[Show abstract][Hide abstract] ABSTRACT: Objective
By-the-book implementation of NIPT and clinical validation for trisomy 21.Study DesignPublicly funded prospective study of 225 cases. Women at risk for trisomy 21 >1/250 based on combined ultrasound and serum markers during first or second trimester were eligible following informed consent. The technique was established from the available literature and performed on 10 mL of venous blood collected prior to CVS or amniocentesis. Investigators were blinded to the fetal karyotype. Results were expressed in z-scores of the percentage of each chromosome.ResultsAmong 976 eligible cases, 225 were processed: 8 were used for pre-testing phase and 23 to build a reference set. 136 euploid cases and 47 with trisomy 21 were then run randomly. 11 cases yielded no result (4.8%). Z-scores were above 3 (7.58 +/−2.41) for chromosome 21 in all 47 trisomies and in none of the euploid cases (0.11+/−1.0). Z-scores were within normal range for the other chromosomes in both groups. Using a cut-off of 3, sensitivity and specificity were of 100% (95%CI: 94.1-100) and 100% (95%CI: 98–100) respectively.ConclusionNIPT for trisomy 21 is a robust strategy that can be translated from seminal publications. Publicly funded studies should refine its indications and cost- effectiveness in prenatal screening and diagnosis. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Discordant chromosomal anomalies in monozygotic twins may be caused by various timing issues of erroneous mitosis and twinning events. Here, we report a prenatal diagnosis of heterokaryotypic monozygotic twins discordant for phenotype. In a 28-year-old woman, ultrasound examination performed at 26 weeks of gestation, detected intrauterine growth restriction and unilateral cleft lip and palate in twin B, whereas twin A had normal fluid, growth and anatomy. Molecular karyotyping in twin B identified a 18q21.2qter deletion, further confirmed by FISH analysis on amniocytes. Interestingly, in twin A, cytogenetic studies (FISH analysis and karyotype) on amniocytes were normal. Genotyping with microsatellite markers confirmed the monozygosity of the twins. At 32 weeks of gestation, selective termination of twin B was performed by umbilical cord coagulation and fetal blood samples were taken from the umbilical cord in both twins. FISH analyses detected mosaicism in both twins with 75% of cells being normal and 25% harboring the 18qter deletion. After genetic counseling, the parents elected to terminate the second twin at 36 weeks of gestation. In postmortem studies, FISH analyses revealed mosaicism on several tissues in both twins. Taking into account this observation, we discuss the difficulties of genetic counseling and management concerning heterokaryotypic monozygotic twins .
European journal of medical genetics 07/2013; 56(9). DOI:10.1016/j.ejmg.2013.06.007 · 1.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although discordant phenotypes in monozygotic twins with developmental disorder are not an exception, underlying genetic discordance is rarely reported. Here, we report on the clinical and cytogenetic details of 4-year-old female monozygotic twins with discordant phenotypes. Twin 1 exhibited global developmental delay, overweight and hyperactivity. Twin 2 had an autistic spectrum disorder. Molecular karyotyping in twin 1 identified a 2p25.3 deletion, further confirmed by FISH analysis on leukocytes. Interestingly, array-CGH was normal in twin 2 but FISH analysis using the same probe as twin 1 showed mosaicism with 1/3 of cells with a 2p25.3 deletion, 1/3 of cells with a 2p25.3 duplication, and 1/3 of normal cells. Genotyping with microsatellite markers confirmed the monozygosity of the twins. We propose that the chromosome imbalance may be due to a mitotic non-allelic recombination occurring during blastomeric divisions of a normal zygote. Such event will result in three distinct cell populations, whose proportion in each embryo formed after separation from the zygote may differ, leading to discordant chromosomal anomalies between twins. We also discuss that the MYTL1L and the SNTG2 genes within the reported region could probably relate to the phenotypic discordance of the monozygotic twins.
[Show abstract][Hide abstract] ABSTRACT: Preimplantation genetic diagnosis (PGD) is authorized in France since 1999. After 10 years, technical results are encouraging. With the development of new technologies, our team is able to diagnosis the large majority of chromosome translocations and 75 monogenic diseases. However, PGD remains limited because of the growing augmentation of demands causing an increasing delay for the first procedure of more than 18 months. Since 2006, 19 couples asked for a PGD with HLA typing. In January 2011, 11 couples have already been included in our PGD program. The birth of the first child after PGD with HLA typing offers new perspectives of treatment for these couples.
Journal de Gynécologie Obstétrique et Biologie de la Reproduction 09/2011; 40(7):682-6. DOI:10.1016/j.jgyn.2011.08.007 · 0.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectifs
Identifier des cellules exprimant les marqueurs de pluripotence SOX2, NANOG et OCT4 dans les tératomes sacro-coccygien (TSC). Le TSC peut compromettre le pronostic vital périnatal et a un risque de récurrence de 10 % après chirurgie. Son origine serait une anomalie de développement précoce du pôle caudal impliquant des cellules pluripotentes (CP).
Matériels et Méthodes
Immunomarquages de CP dans des embryons humains sains, dans des échantillons de TSC périnataux et diagnostiqués après 6 mois. Étude du comportement et du phénotype des cellules tumorales en culture.
Une coexpression de ces marqueurs a été observée dans le pôle caudal d’embryons sains (blastème et tube neural) au cours du 2e mois de développement. Des cellules exprimant ces marqueurs ont été identifiées dans les TSC périnataux et tardifs. Contrairement aux cellules de TSC tardifs, les cellules en culture de TSC néonataux se sont agrégées en structures similaires à des corps embryoïdes.
Des cellules exprimant des marqueurs de pluripotence sont présentes dans les TSC, et pourraient être à l’origine de la tumeur et de son évolution. Leur présence dans la région sacrococcygienne d’embryons sains soutient l’hypothèse d’une anomalie de la neurulation secondaire à l’origine des TSC.
Archives de Pédiatrie 06/2010; 17(6):2-2. DOI:10.1016/S0929-693X(10)70220-7 · 0.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Joubert syndrome (JBTS), related disorders (JSRDs) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein. Individuals with CORS2 frequently had nephronophthisis and polydactyly, and two affected individuals conformed to the oro-facio-digital type VI phenotype, whereas skeletal dysplasia was common in fetuses affected by MKS. A single G218T mutation (R73L in the protein) was identified in all cases of Ashkenazi Jewish descent (n=10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in mutant fibroblasts or after knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 formed a complex with Meckelin, which is encoded by a gene also mutated in JSRDs and MKS. Disruption of tmem216 expression in zebrafish caused gastrulation defects similar to those in other ciliary morphants. These data implicate a new family of proteins in the ciliopathies and further support allelism between ciliopathy disorders.
[Show abstract][Hide abstract] ABSTRACT: Cerebral proliferative glomeruloid vasculopathy (PGV) is a severe disorder of brain angiogenesis, resulting in abnormally thickened and aberrant perforating vessels, forming glomeruloids with inclusion-bearing endothelial cells. This peculiar vascular malformation was delineated by Fowler in 1972 as a stereotyped lethal fetal phenotype associating hydranencephaly-hydrocephaly with limb deformities, called Fowler syndrome (FS) or "proliferative vasculopathy and hydranencephaly-hydrocephaly" or "encephaloclastic proliferative vasculopathy" (OMIM#225790). In PGV, the disruptive impact of vascular malformation on the developing central nervous system (CNS) is now well admitted. However, molecular mechanisms of abnormal angiogenesis involving the CNS vasculature exclusively remain unknown, as no genes have been localized nor identified to date. We observed the pathognomonic FS vascular malformation in 16 fetuses, born to eight families, four consanguineous and four non-consanguineous. A diffuse form of PGV affecting the entire CNS and resulting in classical FS in 14 cases, can be contrasted to two cases with focal forms, confined to restricted territories of the CNS. Interestingly in PGV, immunohistological response to a marker of pericytes (SMA, Smooth in PGV Muscle Actin), was drastically reduced as compared to a match control. Our studies has expanded the description of FS to additional phenotypes, that could be called Fowler-like syndromes and suggest that the pathogenesis of PGV may be related to abnormal pericyte-dependent remodelling of the CNS vasculature, during CNS angiogenesis. Gene identification will determine the molecular basis of PGV and will help to know whether the Fowler-like phenotypes are due to the same underlying molecular mechanisms.
European journal of medical genetics 08/2009; 52(6):386-92. DOI:10.1016/j.ejmg.2009.07.006 · 1.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2009; 23(7):1359-61. DOI:10.1038/leu.2009.79 · 9.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Deletions of chromosome 19 have rarely been reported, with the exception of some patients with deletion 19q13.2 and Blackfan-Diamond syndrome due to haploinsufficiency of the RPS19 gene. Such a paucity of patients might be due to the difficulty in detecting a small rearrangement on this chromosome that lacks a distinct banding pattern. Array comparative genomic hybridisation (CGH) has become a powerful tool for the detection of microdeletions and microduplications at high resolution in patients with syndromic mental retardation.
Using array CGH, this study identified three interstitial overlapping 19q13.11 deletions, defining a minimal critical region of 2.87 Mb, associated with a clinically recognisable syndrome. The three patients share several major features including: pre- and postnatal growth retardation with slender habitus, severe postnatal feeding difficulties, microcephaly, hypospadias, signs of ectodermal dysplasia, and cutis aplasia over the posterior occiput. Interestingly, these clinical features have also been described in a previously reported patient with a 19q12q13.1 deletion. No recurrent breakpoints were identified in our patients, suggesting that no-allelic homologous recombination mechanism is not involved in these rearrangements.
Based on these results, the authors suggest that this chromosomal abnormality may represent a novel clinically recognisable microdeletion syndrome caused by haploinsufficiency of dosage sensitive genes in the 19q13.11 region.
Journal of Medical Genetics 02/2009; 46(9):635-40. DOI:10.1136/jmg.2008.062034 · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pierre Robin sequence (PRS) is an important subgroup of cleft palate. We report several lines of evidence for the existence of a 17q24 locus underlying PRS, including linkage analysis results, a clustering of translocation breakpoints 1.06-1.23 Mb upstream of SOX9, and microdeletions both approximately 1.5 Mb centromeric and approximately 1.5 Mb telomeric of SOX9. We have also identified a heterozygous point mutation in an evolutionarily conserved region of DNA with in vitro and in vivo features of a developmental enhancer. This enhancer is centromeric to the breakpoint cluster and maps within one of the microdeletion regions. The mutation abrogates the in vitro enhancer function and alters binding of the transcription factor MSX1 as compared to the wild-type sequence. In the developing mouse mandible, the 3-Mb region bounded by the microdeletions shows a regionally specific chromatin decompaction in cells expressing Sox9. Some cases of PRS may thus result from developmental misexpression of SOX9 due to disruption of very-long-range cis-regulatory elements.
[Show abstract][Hide abstract] ABSTRACT: The advent of comparative genomic hybridization on DNA chips or CGH-arrays is changing drastically the present clinical practice in the detection and diagnosis of human chromosome abnormalities. Several studies have shown that, using classical and molecular cytogenetics techniques, a chromosome abnormality is observed in at least 15% of mentally-retarded patients with or without a congenital malformation (2–3% of the general population). Also, this technology contributes to the nosology and to our understanding of the molecular basis of numerous malignancies, improving therefore their diagnosis and opening up new avenues for drugs discovery. Today, still limited to some research laboratories, this novel technology is establishing itself as the method of choice to detect and diagnose human constitutional and acquired chromosome abnormalities observed in hospital-based laboratories. In the present review, we are explaining the basic principles of CGH-arrays, showing its main place in the armamentarium of cytogenetic techniques, stating its indications and limitations in the detection and the diagnosis of human chromosome abnormalities and describing the drastic changes induced by its application into hospital-based laboratories.
[Show abstract][Hide abstract] ABSTRACT: Smith-Magenis syndrome (SMS) is rare (prevalence 1 in 25 000) and is associated with psychomotor delay, a particular behavioural pattern and congenital anomalies. SMS is often due to a chromosomal deletion of <4 Mb at the 17p11.2 locus, leading to haploinsufficiency of numerous genes. Mutations of one of these gemes, RAI1, seems to be responsible for the main features found with heterozygous 17p11.2 deletions.
We studied DNA from 30 patients with SMS using a 300 bp amplimers comparative genome hybridisation array encompassing 75 loci from a 22 Mb section from the short arm of chromosome 17.
Three patients had large deletions (10%). Genotype-phenotype correlation showed that two of them had cleft palate, which was not found in any of the other patients with SMS (p<0.007, Fisher's exact test). The smallest extra-deleted region associated with cleft palate in SMS is 1.4 Mb, contains <16 genes and is located at 17p11.2-17p12. Gene expression array data showed that the ubiquitin B precursor (UBB) is significantly expressed in the first branchial arch in the fourth and fifth weeks of human development.
These data support UBB as a good candidate gene for isolated cleft palate.
Journal of Medical Genetics 09/2007; 44(8):537-40. DOI:10.1136/jmg.2006.048736 · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The phenotypic spectrum of 46,XX/46,XY chimeric patients is variable. It ranges from normal male or female genitalia to different degrees of ambiguous genitalia. Chimerism results from the amalgamation of two different zygotes in a single embryo, whereas mosaicism results from a mitotic error in a single zygote. Several other mechanisms resulting in a chimera have been discussed in the literature. Here, we report on a new case of chimerism (46,XX/46,XY) diagnosed at 17 weeks' gestation on amniocentesis performed because of advanced maternal age. Ultrasound examination revealed normal female external genitalia, and a healthy baby girl was delivered at term. We used polymorphic markers spanning the X chromosome and several autosomes in order to identify the genetic mechanism involved. Mosaicism was excluded because of the presence of 3 alleles at 11 autosomal and 4 X chromosome loci. On autosomes, the origin of this third allele was maternal for two pericentromeric markers (located on 2p11.2 band and 8p11.2 band), paternal for six markers and paternal or maternal for the other three markers. On the X chromosome, the origin of the third allele was maternal for all four markers. Thus, two different paternal and maternal haploid sets were observed. These results are compatible with a tetragametic chimera.
Human Reproduction 05/2007; 22(4):1037-41. DOI:10.1093/humrep/del480 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The finding of a mixture of 46,XX and 46,XY cells in an individual has been rarely reported in literature. It usually results in individuals with ambiguous genitalia. Approximately 10% of true human hermaphrodites show this type of karyotype. However, the underlying mechanisms are poorly understood. It may be the result of mosaicism or chimerism. By definition, a chimera is produced by the fusion of two different zygotes in a single embryo, while a mosaic contains genetically different cells issued from a single zygote. Several mechanisms are involved in the production of chimera. Stricto sensu, chimerism occurs from the post-zygotic fusion of two distinct embryos leading to a tetragametic chimera. In addition, there are other entities, which are also referred to as chimera: parthenogenetic chimera and chimera resulting from fertilization of the second polar body. Furthermore, a particular type of chimera called 'androgenetic chimera' recently described in fetuses with placental mesenchymal dysplasia and in rare patients with Beckwith-Wiedemann syndrome is discussed. Strategies to study mechanisms leading to the production of chimera and mosaics are also proposed.