Nicole Bigi

Antenatal spectrum of CHARGE syndrome in 40 fetuses with CHD7 mutations

Background CHARGE syndrome is a rare, usually sporadic disorder of multiple congenital anomalies ascribed to a CHD7 gene mutation in 60% of cases. Although the syndrome is well characterised in children, only one series of 10 fetuses with CHARGE syndrome has been reported to date. Therefore, we performed a detailed clinicopathological survey in our series of fetuses with CHD7 mutations, now extended to 40 cases. CHARGE syndrome is increasingly diagnosed antenatally, but remains challenging in many instances. Method Here we report a retrospective study of 40 cases of CHARGE syndrome with a CHD7 mutation, including 10 previously reported fetuses, in which fetal or neonatal clinical, radiological and histopathological examinations were performed. Results Conversely to postnatal studies, the proportion of males is high in our series (male to female ratio 2.6:1) suggesting a greater severity in males. Features almost constant in fetuses were external ear anomalies, arhinencephaly and semicircular canal agenesis, while intrauterine growth retardation was never observed. Finally, except for one, all other mutations identified in our antenatal series were truncating, suggesting a possible phenotype–genotype correlation. Conclusions Clinical analysis allowed us to refine the clinical description of CHARGE syndrome in fetuses, describe some novel features and set up diagnostic criteria in order to help the diagnosis of CHARGE syndrome after termination of pregnancies following the detection of severe malformations.

Prader‐Willi syndrome: is there a recognizable fetal phenotype?

To determine fetal features, which could lead to the diagnosis of Prader‐Willi syndrome (PWS) during pregnancy.

Identification of proteomic changes during human liver development by 2D-DIGE and mass spectrometry

BACKGROUND/AIMS The aim of this study was to identify human liver proteins that are associated with different stages of liver development. METHODS We collected liver samples from 14 fetuses between 14 and 41 weeks of development, one child and four adults. Proteins which exhibited consistent and significant variations during development by two-dimensional differential in gel electrophoresis (2D-DIGE) were subjected to peptide mass fingerprint analysis by MALDI-TOF mass spectrometry. Real-time PCR analysis confirmed, at the transcriptional level, the data obtained by the proteomic approach. RESULTS Among a total of 80 protein spots showing differential expression, we identified 42 different proteins or polypeptide chains, of which 26 were upregulated and 16 downregulated in developing in comparison to adult liver. These proteins could be classified in specific groups according to their function. By comparing their temporal expression profiles, we identified protein groups that were associated with different developmental stages of human fetal liver and suggest that the changes in protein expression observed during the 20- to 36-week time window play a pivotal role in liver development. CONCLUSIONS The identification of these proteins may represent good markers of human liver and stem cells differentiation.

Severe X-linked chondrodysplasia punctata in nine new female fetuses

Conradi–Hünermann–Happle [X‐linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X‐linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations.

A balance between activating and repressive histone modifications regulates cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo

The genetic mechanisms that regulate CFTR, the gene responsible for cystic fibrosis, have been widely investigated in cultured cells. However, mechanisms responsible for tissue-specific and time-specific expression are not completely elucidated in vivo. Through the survey of public databases, we found that the promoter of CFTR was associated with bivalent chromatin in human embryonic stem (ES) cells. In this work, we analyzed fetal (at different stages of pregnancy) and adult tissues and showed that, in digestive and lung tissues, which expressed CFTR, H3K4me3 was maintained in the promoter. Histone acetylation was high in the promoter and in two intronic enhancers, especially in fetal tissues. In contrast, in blood cells, which did not express CFTR, the bivalent chromatin was resolved (the promoter was labeled by the silencing mark H3K27me3). Cis-regulatory sequences were associated with lowly acetylated histones. We also provide evidence that the tissue-specific expression of CFTR is not regulated by dynamic changes of DNA methylation in the promoter. Overall, this work shows that a balance between activating and repressive histone modifications in the promoter and intronic enhancers results in the fine regulation of CFTR expression during development, thereby ensuring tissue specificity.

Prevalence and timing of pregnancy termination for brain malformations

Objective To determine the prevalence and the timing of pregnancy termination relative to the type of central nervous system (CNS) malformations. Design Retrospective cohort study. Setting Multidisciplinary centre for prenatal diagnosis in the Languedoc-Roussillon region, France. Population A cohort of 481 pregnancy terminations performed between 2005 and 2009. Methods Detailed post-termination fetal and neuropathological analyses were carried out to identify the CNS malformations. Then, the prevalence and timing of pregnancy termination were assessed relative to the identified malformations. Results About one-third of pregnancy terminations (143/481) were performed for severe CNS malformations. Up to 24 weeks of gestation (WG), pregnancy terminations (56.6%) were carried out mainly for defects occurring during the two major first steps of CNS development (neurulation and differentiation of cerebral vesicles). After 24 WG, pregnancy terminations (43.3%) were mainly performed for corpus callosum agenesis (16/17), vermian agenesis (10/12) and gyral anomalies (13/15). For hindbrain malformations and gyral anomalies, there was a significant relationship between the timing of pregnancy termination and the presence of a severe ventriculomegaly at prenatal diagnosis (p=0.002 and p=0.02, respectively). Conclusion By classifying CNS malformations according to the neuropathological analysis, the authors show that the timing and prevalence of pregnancy termination are distributed in a manner that is consistent with what is currently known on the development of brain. They are also influenced by the French prenatal screening policy and the variable expressivity of the brain malformations and associated lesions.

Mosaic parental germline mutations causing recurrent forms of malformations of cortical development

To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be considered not only for the recurrent forms, but also for the sporadic cases of MCD.

Epiphyseal punctate calcifications (stippling) in complete trisomy 9

Marie-José Perez1, Anouck Schneider1, Anne-Marie Chaze1, Nicole Bigi1, Geneviève Lefort1, Caroline Rouleau2, Jean-Michel Faure3, Haissam Rahil4, Nami Wadih5, Alain Couture6, Pierre Boulot3, Patricia Blanchet1, Pierre Sarda1 and David Geneviève1* 1Service de Génétique Médicale et Chromosomique, Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Sud-Languedoc Roussillon, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Université Montpellier 1, Faculté de Médecine de Montpellier-Nimes, Montpellier, France 2Service d’Anatomopathologie, Hôpital Lapeyronie, CHRU de Montpellier, France 3Maternité, Hôpital Arnaud de Villeneuve, CHRU de Montpellier, France 4Laboratoire de Cytogénétique, Clinique Clémentville, Montpellier, France 5Gynécologie, Clinique Notre Dame Espérance, Perpignan, France 6Service de Radiologie Pédiatrique, Hôpital Arnaud de Villeneuve, CHRU de Montpellier, France