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1. Case report: 7p22.3 deletion and 8q24.3 duplication in a patient with epilepsy and psychomotor delay—Does both possibly act to modulate a candidate gene region for the patient’s phenotype?

Author

Rahma Touhami, Hajer Foddha, Eudeline Alix, Afef Jalloul, Soumaya Mougou-Zerelli, Ali Saad, Damien Sanlaville, and Amel Haj Khelil

Subjects
Psychomotor delay, epilepsy, facial dysmorphism, array CGH, deletion/duplication, BRAT1 gene, Genetics, QH426-470
Abstract

Background: Psychomotor delay, epilepsy and dysmorphic features are clinical signs which are described in multiple syndromes due to chromosomal imbalances or mutations involving key genes implicated in the stages of Early Embryonic Development. In this context, we report a 10 years old Tunisian patient with these three signs. Our objective is to determine the cause of developmental, behavioral and facial abnormalities in this patient.Methods: We used banding cytogenetics (karyotype) and Array Comparative Genomic Hybridization (Array CGH) to this purpose.Results: The karyotype was in favor of a derivative of chromosome 7 in the patient and Array CGH analysis revealed a loss of genetic material in 7p22.3-p22.1 (4,56 Mb) with a gain at 8q24.23-q24 (9.20 Mb) resulting from maternal 7/8 reciprocal translocation. An in silico analysis of the unbalanced region was carried out and showed that the 7p22.3-p22.1 deletion contains eight genes. Among them, BRAT1 gene, previously described in several neurodevelopmental diseases, may be a candidate gene which absence could be correlated to the patient’s phenotype. However, the 8q24.23-q24 duplication could be involved in the phenotype of this patient.Conclusion: In this study, we report for the first time a 7p deletion/8q duplication in a patient with psychomoteur delay, epilepsy and facial dysmorphism. Our study showed that Array CGH still useful for delivering a conclusive genetic diagnosis for patients having neurodevelopmental abnormalities in the era of next-generation sequencing.

Published
2023
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2. Chromosomal instability in the prediction of pituitary neuroendocrine tumors prognosis

Author

Hélène Lasolle, Mad-Hélénie Elsensohn, Anne Wierinckx, Eudeline Alix, Clément Bonnefille, Alexandre Vasiljevic, Christine Cortet, Bénédicte Decoudier, Nathalie Sturm, Stephan Gaillard, Amandine Ferrière, Pascal Roy, Emmanuel Jouanneau, Philippe Bertolino, Claire Bardel, Damien Sanlaville, and Gérald Raverot

Subjects
Pituitary neuroendocrine tumors, Prognosis, Genomic instability, Copy number variations, Pituitary adenoma, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract The purpose of this study was to analyze the impact of copy number variations (CNV) on sporadic pituitary neuroendocrine tumors (PitNETs) prognosis, to identify specific prognosis markers according to the known clinico-pathological classification. CGH array analysis was performed on 195 fresh-frozen PitNETs (56 gonadotroph, 11 immunonegative, 56 somatotroph, 39 lactotroph and 33 corticotroph), with 5 years post-surgery follow-up (124 recurrences), classified according to the five-tiered grading classification (invasion, Ki-67, mitotic index and p53 positivity). Effect of alterations on recurrence was studied using logistic regression models. Transcriptomic analysis of 32 lactotroph tumors was performed. The quantity of CNV was dependent on tumor type: higher in lactotroph (median(min–max) = 38% (0–97) of probes) compared to corticotroph (11% (0–77)), somatotroph (5% (0–99)), gonadotroph (0% (0–10)) and immunonegative tumors (0% (0–17). It was not predictive of recurrence in the whole cohort. In lactotroph tumors, genome instability, especially quantity of gains, significantly predicted recurrence independently of invasion and proliferation (p-value = 0.02, OR = 1.2). However, no specific CNV was found as a prognostic marker. Transcriptomic analysis of the genes included in the CNV and associated with prognosis didn’t show significantly overrepresented pathway. In somatotroph and corticotroph tumors, USP8 and GNAS mutations were not associated with genome disruption or recurrence respectively. To conclude, CGH array analysis showed genome instability was dependent on PitNET type. Lactotroph tumors were highly altered and the quantity of altered genome was associated with poorer prognosis though the mechanism is unclear, whereas gonadotroph and immunonegative tumors showed the same ‘quiet’ profile, leaving the mechanism underlying tumorigenesis open to question.

Published
2020
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3. SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors

Author

Solène Castellnou, Alexandre Vasiljevic, Véronique Lapras, Véronique Raverot, Eudeline Alix, Françoise Borson-Chazot, Emmanuel Jouanneau, Gérald Raverot, and Hélène Lasolle

Subjects
sst5, corticotroph pituitary tumors, usp8, pasireotide, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Objective: Somatostatin receptor type 5 (SST5) is inconsistently expressed by corticotroph tumors, with higher expression found in corticotropinomas havin g ubiquitin-specific protease 8 (USP8) mutations. Aims were to study the correlation between characteristics of corticotropinomas and SST5 expression/USP8 mutation status and to describe the response to pasireotide in five patients. Design: Retrospective cohort study. Methods: Clinico-biochemical, radiological and pathological data of 62 patients, operated for a functioning or silent corticotropinoma between 2013 and 2017, were collected. SST5 expression was measured by immunohistochemistry (clone UMB -4, Abcam, IRS > 1 being considered positive), and Sanger sequencing was performed on 50 tumors to screen for USP8 mutations. Results: SST5 expression was positive in 26/62 pituitary tumors. A moderate or strong IRS was found in 15/58 corticotropinomas and in 13/35 functioning corticotropinomas. Among functioning tumors, those expressing SST5 were more frequent in women (22/24 vs 9/15, P = 0.04) and had a lower grade (P = 0.04) compared to others. USP8 mutations were identified in 13/50 pituitary tumors and were more frequent in functioning compared to silent tumors (11/30 vs 2/20, P = 0.05). SST5 expression was more frequent in USP8mut vs USP8wt tumors (10/11 vs 7/19, P = 0.007). Among treated patients, normal urinary free cortisol levels were obtained in three patients (IRS 0, 2 and 6), while a four-fold decrease was observed in one patient (IRS 4). Conclusion: SST5 expression appears to be associated with functioning, USP8mut and lower grade corticotropinomas. A correlation between SST5 expression or USP8mut and response to pasireotide remains to be confirmed.

Published
2020
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4. Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy

Author

Eudeline Alix, Anne-Lise Poulat, Nilay Güneş, Yvonne G. Weber, Maryam Najafi, José M. Serratosa, Ehsan Ghayoor Karimiani, Kaya Bilguvar, Tarek Omar, Katia Hardies, Dana Craiu, Hande Caglayan, Stéphanie Baulac, Fernando Kok, Reza Maroofian, Gaetan Lesca, Heba Morsy, Damien Sanlaville, Carla Marini, Renzo Guerrini, Nina Barišić, Luiza Ramos, Sarah von Spiczak, Miriam Schmidts, Patrick May, Karl Martin Klein, Beyhan Tüysüz, Audrey Labalme, Sarah Weckhuysen, Dilek Uludağ Alkaya, Julitta de Bellescize, Felix Rosenow, Farah Ashrafzadeh, Rudi Balling, Homa Tajsharghi, Amira Nabil, Katalin Sterbova, Felicitas Becker, Nicolas Chatron, Ali-Reza Moslemi, Holger Lerche, Hiltrud Muhle, Ingo Helbig, Haytham Hussien, Sandra Roselli, EuroEpinomics-RES Consortium AR Wo, and İÜC, Cerrahpaşa Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, suppression-burst, hypsarrhythmia, Glutamate decarboxylase, Neonatal onset, arthrogryposis, 03 medical and health sciences, Epilepsy, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Medicine, Medicinsk genetik, cleft palate, Arthrogryposis, omphalocele, Omphalocele, GAD1, business.industry, Neurosciences, Original Articles, medicine.disease, Hypsarrhythmia, 3. Good health, Epileptic spasms, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Epilepsy syndromes, Human medicine, Neurology (clinical), medicine.symptom, business, Medical Genetics, Neurovetenskaper, 030217 neurology & neurosurgery
Abstract

Chatron et al. describe a novel syndrome caused by bi-allelic loss-of-function mutations in GAD1, the gene encoding the GABA synthetic enzyme GAD67. The syndrome is characterized by the unique association of developmental and epileptic encephalopathy, cleft palate, joint contractures and/or omphalocele., Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1−/− mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.

Published
2020

5. Variability in CD39 and CD73 protein levels in uveal melanoma patients

Author

Olivier Harou, Emeline Cros-Perrial, Eudeline Alix, Evelyne Callet-Bauchu, Charlotte Bertheau, Charles Dumontet, Mojgan Devouassoux-Shisheboran, and Lars Petter Jordheim

Subjects
Adenosine, Adenosine Triphosphate, Antigens, CD, Apyrase, Genetics, Humans, Molecular Medicine, General Medicine, 5'-Nucleotidase, Melanoma, Biochemistry
Abstract

Extracellular adenosine is produced from ATP by CD39 and CD73, and can modulate tumor development by acting on cancer cells or immune cells. Adenosine metabolism has been poorly studied in uveal melanoma. We studied the protein levels of CD39 and CD73 in a small, well described cohort of patients with uveal melanoma. Our results show a high variability in the levels of the two proteins, both in positivity and in intensity. Our results suggest that similar studies on larger cohorts could determine the clinical value and the druggability of these enzymes in the given clinical setting. Supplemental data for this article is available online at http://dx.doi.org/10.1080/15257770.2022.2032738

Published
2022
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6. A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 homozygous truncating variants

Author

Nicolas Chatron, Alexandre Vasiljevic, Eudeline Alix, Audrey Putoux, Gaetan Lesca, Deborah Osio, Phillip Cox, Laurent Guibaud, Damien Sanlaville, Annie Buenerd, Audrey Labalme, Peter Marks, and Sara Cabet

Subjects
Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Pyramidal Tracts, Genes, Recessive, Hemiplegia, Biology, Basal Ganglia, 03 medical and health sciences, Fetus, 0302 clinical medicine, Pregnancy, ATP1A2, Prenatal Diagnosis, Exome Sequencing, medicine, Polymicrogyria, Humans, Vascular Calcification, Exome sequencing, Familial hemiplegic migraine, Alternating hemiplegia of childhood, Infant, Newborn, Syndrome, medicine.disease, Meningeal Arteries, Hypoplasia, Malformations of Cortical Development, 030104 developmental biology, Dysplasia, Agenesis, Female, Neurology (clinical), Sodium-Potassium-Exchanging ATPase, 030217 neurology & neurosurgery
Abstract

Polymicrogyria is a heterogeneous malformation of cortical development microscopically defined by an excessive folding of the cortical mantle resulting in small gyri with a fused surface. Polymicrogyria is responsible for a wide range of neurological symptoms (e.g. epilepsy, intellectual disability, motor dysfunction). Most cases have a supposed environmental clastic vascular or infectious origin but progress in genomics has revealed new monogenic entities. We report four cases from two independent families sharing a common recognizable lethal syndromic polymicrogyria of autosomal recessive inheritance. Beyond diffuse polymicrogyria detected prenatally, pathological examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. In all affected cases, exome sequencing showed a pathogenic homozygous nonsense ATP1A2 variant. This resulted in absence of immunodetectable ATP1A2 protein in two brains analysed. ATP1A2 encodes the alpha-2 isoform of the Na+/K+-ATPase, which is highly expressed in brain tissues and has previously been related to familial hemiplegic migraine (MIM#602481) and alternating hemiplegia of childhood (MIM#104290). Through the description of this genetic entity, we emphasize the possibility of dual mode of transmission for disease-causing genes and provide the key neuropathological features that should prompt geneticists to test for mutations in the ATP1A2 gene.

Published
2019

7. Progressive Myoclonus Epilepsy Caused by a Homozygous Splicing Variant of SLC7A6OS

Author

Anna-Elina Lehesjoki, Nicolas Chatron, Samuel F. Berkovic, Betül Baykan, Giuseppe Borsani, Francis Ramond, Nerses Bebek, Karen Oliver, Renaud Touraine, Melanie Bahlo, Eudeline Alix, Mikko Muona, Carolina Courage, Gaetan Lesca, Laure Mazzola, Tarja Joensuu, Audrey Labalme, Medicum, University of Helsinki, and HUSLAB

Subjects
Male, 0301 basic medicine, Exome sequencing, DNA, Complementary, Adolescent, Blotting, Western, Progressive myoclonus epilepsy, Biology, progressive myoclonus epilepsy, 3124 Neurology and psychiatry, Young Adult, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Loss of Function Mutation, Complementary DNA, medicine, Humans, Cognitive Dysfunction, Child, Exome sequencing, progressive myoclonus epilepsy, Genetics, Reverse Transcriptase Polymerase Chain Reaction, Homozygote, Haplotype, 3112 Neurosciences, Brain, Electroencephalography, Myoclonic Epilepsies, Progressive, medicine.disease, Magnetic Resonance Imaging, Pedigree, 030104 developmental biology, Neurology, RNA splicing, Ataxia, Female, Human genome, RNA Splice Sites, Neurology (clinical), Atrophy, 030217 neurology & neurosurgery, Peptide Hydrolases, Founder effect
Abstract

Exome sequencing was performed in 2 unrelated families with progressive myoclonus epilepsy. Affected individuals from both families shared a rare, homozygous c.191A > G variant affecting a splice site in SLC7A6OS. Analysis of cDNA from lymphoblastoid cells demonstrated partial splice site abolition and the creation of an abnormal isoform. Quantitative reverse transcriptase polymerase chain reaction and Western blot showed a marked reduction of protein expression. Haplotype analysis identified a similar to 0.85cM shared genomic region on chromosome 16q encompassing the c.191A > G variant, consistent with a distant ancestor common to both families. Our results suggest that biallelic loss-of-function variants in SLC7A6OS are a novel genetic cause of progressive myoclonus epilepsy. ANN NEUROL 2020

Published
2021

8. SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors

Author

Véronique Raverot, Gerald Raverot, Alexandre Vasiljevic, Emmanuel Jouanneau, V. Lapras, Eudeline Alix, Lasolle Hélène, Françoise Borson-Chazot, and Solène Castellnou

Subjects
pasireotide, lcsh:RC648-665, business.industry, Research, Pituitary tumors, corticotroph pituitary tumors, medicine.disease, lcsh:Diseases of the endocrine glands. Clinical endocrinology, SST5, USP8, Mutation (genetic algorithm), Cancer research, Medicine, Corticotropic cell, business
Abstract

Objective: Somatostatin receptor type 5 (SST5) is inconsistently expressed by corticotroph tumors, with higher expression found in corticotropinomas havin g ubiquitin-specific protease 8 (USP8) mutations. Aims were to study the correlation between characteristics of corticotropinomas and SST5 expression/USP8 mutation status and to describe the response to pasireotide in five patients. Design: Retrospective cohort study. Methods: Clinico-biochemical, radiological and pathological data of 62 patients, operated for a functioning or silent corticotropinoma between 2013 and 2017, were collected. SST5 expression was measured by immunohistochemistry (clone UMB -4, Abcam, IRS > 1 being considered positive), and Sanger sequencing was performed on 50 tumors to screen for USP8 mutations. Results: SST5 expression was positive in 26/62 pituitary tumors. A moderate or strong IRS was found in 15/58 corticotropinomas and in 13/35 functioning corticotropinomas. Among functioning tumors, those expressing SST5 were more frequent in women (22/24 vs 9/15, P = 0.04) and had a lower grade (P = 0.04) compared to others. USP8 mutations were identified in 13/50 pituitary tumors and were more frequent in functioning compared to silent tumors (11/30 vs 2/20, P = 0.05). SST5 expression was more frequent in USP8mut vs USP8wt tumors (10/11 vs 7/19, P = 0.007). Among treated patients, normal urinary free cortisol levels were obtained in three patients (IRS 0, 2 and 6), while a four-fold decrease was observed in one patient (IRS 4). Conclusion: SST5 expression appears to be associated with functioning, USP8mut and lower grade corticotropinomas. A correlation between SST5 expression or USP8mut and response to pasireotide remains to be confirmed.

Published
2020

9. OR23-04 SST5 Expression and USP8 Mutation in Functioning and Silent Corticotroph Pituitary Tumors

Author

V. Lapras, Solène Castellnou, Véronique Raverot, Emmanuel Jouanneau, Françoise Borson-Chazot, Gérald Raverot, Hélène Lasolle, Alexandre Vasiljevic, and Eudeline Alix

Subjects
Neuroendocrinology and Pituitary, Endocrinology, Diabetes and Metabolism, Mutation (genetic algorithm), Pituitary tumors, medicine, Cancer research, Corticotropic cell, Biology, medicine.disease, Pituitary Tumors: Trials and Studies, AcademicSubjects/MED00250
Abstract

Context. Somatostatin receptor type 5 (SST5), a target of pasireotide, is inconsistently expressed by corticotroph tumors. Somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene have been describes in 35% to 60% of corticotropinomas. SST5 expression has been found to be higher in USP8mut corticotropinomas. Objective. To study the correlation between clinical and biochemical characteristics of a large cohort of functioning and silent corticotroph tumor and SST5 expression or USP8 mutation status. To describe SST5 expression and the response to pasireotide in 5 patients. Design. Retrospective cohort study. Setting. University hospitals of Lyon. Patients. 62 patients operated for a corticotroph tumors between 2013 and 2017. Intervention. None. Main Outcome Measure. Clinical, biological, radiological and pathological data were evaluated depending on SST5 expression measured by immunohistochemistry (rabbit monoclonal antibody, clone UMB-4, Abcam). Membrane immune-positivity with an IRS>1 was considered positive. USP8 analysis was performed by Sanger sequencing in 50 tumors. Results. SST5 expression was positive in 26 (41.9%) pituitary tumors. A moderate or strong IRS was found in 24.2% of the cohort and in 32.5% of the functioning pituitary tumors. Compared to SST5-negative pituitary tumors, those expressing SST5 were more frequent in women (92.3% vs 55.6%; p=0.002), fewer were silent (7.7% vs 58.3%; p USP8 mutations were identified in 26% of the cohort and more frequent in functioning (n=11/30, 36.7%) compared to silent corticotroph tumors (n=2/20, 10%; p=0.05). SST5 expression was more frequent in USP8mut vs USP8neg tumors (58.8% vs 7.7%; p Among treated patients, normal urinary free cortisol (UFC) levels were obtained in 3 patients (IRS 0, 2, and 6) and a 4-fold decrease of UFC in one patient (IRS 4). Conclusion. SST5 expression seems to be associated with functioning, well-differentiated pituitary tumors and USP8 mutation. However, a correlation between SST5 expression or USP8mut and response to pasireotide treatment remains to be confirmed.

Published
2020

10. A Case of Trisomy 13 Mosaicism Presenting with a Severe Aortic Root Dilatation and Marfanoid Habitus due to an Unpredictable Cytogenetic Mechanism

Author

Audrey Labalme, Jean-François Obadia, Patrick Edery, Sophie Dupuis-Girod, Marianne Till, Bernard Debost, Pauline Monin, Damien Sanlaville, Lucie Ravella, Nicolas Reynaud, Nadine Hanna, Audrey Putoux, Pauline Arnaud, Catherine Boileau, Coline Poizat-Amar, Jean-Christophe Zech, Eudeline Alix, Marie Faoucher, Caroline Schluth-Bolard, Risques, Ecosystèmes, Vulnérabilité, Environnement, Résilience (RECOVER), Aix Marseille Université (AMU)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), POLE HYDROECOLOGIE DES PLANS D'EAU AIX EN PROVENCE FRA, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Département d'Anesthésie Réanimation, Centre Hospitalier Louis Pradel, Service de génétique et centre de référence pour la maladie de Rendu-Osler, Hospices Civils de Lyon (HCL), Hôpital Debrousse, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Aix Marseille Université (AMU), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), and Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Pathology, medicine.medical_specialty, Derivative chromosome, Trisomy 13 Syndrome, Bicuspid aortic valve, [SDV]Life Sciences [q-bio], Aortic root dilatation, Translocation, Chromosomal translocation, Biology, Translocation, Genetic, Chromosomes, Fluorescence, Marfan Syndrome, Mosaicism, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Genetic, Pair 10/genetics, Genetics, medicine, Humans, Molecular Biology, Genetics (clinical), Aorta, In Situ Hybridization, Fluorescence, In Situ Hybridization, Pair 13/genetics, 0303 health sciences, Comparative Genomic Hybridization, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 10, 030305 genetics & heredity, Breakpoint, Dystrophy, Marfan Syndrome/*etiology, medicine.disease, Telomere, Interstitial telomere, Trisomy 13, Trisomy 13 Syndrome/*diagnosis/genetics, Aorta/*abnormalities, Trisomy, 030217 neurology & neurosurgery, Human
Abstract

In this report, we present a new case of mosaic trisomy 13 with prolonged survival, firstly detected by array-CGH analysis which was carried out because of moderate intellectual disability with postaxial hexadactyly, dermatologic features, ventricular septal defect, bicuspid aortic valve, and aortic dystrophy in a 19-year-old male patient. In a subset of 15% of the cells, the patient carried a derivative chromosome 10 generated by a nonreciprocal (10;13) translocation inherited from his healthy mother who carried the translocation in a balanced and homogeneous state. FISH analyses showed interstitial telomeric sequences at the breakpoints. To our knowledge, this is the second report of a patient with trisomy 13 mosaicism displaying a severe aortic root dilatation. We also discuss the mechanisms which could explain the mosaic state, the most likely one being related to the instability of the interstitial telomere.

Published
2020

11. Growth charts in Kabuki syndrome 1

Author

Claire Jeandel, Caroline Michot, Odile Boute, Mario Abaji, Stanislas Lyonnet, Julie Reversat, Lucile Pinson, Sandrine Akouete, Bertrand Isidor, Marie-Ange Delrue, Valérie Cormier-Daire, Isabelle Touitou, Pierre Sarda, Bérénice Doray, Tiffany Busa, Anne Moncla, Véra Georgescu, Alice Goldenberg, Damien Sanlaville, Cyril Amouroux, Elodie Sanchez, Mélanie Fradin, Guilaine Boursier, Didier Lacombe, Mouna Barat-Houari, Annick Toutain, Brigitte Gilbert-Dussardier, David Geneviève, Fabienne Giuliano, Kim Hanh Le Quan Sang, Joelle Roume, Marianne Till, Yves Alembick, Nicole Philip, Elise Schaefer, Marjolaine Willems, Claire Duflos, Aurélia Jacquette, Eudeline Alix, Sébastien Moutton, Adeline Bonnard, Vincent Gatinois, Marie-Pierre Cordier, Clarisse Baumann, Martine Le Merrer, Marie-Line Jacquemont, Lydie Burglen, Valentin Ruault, Laurence Faivre, Carole Corsini, Sylvie Manouvrier, Svetlana Gorokhova, Anna Pelet, Delphine Héron, Sylvie Odent, Jeanne Amiel, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département d'Information Médicale [CHRU Montpellier], Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpital Robert Debré Paris, Hôpital Robert Debré, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital saint Pierre, GH Sud Réunion, Centre de référence des maladies endocriniennes rares de la croissance et du développement [CHU Pitié-Salpêtrière], Département Pédiatrie [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Département génétique méd, mal rares et médecine personnalisée [CHRU de Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], Salvy-Córdoba, Nathalie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy]

Subjects
Male, MESH: Neoplasm Proteins, CHILDREN, Growth, MESH: Growth Charts, Body Mass Index, MALFORMATION, Parental target size, MESH: Child, KDM6A, Growth Charts, Child, Specific curves, Genetics (clinical), 2. Zero hunger, Genetics & Heredity, Histone Demethylases, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, Increase size, Circumference, MESH: Hematologic Diseases, Adult height, 3. Good health, Neoplasm Proteins, DNA-Binding Proteins, Vestibular Diseases, Child, Preschool, Cohort, MLL2, Female, MESH: Vestibular Diseases, Life Sciences & Biomedicine, MESH: Face, growth hormone deficiency, MESH: Abnormalities, Multiple, MESH: Mutation, Adolescent, growth, Population, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Growth hormone deficiency, MESH: Body Mass Index, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, EARS, MESH: Body Height, MESH: Histone Demethylases, Genetics, medicine, Humans, Abnormalities, Multiple, education, 030304 developmental biology, MESH: Adolescent, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Science & Technology, Kabuki syndrome, MESH: Humans, business.industry, MUTATIONS, Body Weight, MESH: Child, Preschool, specific curves, MAKE-UP-SYNDROME, medicine.disease, Hematologic Diseases, Body Height, MESH: Male, MESH: Body Weight, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, parental target size, Face, Mutation, business, Body mass index, MESH: Female, MESH: DNA-Binding Proteins, Demography
Abstract

Kabuki syndrome (KS, KS1: OMIM 147920 and KS2: OMIM 300867) is caused by pathogenic variations in KMT2D or KDM6A. KS is characterized by multiple congenital anomalies and neurodevelopmental disorders. Growth restriction is frequently reported. Here we aimed to create specific growth charts for individuals with KS1, identify parameters used for size prognosis and investigate the impact of growth hormone therapy on adult height. Growth parameters and parental size were obtained for 95 KS1 individuals (41 females). Growth charts for height, weight, body mass index (BMI) and occipitofrontal circumference were generated in standard deviation values for the first time in KS1. Statural growth of KS1 individuals was compared to parental target size. According to the charts, height, weight, BMI, and occipitofrontal circumference were lower for KS1 individuals than the normative French population. For males and females, the mean growth of KS1 individuals was -2 and -1.8 SD of their parental target size, respectively. Growth hormone therapy did not increase size beyond the predicted size. This study, from the largest cohort available, proposes growth charts for widespread use in the management of KS1, especially for size prognosis and screening of other diseases responsible for growth impairment beyond a calculated specific target size. ispartof: AMERICAN JOURNAL OF MEDICAL GENETICS PART A vol:182 issue:3 pages:446-453 ispartof: location:United States status: published

Published
2019

13. Prenatal Diagnosis of Trisomy 2p due to Terminal 2p Duplication including Interstitial Telomeric Sequences

Author

Damien Sanlaville, Marianne Till, Caroline Schluth-Bolard, Lyvia Marlet, Dominique Boggio, Eudeline Alix, Jocelyne Attia, and Fabienne Raskin-Champion

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Heart malformation, Trisomy, Prenatal diagnosis, Biology, 03 medical and health sciences, Pregnancy, Prenatal Diagnosis, Gene duplication, Genetics, medicine, Humans, Molecular Biology, In Situ Hybridization, Fluorescence, Genetics (clinical), Comparative Genomic Hybridization, Breakpoint, Chromosome, Karyotype, Telomere, medicine.disease, Chromosome Banding, Fetal Diseases, 030104 developmental biology, Chromosomes, Human, Pair 2, Female
Abstract

We report on a prenatally diagnosed unusual case of inverted terminal duplication of the short arm of chromosome 2, leading to interstitial telomeric sequences (ITSs) and partial trisomy 2p. To our knowledge, there are only 4 further cases of pure partial trisomy 2p reported prenatally. Here, the mother was referred at 22 weeks of gestation for isolated fetal congenital heart malformation at ultrasound. The karyotype of amniotic fluid cells displayed a large duplication of the short arm of chromosome 2 that was further investigated by array-CGH, which detected a 1-copy gain of 43.75 Mb in chromosome 2 at 2p21p25.3. FISH confirmed the presence of an inverted duplication in the short arm of chromosome 2 involving the region 2p21pter and revealed the presence of ITSs at the breakpoint in chromosome 2p21. This report contributes to the prenatal description of the syndrome. We also discuss the possible mechanisms leading to this duplication and the formation of ITSs which are rarely described in constitutional rearrangements.

Published
2017

14. Refining the phenotypical and mutational spectrum of Taybi-Linder syndrome

Author

C.E.M. de Die-Smulders, Raoul C.M. Hennekam, Audrey Putoux, Alain Verloes, Séverine Drunat, Patrick Edery, Annette Uwineza, F. Champion, A. Besson, J. Michel, Aimee D C Paulussen, Dominique Boggio, Marie-Josée Perez, Sylvie Mazoyer, W.K. van Putten, Gaetan Lesca, Isabella Borg, Y. Musizzano, Damien Sanlaville, Alexandre Vasiljevic, Amerh Alqahtani, Ferechté Razavi, Lucile Pinson, Laurent Guibaud, Eudeline Alix, Sheela Nampoothiri, and Thatjana Gardeitchik

Subjects
0301 basic medicine, Genetics, Microcephaly, Mutation, Corpus Callosum Agenesis, Mild intrauterine growth retardation, Dwarfism, Biology, Compound heterozygosity, medicine.disease, medicine.disease_cause, Short stature, 03 medical and health sciences, 030104 developmental biology, Minor spliceosome, medicine, medicine.symptom, Genetics (clinical)
Abstract

Taybi-Linder syndrome (TALS, OMIM 210710) is a rare autosomal recessive disorder belonging to the group of microcephalic osteodysplastic primordial dwarfisms (MOPD). This syndrome is characterized by short stature, skeletal anomalies, severe microcephaly with brain malformations and facial dysmorphism, and is caused by mutations in RNU4ATAC. RNU4ATAC is transcribed into a non-coding small nuclear RNA which is a critical component of the minor spliceosome. We report here four foetuses and four unrelated patients with RNU4ATAC mutations. We provide antenatal descriptions of this rare syndrome including unusual features found in two twin foetuses with compound heterozygosity for two rare mutations who presented with mild intrauterine growth retardation and atypical dysmorphic facial features. We also carried out a literature review of the patients described up to now with RNU4ATAC mutations, affected either with TALS or Roifman syndrome, a recently described allelic disorder.

Published
2016

15. Multisystem disorders, severe developmental delay and seizures in two affected siblings, expanding the phenotype of PIGC deficiency

Author

Damien Sanlaville, Linda Pons, Isabelle Sabatier, Marie Faoucher, Audrey Labalme, Gaetan Lesca, and Eudeline Alix

Subjects
Male, Heterozygote, Enzyme complex, Developmental Disabilities, Compound heterozygosity, Organomegaly, Seizures, Intellectual Disability, Exome Sequencing, Intellectual disability, Genetics, Humans, Medicine, Abnormalities, Multiple, Global developmental delay, Genetics (clinical), Exome sequencing, business.industry, Protein anchor, Siblings, Homozygote, Infant, Membrane Proteins, General Medicine, medicine.disease, Phenotype, Pedigree, Hexosyltransferases, Child, Preschool, Mutation, Codon, Terminator, Female, medicine.symptom, business
Abstract

PIGC (OMIM 601730 ) encodes the PIGC protein, which is part of an enzyme complex involved in the biosynthesis of the glycosylphosphatidylinositol protein anchor. The other proteins in the complex include PIGA, PIGH, PIGQ, PIGY, PIGP and DPM2. Homozygous and compound heterozygous mutations in PIGC have recently been described to cause severe global developmental delay, intellectual disability, and seizures in two unrelated families, without indication of another system involvement or dysmorphism. Here we describe two siblings, born to second cousin parents, displaying severe psychomotor delay, seizures, organomegaly, cardiopulmonary anomalies, and similar facial dysmorphism. Exome sequencing in the boy revealed a homozygous variant in PIGC gene, c.12_13insTTGTGACTAACA leading to a premature stop codon p.(Gln4_Pro5insLeu*). His affected sister was also found to be homozygous, and their parents were found to be heterozygous. This is the first detailed clinical description of two related patients suggesting that PIGC deficiency can cause a severe recognisable phenotype including multisystem disorders, in association to previously reported severe developmental delay and seizures.

Published
2020

17. Functional variants of POC5 identified in patients with idiopathic scoliosis

Author

Simon Girard, Charles Marcaillou, Amandine Campan-Fournier, Jean-Claude Bernard, Shunmoogum A. Patten, Florina Moldovan, Charlotte Zaouter, Bernard Biot, Alicia Besson, Nicolas Fraisse, Rita Menassa, Guy A. Rouleau, Raphaelle Lamy, Kariman Abelin-Genevois, Meijiang Liao, Jérôme Berard, Vincent Cunin, Gaetan Lesca, Patrick Edery, Françoise Clerget-Darpoux, Khaled Fendri, Audrey Labalme, Pierre Drapeau, Patricia Margaritte-Jeannin, Eudeline Alix, Melanie Letexier, Coline Poizat, and Damien Sanlaville

Subjects
Male, Linkage disequilibrium, DNA Mutational Analysis, Population, Mutation, Missense, Biology, medicine.disease_cause, Bioinformatics, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Gene Frequency, Gene mapping, Genetic linkage, medicine, Animals, Humans, Missense mutation, Genetic Predisposition to Disease, education, Genetic Association Studies, Zebrafish, Exome sequencing, Genetics, education.field_of_study, Mutation, Genetic heterogeneity, Brief Report, General Medicine, Pedigree, Scoliosis, Case-Control Studies, Female, Carrier Proteins
Abstract

Idiopathic scoliosis (IS) is a spine deformity that affects approximately 3% of the population. The underlying causes of IS are not well understood, although there is clear evidence that there is a genetic component to the disease. Genetic mapping studies suggest high genetic heterogeneity, but no IS disease-causing gene has yet been identified. Here, genetic linkage analyses combined with exome sequencing identified a rare missense variant (p.A446T) in the centriolar protein gene POC5 that cosegregated with the disease in a large family with multiple members affected with IS. Subsequently, the p.A446T variant was found in an additional set of families with IS and in an additional 3 cases of IS. Moreover, POC5 variant p.A455P was present and linked to IS in one family and another rare POC5 variant (p.A429V) was identified in an additional 5 cases of IS. In a zebrafish model, expression of any of the 3 human IS-associated POC5 variant mRNAs resulted in spine deformity, without affecting other skeletal structures. Together, these findings indicate that mutations in the POC5 gene contribute to the occurrence of IS.

Published
2015

18. Centralization errors in comparative genomic hybridization array analysis of pituitary tumor samples

Author

Jessica Michel, Clément Bonnefille, Claire Bardel, Damien Sanlaville, Hélène Lasolle, Gérald Raverot, Eudeline Alix, Mad-Hélénie Elsensohn, and Pascal Roy

Subjects
0301 basic medicine, Normalization (statistics), Adult, Male, Cancer Research, Pathology, medicine.medical_specialty, Microarray, DNA Copy Number Variations, Biology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Genetics, medicine, Chromosomes, Human, Humans, Pituitary Neoplasms, In Situ Hybridization, Fluorescence, Aged, Oligonucleotide Array Sequence Analysis, Comparative Genomic Hybridization, medicine.diagnostic_test, Pituitary tumors, Fish analysis, Middle Aged, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Child, Preschool, Female, Fluorescence in situ hybridization, Comparative genomic hybridization
Abstract

Reliable interpretation of comparative genomic hybridization array (aCGH) results requires centralization and normalization of the data. We evaluated the reliability of aCGH centralization by comparing aCGH results (with classical centralization-normalization steps) to fluorescence in situ hybridization (FISH) results. In addition, we propose a method to correct centralization bias. Sixty-six pituitary tumors were analyzed (Agilent aCGH + SNP 4 × 180K microarray). For each tumor, the FISH-based log2 (ratios) of a subset of chromosomes were compared with the corresponding aCGH raw log2 (ratios). With our new normalization-centralization process, this difference was added to all log2 (ratios), before performing loess regression on non-altered probes only. Finally, the mean log2 (ratio) and the percentage of normal probes were compared between CGHnormaliter and our new FISH-based method. For 11 tumors, FISH results and raw CGH log2 (ratios) differed significantly. In addition, nine tumors showed discrepancies between results generated by CGHnormaliter and our new-method. Such discrepancies seemed to occur with tumours with many abnormalities (0%-40% normal probes), rather than in those tumours with fewer abnormalities (31%-100% normal probes). Five tumors had too few normal probes to allow normalization. In these tumors, which can exhibit many changes in DNA copy number, we found that centralization bias was frequent and uncorrected by current normalization methods. Therefore, an external control for centralization, such as FISH analysis, is required to insure reliable interpretation of aCGH data.

Published
2017

19. Développement embryonnaire précoce

Author

Françoise Clerget-Darpoux, Anne-Louise Leutenegger, Patrick Edery, and Eudeline Alix

Subjects
Growth retardation, business.industry, Medicine, Base sequence, General Medicine, Congenital disease, business, Bioinformatics, General Biochemistry, Genetics and Molecular Biology
Published
2012

20. Valeur pronostique des altérations génomiques des tumeurs hypophysaires par analyse en CGHarray

Author

C. Bonnefille, Damien Sanlaville, Mad-Hélénie Elsensohn, Gérald Raverot, Pascal Roy, C. Bardel, Hélène Lasolle, J. Michel, and Eudeline Alix

Subjects
Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract

Objectif Rechercher des variations du nombre de copies associees au pronostic des tumeurs hypophysaires. Materiels et methode Au total, 196 tumeurs congelees analysees en CGHarray (Agilent SurePrint G3 Human CGH + SNP Microarray 4×180K). L’analyse des alterations apres centralisation, normalisation et segmentation, a utilise un clustering hierarchique ascendant. L’effet de la quantite d’alterations sur la recidive tumorale a ete etudie par regression logistique multivariee, ajustee sur la classification histologique (invasion, Ki-67, index mitotique, p53), le sexe et l’âge. Resultats Parmi les 67 gonadotropes, 31 corticotropes, 38 prolactinomes et 60 somatotropes, 182 etaient des macroadenomes, 84 des tumeurs invasives. Le sexe-ratio hommes-femmes etait de 1,3/1. Une totalite de 124 patients (63 %) ont recidive durant les 5 ans de suivi. Au total, 84 tumeurs (43 %) presentaient un genome altere (plus de 5 % de sondes alterees). Le clustering a permis de classer les tumeurs selon le type tumoral principalement. La quantite de sondes alterees etait plus elevee parmi les prolactinomes (mediane = 38 %, min = 0 %, max = 96 %) comparativement aux autres tumeurs : corticotropes (mediane = 12 %, min = 0 %, max = 76 %), somatotropes (mediane = 4 %, min = 0 %, max = 99 %), et gonadotropes (mediane = 0 %, min = 0 %, max = 22 %). La quantite de sondes alterees n’etait pas associee a la survenue d’un recidive dans l’ensemble de la cohorte (p-value = 0,52), alors que la quantite de sondes gagnees etait associee a un risque plus important de recidive parmi les prolactinomes (p-value = 0,03, OR = 1,5). Conclusion L’analyse en CGHarray des tumeurs hypophysaires a montre une grande instabilite genomique, a l’exception des gonadotropes. La presence d’alterations est fortement associee au type tumoral, mais pas a la recidive a l’exception des prolactinomes. Grant PITUIGENE ClinicalTrials.gov Identifier : NCT01903967 .

Published
2018

21. The workflow from post-mortem human brain sampling to cell microdissection: a Brain Net Europe study

Author

Isabelle Quadrio, Patrick Massoma, Catherine Rey, Armand Perret-Liaudet, Jérôme Honnorat, Hans A. Kretzschmar, Aline Dorey, Nathalie Streichenberger, David Meyronet, Eudeline Alix, Corinne Perrin, Nicole Thomasset, Thomas Arzberger, and Karen Silva

Subjects
Adult, Male, Cell, Brain tissue, Computational biology, Tissue Banks, Biology, Bioinformatics, Specimen Handling, Workflow, medicine, Humans, Sampling (medicine), Biological Psychiatry, Microdissection, Laser capture microdissection, Aged, Aged, 80 and over, Neurons, Brain Diseases, Staining and Labeling, Brain, Proteins, Human brain, Middle Aged, Europe, Psychiatry and Mental health, Autofluorescence, medicine.anatomical_structure, Neurology, Postmortem Changes, Female, Neurology (clinical)
Abstract

Brain banks manage and store fully clinically and pathologically characterised brains. The diversity of techniques used in research projects increases. These biological resource centres are made to adapt brain tissue processing. Furthermore, the development of more sensitive techniques to analyse nucleic acids and proteins offers new fields of exploration when combined with laser capture microdissection in order to decipher the physiopathology of diseases at the cell level. In this study, our goal was to evaluate procedures and set a workflow compatible with the constraints of brain banks, from brain sampling to laser capture microdissection and pre-analytical quality assessment. We compared various methods of freezing brain tissue, focused on morphological quality preservation of brain microscopical structures and on the quality of nucleic acid or protein yields. Staining protocols combined with strategies to lower neurones autofluorescence were adapted for the same purpose. Finally, we found that laser capture microdissection is possible in the setting of brain banks. However, the entire process has to be envisioned from the autopsy to the analysis. The impact on protein or nucleic acid quality is a limitation that restricts the amount of samples available for this purpose.

Published
2014

22. Finger creases lend a hand in Kabuki syndrome

Author

Yves Alembick, Muriel Holder, David Geneviève, Sylvain Poisson, Caroline Michot, Valérie Cormier-Daire, Jeanne Amiel, Lucile Pinson, Damien Sanlaville, Alice Goldenberg, Laurence Faivre, Delphine Héron, Marie-Ange Delrue, Mélanie Fradin, Marianne Till, Sylvie Odent, Annick Toutain, Nicole Philip, Martine Le Merrer, Marie-Line Jacquemont, Marie-Pierre Cordier, Fabienne Giuliano, Kim Hanh Le Quan Sang, Bertrand Isidor, Marjolaine Willems, Anne Moncla, Brigitte Gilbert-Dussardier, Anna Pelet, Aurélia Jacquette, Pierre Sarda, Elodie Sanchez, Carole Corsini, Elise Schaefer, Stanislas Lyonnet, Didier Lacombe, Joelle Roume, Eudeline Alix, Bérénice Doray, Lydie Burglen, Honorine Kayirangwa, Tiffany Busa, Clarisse Baumann, Le Corre, Morgane, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Génétique Médicale, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Service de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Service de Génétique, Hôpital saint Pierre, GH Sud Réunion, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Hôpital Poissy-saint Germain, Unité Fonctionnelle de Génétique Clinique [CHU Pitié Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Service de génétique médicale, Hôpital l'Archet, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital de Hautepierre [Strasbourg], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Hospices Civils de Lyon ( HCL ) -CHU de Lyon-Centre Neuroscience et Recherche, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Hôpital Bretonneau-CHRU Tours, Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Maladies Rares - Génétique et Métabolisme ( MRGM ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Centre hospitalier universitaire de Poitiers ( CHU Poitiers ) -Centre de Référence Anomalies du Développement Ouest, Unité Fonctionnelle de Génétique Clinique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]-Centre de référence 'Déficiences Intellectuelles de Causes Rares' - Paris-Groupe de Recherche Clinique 'Déficience Intellectuelle et Autisme' - Paris, Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service de Génétique et d'Embryologie Médicale, and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP]

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, [SDV.GEN] Life Sciences [q-bio]/Genetics, Highly variable features, Fingers, 03 medical and health sciences, 0302 clinical medicine, Genetics, Medicine, Rare syndrome, Humans, Abnormalities, Multiple, Child, Genetics (clinical), attenuation, 030304 developmental biology, finger crease, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Kabuki syndrome, business.industry, Infant, General Medicine, novel clinical feature, medicine.disease, Dermatology, Hematologic Diseases, 3. Good health, Vestibular Diseases, Child, Preschool, Face, Orthopedic surgery, MLL2, Female, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery
Abstract

International audience; Kabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS.

Published
2013

23. Neuropathological features in a female fetus with OPHN1 deletion and cerebellar hypoplasia

Author

Jérôme Massardier, Patrick Edery, Eudeline Alix, Marianne Till, Caroline Schluth-Bolard, Jessica Michel, Audrey Labalme, Vincent des Portes, Laurent Guibaud, Delphine Rocas, Alexandre Vasiljevic, Renaud Touraine, Pascale de Haas, Marie-Pierre Cordier, Helene Guilbert, and Damien Sanlaville

Subjects
Adult, Cerebellum, Developmental Disabilities, Biology, Cisterna magna, Nervous System Malformations, White matter, Purkinje Cells, Fetus, Pregnancy, X Chromosome Inactivation, Cisterna Magna, Genetics, medicine, Humans, Genetics (clinical), GTPase-Activating Proteins, Nuclear Proteins, General Medicine, Anatomy, medicine.disease, Hypoplasia, Cytoskeletal Proteins, medicine.anatomical_structure, Heterotopia (medicine), Karyotyping, Cerebellar vermis, Mental Retardation, X-Linked, Gestation, Female, Nervous System Diseases, Gene Deletion
Abstract

We report the case of a 33-year-old pregnant woman. The third-trimester ultrasound scan during pregnancy revealed fetal bilateral ventricular dilatation, macrosomia and a transverse diameter of the cerebellum at the 30th centile. A brain MRI scan at 31 weeks of gestation led to a diagnosis of hypoplasia of the cerebellar vermis without hemisphere abnormalities and a non compressive expansion of the cisterna magna. The fetal karyotype was 46,XX. The pregnancy was terminated and array-CGH analysis of the fetus identified a 238 kb de novo deletion on chromosome Xp12, encompassing part of OPHN1 gene. Further studies revealed a completely skewed pattern of X inactivation. OPHN1 is involved in X-linked mental retardation (XLMR) with cerebellar hypoplasia and encodes a Rho-GTPase-activating protein called oligophrenin-1, which is produced throughout the developing mouse brain and in the hippocampus and Purkinje cells of the cerebellum in adult mice. Neuropathological examination of the female fetus revealed cerebellar hypoplasia and the heterotopia of Purkinje cells at multiple sites in the white matter of the cerebellum. This condition mostly affects male fetuses in humans. We report here the first case of a de novo partial deletion of OPHN1, with radiological and neuropathological examination, in a female fetus.

Published
2012

24. Clinical and molecular spectrum of renal malformations in Kabuki syndrome

Author

Christine Binquet, Jean-Benoît Courcet, Valérie Cormier-Daire, Marjolaine Willems, Sylvain Poisson, Brigitte Gilbert-Dussardier, Elodie Sanchez, Rémi Salomon, Marie Ange Delrue, Sylvie Odent, Eudeline Alix, Annick Toutain, Aurélia Jaquette, Clarisse Baumann, Le Quan Sang Kim-Han, Damien Sanlaville, Anna Pelet, Honorine Kayirangwa, Laurence Faivre, Martine Le Merrer, Christiane Mousson, Alice Goldenberg, Marie-Pierre Cordier, Marie-Line Jacquemont, Anne Moncla, Stéphanie Perez-Martin, Caroline Michot, Sandrine Vinault, Joelle Roume, Frédéric Huet, Didier Lacombe, Lucille Pinson, Catherine Vincent-Delorme, Stanislas Lyonnet, Marianne Till, David Geneviève, Pierre Sarda, Antoine Burguet, Nicole Philip, Jeanne Amiel, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants (UMR_S 953), Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Service de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de Génétique Chromosomique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Référence ' Anomalies du Développement et Syndromes Malformatifs Sud - Est PACA ', Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Génétique Médicale, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique, Hôpital Poissy-saint Germain, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Service de néphrologie (CHU de Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, CHU de Montpellier, Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Service de Cytogénétique (HFME), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants ( UMR_S 953 ), Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service Pédiatrique, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Hospices Civils de Lyon ( HCL ) -CHU de Lyon-Centre Neuroscience et Recherche, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, CHU de Poitiers-Centre de Référence Anomalies du Développement Ouest, CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Bretonneau-CHRU Tours, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Hopital Necker-Enfants Malades-Assistance publique - Hôpitaux de Paris (AP-HP), Service de Cytogénétique ( HFME ), Hôpital Femme Mère Enfant [CHU - HCL] ( HFME ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris-Sud - Paris 11 (UP11), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Hôpital du Bocage, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris-Sud - Paris 11 ( UP11 ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Hôpital du Bocage, Centre hospitalier universitaire de Poitiers ( CHU Poitiers ) -Centre de Référence Anomalies du Développement Ouest, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Hospices Civils de Lyon ( HCL ) -Hôpital Femme Mère Enfant [CHU - HCL] ( HFME ), Hospices Civils de Lyon ( HCL ), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB)

Subjects
Male, Pathology, Genotyping Techniques, urologic and male genital diseases, Kidney, Cohort Studies, chemistry.chemical_compound, Child, Ultrasonography, Histone Demethylases, 0303 health sciences, 030305 genetics & heredity, Nuclear Proteins, Hypoplasia, 3. Good health, Neoplasm Proteins, DNA-Binding Proteins, medicine.anatomical_structure, Vestibular Diseases, Child, Preschool, Creatinine, Biological Markers, Female, France, Abnormalities, Multiple, Cohort study, Glomerular Filtration Rate, Adult, Genetic Markers, medicine.medical_specialty, Adolescent, Urinary system, Urology, Renal function, 03 medical and health sciences, Young Adult, medicine, Humans, Abnormalities, Multiple, Preschool, Genetic Association Studies, 030304 developmental biology, Retrospective Studies, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Infant, Retrospective cohort study, medicine.disease, Hematologic Diseases, chemistry, Face, Pediatrics, Perinatology and Child Health, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Kabuki syndrome, Biomarkers
Abstract

International audience; OBJECTIVE: To determine the frequency and types of renal malformations, and to evaluate renal function in a cohort of patients with Kabuki syndrome (KS). STUDY DESIGN: Renal ultrasound scans and plasma creatinine measurements were collected from a French cohort of 94 patients with genotyped KS. Renal function was evaluated based on the estimated glomerular filtration rate. A genotype-phenotype study was conducted for renal and urinary tract malformations. RESULTS: Renal malformations were present in 22% of cases, and urinary tract anomalies were present in 15%. Renal malformations were observed in 28% of the MLL2 mutation-positive group and in 0% of the MLL2 mutation-negative group (P = .015). No correlation was found between the presence or absence of renal or urinary tract malformations and the location or type of MLL2 mutation. Renal function was normal except for 1 patient with a MLL2 mutation diagnosed in the first days of life and severe renal disease due to unilateral renal agenesia and controlateral severe hypoplasia that progressed to the terminal stage at age 2 years. CONCLUSION: Our study emphasizes the need for ultrasound and renal function screening in children diagnosed with KS.

Published
2012

25. Prostaglandin E2 metabolism in rat brain: Role of the blood-brain interfaces

Author

Jean-François Ghersi-Egea, Charlotte Schmitt, Nathalie Strazielle, and Eudeline Alix

Subjects
medicine.medical_specialty, Neurology, Hematology, business.industry, Research, Brain maturation, Metabolism, Rat brain, lcsh:RC346-429, Cellular and Molecular Neuroscience, Mediator, Developmental Neuroscience, Internal medicine, medicine, Choroid plexus, Prostaglandin E2, business, Neuroscience, lcsh:Neurology. Diseases of the nervous system, medicine.drug
Abstract

Background Prostaglandin E2 (PGE2) is involved in the regulation of synaptic activity and plasticity, and in brain maturation. It is also an important mediator of the central response to inflammatory challenges. The aim of this study was to evaluate the ability of the tissues forming the blood-brain interfaces to act as signal termination sites for PGE2 by metabolic inactivation. Methods The specific activity of 15-hydroxyprostaglandin dehydrogenase was measured in homogenates of microvessels, choroid plexuses and cerebral cortex isolated from postnatal and adult rat brain, and compared to the activity measured in peripheral organs which are established signal termination sites for prostaglandins. PGE2 metabolites produced ex vivo by choroid plexuses were identified and quantified by HPLC coupled to radiochemical detection. Results The data confirmed the absence of metabolic activity in brain parenchyma, and showed that no detectable activity was associated with brain microvessels forming the blood-brain barrier. By contrast, 15-hydroxyprostaglandin dehydrogenase activity was measured in both fourth and lateral ventricle choroid plexuses from 2-day-old rats, albeit at a lower level than in lung or kidney. The activity was barely detectable in adult choroidal tissue. Metabolic profiles indicated that isolated choroid plexus has the ability to metabolize PGE2, mainly into 13,14-dihydro-15-keto-PGE2. In short-term incubations, this metabolite distributed in the tissue rather than in the external medium, suggesting its release in the choroidal stroma. Conclusion The rat choroidal tissue has a significant ability to metabolize PGE2 during early postnatal life. This metabolic activity may participate in signal termination of centrally released PGE2 in the brain, or function as an enzymatic barrier acting to maintain PGE2 homeostasis in CSF during the critical early postnatal period of brain development.

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