea., (Copyright 2006 Movement Disorder Society.)

Objectives: To create a follow-up protocol for pregnant patients with Marfan syndrome., Patients and Methods: We retrospectively reviewed the charts of patients who delivered in the Jeanne de Flandre University Hospital between June 1996 and June 1999. Four pregnant patients with Marfan syndrome were identified., Results: Three of these patients had Bentall procedure. One of them had vaginal delivery and the two others underwent cesarean section. One of these two patients developed aortic valve thrombus at 14 weeks of amenorrhea. The fourth patient did not have surgery and had two vaginal deliveries., Discussion: According to our results and after reviewing literature pregnant patients with Marfan syndrome were divided into two groups. The 1st group was comprised of patients who underwent Bentall procedure. The 2nd one was comprised of patients who did not undergo any surgical procedure. The possibility of vaginal delivery for patients who underwent Bentall procedure (one case) and the interest of Propanolol and anticoagulant treatment are emphasized., Conclusion: The multivariant approach of pregnant patients with Marfan syndrome is stressed out with special reference to the potential complications of this syndrome such as aortic dissection and to the problems related to the anticoagulant treatment.

Objective: We describe the different ultrasound findings suggestive of trisomy 18., Patients and Methods: We conducted a retrospective study in 40 cases of trisomy 18 diagnosed in the department of obstetrics at the Lille University Hospital between 1988 and 1998., Results: Eighty percent of the women in this series were multiparous. Mean maternal age at discovery of the trisomy as 33.2 years and the mean gestational age was 20.4 weeks. Fifty-five percent of the cases were discovered during the second trimester of pregnancy, 22.5% during the third trimester and 22.5% during the first trimester. One ultrasound abnormality, at least, was detected in 36/40 cases (90%) a percentage that reached 96.8% taking into consideration the ultrasound examinations performed during the second and third trimesters (30/31 cases). The most frequently detected ultrasound abnormalities were: intra uterine growth retardation (IUGR: 50%), poly-hydramnios (42.5%), limb abnormalities (42.5%), cardiac defects (30%), facial abnormalities (37.5%), meningomyelocele (32.5%), digestive abnormalities (32.5%), urinary tract abnormalities (27.5%), lymphangiectasia and cystic hygroma (15%), and single umbilical artery (12.5%). Medical termination of pregnancy (TOP) was performed in 28 cases. There was one spontaneous miscarriage at 8 weeks and one in utero death (IUD) at 39 weeks in a patient who desired to continue her pregnancy. In 6 cases, the issue of the pregnancy was unknown because the patients were lost to follow-up. In 4 cases (10%), pregnancy was continued to delivery of live babies that only survived a few minutes to 7 days., Conclusion: The ultrasound signs suggestive of trisomy 18 change according to the term of pregnancy. At the first trimester, most of the signs are nonspecific, such as cystic hydroma or lymphangiectasia, and do not suggest the need for a karyotype. At the end of the second trimester, an association of various signs that alone would not be highly suspect suggest the need for further exploration in search of other signs: early IUGR, associated or not with poly-hydramnios, limb abnormalities, cardiac defects, omphalocele, diaphragmatic hernia, meningomyelocele, enlarged cisterna magna, choroid plexus cysts, single umbilical artery, facial dysmorphism, facial cleft, hydronephrosis.

Uptake of fatty acids into cells is a controlled process in part regulated by fatty acid transport proteins (FATPs), which facilitate the transport of fatty acids across the cell membrane. In this study the structure of the human FATP-1 (HGMW-approved symbol SLC27A1) cDNA and gene was determined, and the expression of its mRNA in human was characterized. Muscle and adipose tissue have the highest levels of FATP-1 mRNA, small intestine has intermediate levels, and FATP-1 mRNA is barely detectable in liver. The human FATP-1 gene has 12 exons and extends over more than 13 kb of genomic DNA. The FATP gene maps to chromosome 19p13.1 by fluorescence in situ hybridization, a region previously suggested to be implicated in the determination of small dense low-density lipoprotein (LDL). Knowledge of the gene structure and chromosomal localization will allow screening for FATP mutations in humans with metabolic disorders, whereas knowledge of its expression pattern and factors regulating its expression could be of importance in understanding its biology., (Copyright 2000 Academic Press.)

The prenatal diagnosis of trisomy for the distal half of the short arm of n(o) 9 chromosome (partial trisomy 9p) has been realized from a morphologic ultrasound. A genetic investigation has permitted to establish that this trisomy was due to a bad segregation of a stable translocation present in the patient's mother. To our knowledge, the ultrasound prenatal diagnosis of partial trisomy 9p has never been reported in the literature. The prognosis of this syndrome remains very pejorative and the termination of pregnancy is the most often proposed solution.

The present study was undertaken to determine whether differences among Alport kindreds in the antigenic phenotypes of their basement membranes result from defects at distinct genetic loci or from allelic mutations at a single locus. We analyzed linkage of the Alport gene to polymorphic loci on the X chromosome in three families with Alport syndrome. In two of the families, epidermal basement membranes of affected members showed altered immunohistologic reactivity with a discriminating antibody (FNS1) that identified a 26 kD peptide in the NCl domain of basement membrane collagen. In the third family epidermal basement membranes of affected individuals reacted normally with the antibody. The disease gene mapped to the Xq21-q22 region of the long arm of the X chromosome in the two families with altered basement membrane antigenicity and in the family with normal basement membrane antigens. We conclude that Alport syndrome in each of these kindreds arose from allelic mutations at a single genetic locus, although we cannot at this time exclude the possibility that two or more tightly linked genes are involved. As the genes for the known chains of type IV collagen are on chromosome 13, our findings suggest that the Alport gene may encode a new basement membrane collagen chain.

A locus responsible for a restriction fragment length polymorphism (RFLP) has been identified by hybridization of Eco RI fragments to the random human DNA sequence in recombinant plasmid pAW101. We have examined DNA extracted from 20 human X Chinese hamster somatic cell hybrids for the presence of sequences homologous to the human insert in pAW101. The hybrids were derived from six different human donors, five of whom were heterozygous, producing two bands on Southern transfers. The presence of homologous sequences in the hybrids correlated exclusively with the presence of human chromosome 14. Three hybrids contained chromosome 14 in a frequency of greater than one per cell and were positive for two alleles. Two hybrids contained only the distal half of the long arm of 14 as part of a translocation and were still positive. These results assign the first highly polymorphic random RFPL locus (D14S1) to region q21 leads to qter of chromosome 14.

The human protooncogene NRAS and the genes for the beta-subunit of nerve growth factor (NGFB) and for amylase (AMY) have previously been assigned to the proximal short arm of chromosome 1, but their precise positions have not been unequivocally established. By in situ hybridization of DNA probes for the three genes, we have ascertained the location of complementary sequences in mouse-human somatic cell hybrids that contained translocations of chromosome 1. The results agreed with the presence or absence of the human sequences as determined by Southern blotting of hybrid cell DNA. The in situ data confirmed that the genes were present on the cytologically recognized rearranged chromosome. Compared to the autoradiographic silver grain distribution on normal human chromosome 1, our in situ results obtained with the translocation chromosomes allowed much greater precision of mapping. Both NRAS and NGFB map to band 1p22, and AMY was confirmed in band 1p21.

We have mapped the genes for murine immunoglobulin lambda light chains to the region of chromosome 16 proximal to band B5 by hybridizing a cDNA probe for gamma light chains to the DNA of a series of hybrid clones made between mouse fibroblasts carrying Searle's translocation, T(X;16)16H, and Chinese hamster cells. Based on homology, we predict that the human Ig gamma gene (IGL) will map to the proximal two-thirds of HSA 22.

The localization of protooncogenes on human chromosomes may coincide with chromosome breakpoints of consistent translocations in leukaemias or lymphomas, suggesting a direct involvement of oncogenes in carcinogenesis. For example, in Burkitt's lymphoma consistent translocations may be associated with rearrangements of c-myc. Our assignment of the c-Harvey-ras1 oncogene to chromosome 11, precisely to region 11p11 leads to p15 (ref. 5; not 11p13 as stated in ref. 6), has raised the possibility that this oncogene might have a role in the predisposition to nephroblastoma (Wilms' tumour, WT) seen in the aniridia-WT association (AWTA) that is frequently caused by an interstitial deletion of band 11p (ref. 8). We have now studied the organization and copy number of sequences at three loci mapped to 11p: c-Ha-ras1, insulin and gamma-globin in cells from four individuals with structural rearrangements of the short arm of chromosome 11. Our results reported here rule out a close physical linkage between c-Ha-ras1 and the genes responsible for AWTA, and suggest a more distal localization of the beta-globin cluster than currently assumed.

Fragments of the recently cloned human gene for the beta subunit of nerve growth factor (beta-NGF) were used as hybridization probes in analyzing two sets of rodent-human somatic cell hybrids for the presence of human beta-NGF sequences. Results from the first set of hybrids assigned the human beta-NGF gene to chromosome 1 and ruled out the presence of sequences of comparable homology on any other chromosome. With the second set of hybrids, which contained seven different, but overlapping, regions of chromosome 1, the NGF locus was mapped to band 1p22.

We investigated the reliability of chorionic villous biopsy as a method to obtain tissues reflecting the genetic constitution of the embryo. In 12 pregnancies before elective termination, we searched for detectable maternal tissue after careful dissection of villi from small 2-5-mg specimens that yielded 7 micrograms of DNA per mg tissue. In Southern blotting experiments (1-2 micrograms DNA per lane), restriction fragment length polymorphisms (RFLPs) at an autosomal (D14S1) and a sex chromosomal (DXYS1) locus allowed recognition of maternally and embryonically derived alleles. Pure villi were obtained in six of the seven informative cases. One biopsy was not dissected satisfactorily; a mixture of embryonic and maternal DNA was found. Nonvillous tissues were mostly maternally derived in eight informative cases. Sex determination by molecular analysis (alleles at the DXYS1 locus) agreed with the karyotypes of uncultured or cultured villi. In one continuing pregnancy, distinct RFLPs indicated maternal inheritance of the alpha-thalassemia 1 trait in a female embryo without detectable maternal contamination. Reliable prenatal diagnosis depends on the specimen's purity. Maternal contamination can be evaluated by DNA analyses.

Panels of somatic cell hybrid lines carrying various structural rearrangements of the human X chromosome short arm were analyzed with 21 X-chromosome-specific cloned DNA fragments. We mapped these molecular markers to five different regions of the short arm of the X chromosome. The results were confirmed by gene-dosage studies of human lymphoblasts with structurally abnormal X chromosomes. The ornithine transcarbamylase gene and four anonymous DNA sequences map within band Xp21, flanking the presumed locus for Duchenne muscular dystrophy.

The human cellular homolog of the transforming DNA sequence isolated from the bladder carcinoma cell line EJ was localized on the short arm of human chromosome 11 by Southern blot analysis of human-rodent hybrid cell DNA. This locus contains human sequences homologous to the Harvey murine sarcoma virus v-Ha-ras oncogene.

Three cloned single copy sequences isolated from a random partial plasmid library of human EcoRI-HindIII restriction fragments detect MspI site polymorphisms in human DNA. Since at least two of them have allele frequencies that make them suitable for family linkage studies, we have determined their chromosomal localizations. DNA samples extracted from a panel of 31 Chinese hamster x human somatic cell hybrids, that were derived from six different human donors, were analyzed for the presence of human EcoRI or HindIII fragments hybridizing with the three probes. The results were correlated with the human chromosome contents of the hybrids. Concordancy was observed for clone pMS 1-14 (preliminary locus designation DOSLC3) and human chromosome 15, for clone pMS 1-27 (DOSLC2) and chromosome 20, and for clone pMS 1-37 (DOSLC1) and chromosome 3. Two independent hybrids had retained only the long arm of chromosome 3 and did not hybridize with this probe. Therefore, we assign this locus (now termed D3S3) to the short arm of chromosome 3.

The gene for the mitochondrial enzyme ornithine transcarbamylase was mapped to the short arm of the X chromosome by in situ hybridization experiments, with DNA complementary to the human ornithine transcarbamylase gene used as a probe. A series of cell lines with X chromosome abnormalities was used to localize the gene to band Xp21.1. Because the gene maps near the Duchenne muscular dystrophy locus, the ornithine transcarbamylase probe may be useful in carrier detection and prenatal diagnosis of Duchenne muscular dystrophy as well as of ornithine transcarbamylase deficiency.

We are reporting a male patient who suffered from chronic granulomatous disease associated with cytochrome b-245 deficiency and McLeod red cell phenotype, Duchenne muscular dystrophy, and retinitis pigmentosa. On cytogenetic analysis, he seemed to have a very subtle interstitial deletion of part of band Xp21. Since it was impossible to know whether this material was truly deleted or inserted elsewhere in the genome, somatic cell and molecular studies were carried out. In somatic cell hybrids, the deleted X chromosome was isolated on a Chinese hamster background. Southern blot analysis with 20 single-copy probes, that had been mapped to the X short arm, led to the discovery of one (probe 754) that is missing from this patient's X chromosome and also from his total DNA. This proves that he, indeed, has a deletion rather than a balanced insertion. The results provide cytological mapping information for the X-linked phenotypes present in this patient. Furthermore, probe 754 recognizes a restriction fragment length polymorphism of high frequency that makes it the most powerful probe currently available for linkage studies with X-linked muscular dystrophy.

Currently, molecular methods are the most accurate diagnostic tools for carrier detection and prenatal diagnosis of Duchenne muscular dystrophy (DMD). This report illustrates the value of molecular diagnosis as opposed to previous diagnostic methods, the need for frequent re-evaluations as new methodologies develop, and the necessity for in-depth genetic counseling. In Family 1, the proposita was predicted to be a carrier by an indirect assay (abnormal in vitro muscle ribosomal protein synthesis). DNA analysis using restriction fragment length polymorphisms (RFLPs) indicated that she was not a carrier. She gave birth to a predicted non-affected male, who inherited the gene in question. In Family 2 the proposita, an obligate carrier, was initially evaluated by RFLP analysis. Two pregnancies were monitored by first trimester chorionic villous sampling. Re-evaluation indicated that all affected individuals, including one of the embryos, carried a deletion of the dystrophin gene. The identification of an RFLP within the region containing the deletion allowed unambiguous determination of the carrier status of all individuals.

Human phosphofructokinase (PFK; EC 2.7.1.11) is under the control of three structural loci which encode muscle-type (M), live-type (L), and platelet-type (P) subunits; human diploid fibroblasts and leukocytes express all three loci. In order to assign human PFKM locus to a specific chromosome we have analyzed human x Chinese hamster somatic cell hybrids for the expression of human M subunits, using an anti-human M subunit-specific mouse monoclonal antibody. In 18 of 19 hybrids studied, the expression of the PFKM locus segregated concordantly with the presence of chromosome 1 (discordance rate 0.05) as indicated by chromosome and isozyme marker analysis. The discordance rates for all the other chromosomes were 0.32 or greater, indicating that the PFKM locus is on chromosome 1. For the regional mapping of PFKM, eight hybrids were studied that contained one of five distinct regions of chromosome 1. These results further localize the human PFKM locus to region cen leads to q32 chromosome 1.

The human N-ras oncogene, isolated from the HL-60 promyelocytic leukemia cell line, is distantly related to viral oncogenes of Kirsten and Harvey sarcoma viruses. We have determined its chromosomal location by Southern blot analysis of DNAs from 37 human x rodent hybrid cell lines derived from 8 different human donors, some of whom carried balanced rearrangements of chromosome 1. The results indicate that the N-ras oncogene (RASN) is localized on the proximal part of the short arm of human chromosome 1, in region p3200 leads to cen.

We have isolated cDNA clones complementary to a c-Ki-ras cellular oncogene that is amplified in Y1 mouse adrenal tumor cells, with the amplified sequences located on double-minute chromatin bodies (DMs) and homogeneously staining chromosomal regions (HSRs). Characterization of the cDNAs included the isolation of corresponding genomic clones, Northern blot analysis of RNA, and DNA sequence analysis. Our studies demonstrate that the c-Ki-ras gene amplified in the Y1 cells is homologous to the human c-Ki-ras2 gene. We have also obtained evidence that, in addition to c-Ki-ras, at least one other transcription unit has been amplified in the mouse adrenal tumor cells. Moreover, by Southern blot analysis of Chinese hamster-mouse somatic cell hybrids, we have determined that the amplified DNA sequences associated with DMs and HSRs, including the c-Ki-ras gene, are present in normal mouse cells on chromosome 6.

Two unrelated males, a 43-year-old man with azoospermia and a 4-year-old boy with stature at the 10th centile, had similar karyotypes: 46,X,min. The minutes, present in all cells analyzed, stained weakly with G-, C-, and Q-banding methods. To elucidate their origin we used molecular techniques: In HaeIII digests of total genomic DNA from both individuals, no Y-specific reiterated sequences were detected. However, restriction fragment analysis with probe pDP31 demonstrated that the patients' DNA contained the Y-specific fragment. In situ hybridization with the same probe showed that these sequences were present on the minute chromosomes and have not been translocated elsewhere.

Monozygotic twins discordant for the Wiedemann-Beckwith syndrome (WBS) were studied by cytogenetic and molecular methods to determine if a genetic lesion could be detected in the affected child. Probes known to be localized on the short arm of chromosome 11 and a low copy-repetitive probe were used. No genetic lesions could be ascertained in normal or affected tissue obtained from the WBS twin.

The chromosomal assignments of an expressed beta-tubulin gene and two related sequences have been determined by Southern blot analysis of DNA from a panel of human x Chinese hamster somatic cell hybrids cleaved with Hind III or EcoRI. Probes containing the 3' untranslated regions of the expressed gene M40 and of pseudogene 21 beta were used to localize the M40 sequence (gene symbol TUBB) to chromosome 6 region 6p21----6pter, the 21 beta pseudogene (TUBBP1) to chromosome 8 region 8q21----8pter and a third related sequence (TUBBP2) to chromosome 13. Asynteny of expressed genes and related processed pseudogenes has now been demonstrated for several gene families.