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1. Protein‐extending ACTN2 frameshift variants cause variable myopathy phenotypes by protein aggregation

Author

Johanna Ranta‐aho, Kevin J. Felice, Per Harald Jonson, Jaakko Sarparanta, Cédric Yvorel, Ines Harzallah, Renaud Touraine, Lynn Pais, Christina A. Austin‐Tse, Vijay S. Ganesh, Melanie C. O'Leary, Heidi L. Rehm, Michael K. Hehir, Sub Subramony, Qian Wu, Bjarne Udd, and Marco Savarese

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Objective The objective of the study is to characterize the pathomechanisms underlying actininopathies. Distal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begin in the distal parts of arms and legs. Recently, variants in a new disease gene, ACTN2, have been shown to cause distal myopathy. ACTN2, a gene previously only associated with cardiomyopathies, encodes alpha‐actinin‐2, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha‐actinin‐2 is to link actin and titin to the sarcomere Z‐disk. New ACTN2 variants are continuously discovered; however, the clinical significance of many variants remains unknown. Thus, lack of clear genotype–phenotype correlations in ACTN2‐related diseases, actininopathies, persists. Methods Functional characterization in C2C12 cell model of several ACTN2 variants is conducted, including frameshift and missense variants associated with dominant and recessive actininopathies. We assess the genotype–phenotype correlations of actininopathies using clinical data from several patients carrying these variants. Results The results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha‐actinin‐2 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do form alpha‐actinin‐2 aggregates. Interpretation The results suggest that alpha‐actinin‐2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus, we recommend that protein‐extending frameshift variants in ACTN2 should be classified as pathogenic. However, this mechanism is likely elicited by only a limited number of variants. Alternative functional characterization methods should be explored to further investigate other molecular mechanisms underlying actininopathies.

Published
2024
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2. Severe Perinatal Presentations of Günther’s Disease: Series of 20 Cases and Perspectives

Author

Claire Goudet, Cécile Ged, Audrey Petit, Chloe Desage, Perrine Mahe, Aicha Salhi, Ines Harzallah, Jean-Marc Blouin, Patrick Mercie, Caroline Schmitt, Antoine Poli, Laurent Gouya, Vincent Barlogis, and Emmanuel Richard

Subjects
erythropoietic porphyria, congenital erythropoietic porphyria, UROS deficiency, Günther’s disease, hemolytic anemia, hydrops fetalis, Science
Abstract

(1) Background: Congenital erythropoietic porphyria (CEP), named Günther’s disease, is a rare recessive type of porphyria, resulting from deficient uroporphyrinogen III synthase (UROS), the fourth enzyme of heme biosynthesis. The phenotype ranges from extremely severe perinatal onset, with life-threatening hemolytic anaemia, to mild or moderate cutaneous involvement in late-onset forms. This work reviewed the perinatal CEP cases recorded in France in order to analyse their various presentations and evolution. (2) Methods: Clinical and biological data were retrospectively collected through medical and published records. (3) Results: Twenty CEP cases, who presented with severe manifestations during perinatal period, were classified according to the main course of the disease: antenatal features, acute neonatal distress and postnatal diagnosis. Antenatal symptoms (seven patients) were mainly hydrops fetalis, hepatosplenomegaly, anemia, and malformations. Six of them died prematurely. Five babies showed acute neonatal distress, associated with severe anemia, thrombocytopenia, hepatosplenomegaly, liver dysfunction, and marked photosensitivity leading to diagnosis. The only two neonates who survived underwent hematopoietic stem cell transplantation (HSCT). Common features in post-natal diagnosis (eight patients) included hemolytic anemia, splenomegaly, skin sensitivity, and discoloured teeth and urine. All patients underwent HSCT, with success for six of them, but with fatal complications in two patients. The frequency of the missense variant named C73R is striking in antenatal and neonatal presentations, with 9/12 and 7/8 independent alleles, respectively. (4) Conclusions: The most recent cases in this series are remarkable, as they had a less fatal outcome than expected. Regular transfusions from the intrauterine period and early access to HSCT are the main objectives.

Published
2024
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3. Screening of the duplication 24 pb of ARX gene in Moroccan patients with X-linked Intellectual Disability

Author

Yousra Benmakhlouf, Renaud Touraine, Ines Harzallah, Zeineb Zian, Kaoutar Ben Makhlouf, Amina Barakat, Naima Ghailani Nourouti, and Mohcine Bennani Mechita

Subjects
Duplication 24 pb, ARX, X-linked intellectual disability, Nonsyndromic ID, Morocco, Medicine, Biology (General), QH301-705.5, Science (General), Q1-390
Abstract

Abstract Objective Intellectual Disability (ID) represents a neuropsychiatric disorder, which its etiopathogenesis remains insufficiently understood. Mutations in the Aristaless Related Homeobox gene (ARX) have been identified to cause syndromic and nonsyndromic (NS-ID). The most recurrent mutation of this gene is a duplication of 24pb, c.428-451dup. Epidemiological and genetic studies about ID in the Moroccan population remain very scarce, and none study is carried out on the ARX gene. This work aimed to study c.428–451dup (24 bp) mutation in the exon 2 of the ARX gene in 118 males’ Moroccan patients with milder NS-ID to evaluate if the gene screening is a good tool for identifying NS-ID. Results Our mutational analysis did not show any dup(24pb) in our patients. This is because based on findings from previous studies that found ARX mutations in 70% of families with NS-ID, and in most cases, 1.5–6.1% of individuals with NS-ID have this duplication. Since 1/118 = 0.0084 (0.84%) is not much different from 1.5%, then it is reasonable that this could a sample size artifact. A complete screening of the entire ARX gene, including the five exons, should be fulfilled. Further investigations are required to confirm these results.

Published
2021
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4. Multiple Arterial Thrombosis in a 78-Year-Old Patient: Catastrophic Thrombotic Syndrome in COVID-19Novel Teaching Point

Author

David Kenizou, MD, Clemence Perrin, MD, Ines Harzallah, MD, Didier Bresson, MD, Patrick Allimant, MD, Mihaela Calcaianu, MD, Bree Lawson, MD, Béatrice Morisset, MD, Stephane Zuily, MD, PhD, Laurent Jacquemin, MD, Marine Kinnel, MD, and Nicolas Girerd, MD, PhD

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

We describe a patient with coronavirus disease 2019 (COVID-19) and multiple concomitant thromboses occurring on the 9th day of hospital stay. Thromboses were found in distinct zones of the aorta, as well as in the renal, humeral, and pulmonary arteries. The extensive biological workup performed following this catastrophic thrombotic syndrome found no evidence for underlying prothrombotic disease. In light of current evidence regarding endothelium abnormalities related to COVID-19, this extreme case of catastrophic thrombotic syndrome suggests that COVID-19 can induce severe arterial thrombosis following intense endothelial activation. Résumé: Nous décrivons le cas d’un patient atteint de la maladie à coronavirus 2019 (COVID-19) et présentant de multiples thromboses concomitantes survenant au 9e jour d'hospitalisation. Les thromboses ont été identifiées dans des zones distinctes de l'aorte, ainsi que dans les artères rénales, humérales et pulmonaires. Un examen biologique approfondi effectué à la suite de ce syndrome thrombotique catastrophique n'a révélé aucun signe de maladie prothrombotique sous-jacente. À la lumière de ces éléments concernant les anomalies de l'endothélium liées à la COVID-19, ce cas extrême de syndrome thrombotique catastrophique suggère que la COVID-19 peut induire une thrombose artérielle sévère suite à une activation endothéliale intense.

Published
2021
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5. Golimumab pharmacokinetics in ulcerative colitis: a literature review

Author

Ines Harzallah, Josselin Rigaill, Nicolas Williet, Stephane Paul, and Xavier Roblin

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Golimumab (GLM) is the latest anti-tumor necrosis factor (TNF) that gained its marketing license. Thanks to the PURSUIT induction and maintenance trials, it was approved for the treatment of ulcerative colitis (UC) in 2013. The other anti-TNF drugs available are infliximab and adalimumab. These two drugs have validated algorithms concerning prescription and therapeutic drug monitoring (TDM) but little is known about GLM. The available data on GLM’s exposure–response relationship in UC are from the PURSUIT trials and are recently published. The data reveal all the factors that may impact the pharmacokinetic (PK) parameters: dosage, body weight (BW), concomitant drugs, the presence of anti-drug antibodies (ADAbs), sex and age. In addition, the GLM trough level at steady-state appears to be correlated with the patient’s improvement which may make it a precious indicator to predict the clinical response. There is, however, no consensus on a possible therapeutic level or cutoff associated with clinical response, remission, or any other outcome measure such as endoscopic healing in UC. This lack of a threshold value, and its validation with different assay techniques, makes it difficult to use GLM TDM in clinical practice. As with other anti-TNF agents, GLM is associated with development of ADAbs, of which the prevalence and effects are still insufficiently described. The objective of this review is to describe current data and understanding of the PK of GLM including serum concentrations of GLM and ADAbs in UC patients. Better understanding of these parameters could lead to improved patient care with GLM.

Published
2017
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6. Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders

Author

Thomas Husson, François Lecoquierre, Gaël Nicolas, Anne-Claire Richard, Alexandra Afenjar, Séverine AUDEBERT-BELLANGER, Catherine Badens, Frédéric Bilan, Varoona Bizaoui, Anne Boland, Marie-Noelle Bonnet-Dupeyron, Elise Brischoux-Boucher, Céline Bonnet, Marie Bournez, Odile Boute, Perrine Brunelle, Roseline Caumes, Perrine Charles, Nicolas Chassaing, Nicolas Chatron, Benjamin Cogné, Estelle Colin, Valérie Cormier-Daire, Rodolphe Dard, Benjamin Dauriat, Julian Delanne, Jean-François Deleuze, Florence Demurger, Anne-Sophie Denommé-Pichon, Christel Depienne, Anne Dieux Coeslier, Christèle Dubourg, Patrick Edery, salima EL CHEHADEH, Laurence Faivre, Mélanie FRADIN, Aurore Garde, David Geneviève, Brigitte Gilbert-Dussardier, Cyril Goizet, Alice Goldenberg, Evan Gouy, Anne-Marie Guerrot, Anne Guimier, Ines HARZALLAH, Delphine Héron, Bertrand Isidor, Xavier Le Guillou Horn, Boris Keren, Alma Kuechler, Elodie Lacaze, Alinoë Lavillaureix, Daphné Lehalle, Gaetan Lesca, James Lespinasse, Jonathan Levy, Stanislas Lyonnet, Godelieve Morel, Nolwenn Jean Marçais, Sandrine Marlin, Luisa Marsili, Cyril Mignot, Sophie Nambot, Mathilde Nizon, Robert Olaso, Laurent PASQUIER, Laurine Perrin, Florence Petit, Amélie Piton, Fabienne Prieur, Audrey Putoux, Marc Planes, Sylvie Odent, Chloé Quelin, Sylvia Quemener, Mélanie Rama, Marlène RIO, Massimiliano Rossi, Elise Schaefer, Sophie Rondeau, Pascale SAUGIER-VEBER, Thomas Smol, Sabine Sigaudy, Renaud TOURAINE, Frédéric Tran-Mau-Them, Aurélien Trimouille, Clémence Vanlerberghe, Valérie Vantalon, Gabriella Vera, Marie Vincent, Alban Ziegler, Olivier Guillin, Dominique Campion, and Camille Charbonnier

Abstract

Variants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers of certain Mendelian neurodevelopmental disorders has raised hopes to help classify VUS. However, prediction abilities of most published episignatures have not been independently investigated yet, which is a prerequisite for an informed and rigorous use in a diagnostic setting. We generated DNA methylation data from 102 carriers of (likely) pathogenic variants in ten different genes, 58 VUS carriers, and 25 healthy controls. Combining published episignature information and new validation data with a k-nearest-neighbour classifier within a leave-one-out scheme, we provide unbiased specificity and sensitivity estimates for each of the signatures. Our procedure reached 100% specificity, but the sensitivities unexpectedly spanned a very large spectrum. While ATRX, DNMT3A, KMT2D, and NSD1 signatures displayed a 100% sensitivity, CREBBP-RSTS and one of the CHD8 signatures reached less than 40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70%-100% sensibility at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples. Our results call for cautiousness and demonstrate that episignatures do not perform equally well. Some signatures are ready for confident use in a diagnostic setting. Yet, it is imperative to characterise the actual validity perimeter and interpretation of each episignature with the help of larger validation sample sizes and in a broader set of episignatures.

Published
2023
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8. Antiphospholipid antibodies in patients with coronavirus disease 2019 infection hospitalized in conventional unit

Author

Marjolaine Talbot, Amer Hamadé, Ines Harzallah, Bastien Woehl, Lucas Jambert, and Jonathan Tousch

Subjects
Male, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), 030204 cardiovascular system & hematology, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Internal medicine, medicine, Humans, In patient, Enoxaparin, neoplasms, Aged, Retrospective Studies, Aged, 80 and over, Lupus anticoagulant, biology, SARS-CoV-2, business.industry, Incidence, Incidence (epidemiology), Anticoagulants, COVID-19, Venous Thromboembolism, Hematology, General Medicine, Heparin, Middle Aged, Triple-Positive, medicine.disease, COVID-19 Drug Treatment, Cohort, Antibodies, Antiphospholipid, biology.protein, Antibody, business, 030215 immunology, medicine.drug
Abstract

Antiphospholipid (aPL) antibodies can arise transiently at times of viral diseases. The objective of this work was to evaluate the incidence of aPL antibodies in patients hospitalized in conventional unit for coronavirus disease 2019 (COVID-19) infection and confirmed venous thromboembolic events (VTE) associated with aPL antibodies. 41 patients infected with COVID-19 were tested for aPL antibodies. None had reported history of aPL syndrome. Arterial and venous duplex ultrasound of lower limbs was performed in all patients at Day 0 and Day 5. All patients had antithrombotic-prophylaxis upon admission using lower molecular weight heparin with Enoxaparin. Biological parameters were collected and analyzed. Nine patients (22%) developed VTE and seven (17%) were positive for aPL antibodies of which five had isolated positive lupus anticoagulant. The sixth patient was double aPL positive IgM anticardiolipin (147.8 U/ml) and anti-Beta2 Glyco protein 1 (97.3 U/ml) antibodies. The seventh was triple positive, IgM anticardiolipin 85.6 UI/ml, IgM anti-Beta2 Glyco protein 1 63.0 U/ml and positive lupus anticoagulant. Among the seven patients with aPL antibodies 2 (28.60%) had VTE. However, the incidence of VTE in patients negative for aPL antibodies was also significant as 20.6% (seven of 34). aPL antibodies were significantly associated with the transfer to ICUs of, P = 0.018. Not only the incidence of aPL antibodies was quite significant within our cohort, but also we observed 28.6% of VTE in aPL-positive patients. We strongly recommend routine testing for aPL antibodies in COVID-19 patients and systematic screening with duplex ultrasound search of vascular complications.

Published
2020
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9. Factor VIII and IX assays for post‐infusion monitoring in hemophilia patients: Guidelines from the French BIMHO group (GFHT)

Author

Emmanuelle, Jeanpierre, Claire, Pouplard, Dominique, Lasne, Véronique, Le Cam Duchez, Valérie, Eschwege, Claire, Flaujac, Hubert, Galinat, Ines, Harzallah, Valérie, Proulle, Motalib, Smahi, Frédéric, Sobas, Nataliia, Stepina, Pierre, Toulon, Sophie, Voisin, Catherine, Ternisien, Christophe, Nougier, and Annelise, Voyer

Subjects
medicine.medical_specialty, Clinical Decision-Making, Haemophilia A, Hemophilia A, Hemophilia B, Gastroenterology, Factor IX, 03 medical and health sciences, Collaborative group, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Haemophilia B, In patient, Blood Coagulation, Factor VIII, Plasma samples, business.industry, Disease Management, Chromogenic substrate assay, Hematology, General Medicine, medicine.disease, Recombinant Proteins, Hemorrhagic diseases, Treatment Outcome, 030220 oncology & carcinogenesis, Blood Coagulation Tests, Drug Monitoring, business, 030215 immunology, medicine.drug
Abstract

Replacement therapy with plasma-derived or recombinant FVIII and FIX (pdFVIII/pdFIX or rFVIII/rFIX) concentrates is the standard of treatment in patients with haemophilia A and B, respectively. Measurement of factor VIII (FVIII:C) or factor IX (FIX:C) levels can be done by one-stage clotting assay (OSA) or chromogenic substrate assay (CSA). The French study group on the Biology of Hemorrhagic Diseases (a collaborative group of the GFHT and MHEMO network) presents a literature review and proposals for the monitoring of FVIII:C and FIX:C levels in treated haemophilia A and B patients, respectively. The use of CSA is recommended for the monitoring of patients treated with pdFVIII or rFVIII including extended half-life (EHL) rFVIII. Except for rFVIII-Fc, great caution is required when measuring FVIII:C levels by OSA in patients substituted by EHL-rFVIII. The OSA is recommended for the monitoring of patients treated with pdFIX or rFIX. Large discordances in the FIX:C levels measured for extended half-life rFIX (EHL-rFIX), depending on the method and reagents used, must lead to great attention when OSA is used for measuring FIX:C levels in patients substituted by EHL-rFIX. Data of most of recent studies, obtained with spiked plasmas, deserve to be confirmed in plasma samples of treated patients.

Published
2020
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10. Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy and periventricular calcifications

Author

Erik Rosenhahn, Thomas J. O’Brien, Maha S. Zaki, Ina Sorge, Dagmar Wieczorek, Kevin Rostasy, Antonio Vitobello, Sophie Nambot, Fowzan S. Alkuraya, Mais O. Hashem, Amal Alhashem, Brahim Tabarki, Abdullah S. Alamri, Ayat H. Al Safar, Dalal K. Bubshait, Nada F. Alahmady, Joseph G. Gleeson, Mohamed S. Abdel-Hamid, Nicole Lesko, Sofia Ygberg, Sandrina P. Correia, Anna Wredenberg, Shahryar Alavi, Seyed M. Seyedhassani, Mahya Ebrahimi Nasab, Haytham Hussien, Tarek Omar, Ines Harzallah, Renaud Touraine, Homa Tajsharghi, Heba Morsy, Henry Houlden, Mohammad Shahrooei, Maryam Ghavideldarestani, Johannes R. Lemke, Heinrich Sticht, Rami Abou Jamra, Andre E. X. Brown, Reza Maroofian, and Konrad Platzer

Abstract

PPFIBP1 encodes for the liprin-β1 protein which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 14 individuals from 10 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy and progressive microcephaly. Further common clinical findings included muscular hypertonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired hearing and vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM-domain region that is essential for protein-protein interaction. For further insight in the effects of PPFIBP1 loss-of-function, we performed automated behavioural phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model which revealed defects in spontaneous and light-induced behaviour and confirmed resistance to the acetylcholinesterase inhibitor aldicarb suggesting a defect in the neuronal presynaptic zone. In conclusion, we present bi-allelic loss-of-function variants in PPFIBP1 as a novel cause of an autosomal recessive neurodevelopmental disorder.

Published
2022
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11. Exome sequencing as a first-tier test for copy number variant detection : retrospective evaluation and prospective screening in 2418 cases

Author

Quentin Testard, Xavier Vanhoye, Kevin Yauy, Marie-Emmanuelle Naud, Gaelle Vieville, Francis Rousseau, Benjamin Dauriat, Valentine Marquet, Sylvie Bourthoumieu, David Genevieve, Vincent Gatinois, Constance Wells, Marjolaine Willems, Christine Coubes, Lucile Pinson, Rodolphe Dard, Aude Tessier, Bérénice Hervé, François Vialard, Ines Harzallah, Renaud Touraine, Benjamin Cogné, Wallid Deb, Thomas Besnard, OIivier Pichon, Béatrice Laudier, Laurent Mesnard, Alice Doreille, Tiffany Busa, Chantal Missirian, Véronique Satre, Charles Coutton, Tristan Celse, Radu Harbuz, Laure Raymond, Jean-François Taly, and Julien Thevenon

Subjects
Oncology, medicine.medical_specialty, DNA Copy Number Variations, business.industry, High-Throughput Nucleotide Sequencing, Aneuploidy, Retrospective cohort study, medicine.disease, DNA sequencing, Internal medicine, Cohort, Genetics, medicine, Humans, Exome, Prospective Studies, Copy-number variation, business, Prospective cohort study, Genetics (clinical), Exome sequencing, Retrospective Studies
Abstract

BackgroundDespite the availability of whole exome (WES) and genome sequencing (WGS), chromosomal microarray (CMA) remains the first-line diagnostic test in most rare disorders diagnostic workup, looking for copy number variations (CNVs), with a diagnostic yield of 10%–20%. The question of the equivalence of CMA and WES in CNV calling is an organisational and economic question, especially when ordering a WGS after a negative CMA and/or WES.MethodsThis study measures the equivalence between CMA and GATK4 exome sequencing depth of coverage method in detecting coding CNVs on a retrospective cohort of 615 unrelated individuals. A prospective detection of WES-CNV on a cohort of 2418 unrelated individuals, including the 615 individuals from the validation cohort, was performed.ResultsOn the retrospective validation cohort, every CNV detectable by the method (ie, a CNV with at least one exon not in a dark zone) was accurately called (64/64 events). In the prospective cohort, 32 diagnoses were performed among the 2418 individuals with CNVs ranging from 704 bp to aneuploidy. An incidental finding was reported. The overall increase in diagnostic yield was of 1.7%, varying from 1.2% in individuals with multiple congenital anomalies to 1.9% in individuals with chronic kidney failure.ConclusionCombining single-nucleotide variant (SNV) and CNV detection increases the suitability of exome sequencing as a first-tier diagnostic test for suspected rare Mendelian disorders. Before considering the prescription of a WGS after a negative WES, a careful reanalysis with updated CNV calling and SNV annotation should be considered.

Published
2021
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12. Impact of aPTT reagents on measurement of a PEGylated recombinant FVIII (Adynovi ® /Adynovate ® ): A French multicentric field assay study

Author

Yoan Repesse, Christophe Nougier, Ines Harzallah, Emmanuelle Jeanpierre, Anne Ryman, Sophie Voisin, Claire Pouplard, Dominique Lasne, Catherine Ternisien, François Grand, and Anne Francoise Sapin

Subjects
Chromatography, Field (physics), business.industry, law, Biochemistry (medical), Clinical Biochemistry, Recombinant DNA, Medicine, Hematology, General Medicine, business, law.invention
Published
2021
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13. Impact of aPTT reagents on measurement of a PEGylated recombinant FVIII (Adynovi

Author

Catherine, Ternisien, Dominique, Lasne, Francois, Grand, Ines, Harzallah, Emmanuelle, Jeanpierre, Yoan, Repesse, Anne, Ryman, Anne Francoise, Sapin, Sophie, Voisin, Christophe, Nougier, and Claire, Pouplard

Subjects
Factor VIII, Humans, Indicators and Reagents, Partial Thromboplastin Time, Hemophilia A, Polyethylene Glycols
Published
2021

14. Multiple Arterial Thrombosis in a 78-Year-Old Patient: Catastrophic Thrombotic Syndrome in COVID-19

Author

Mihaela Calcaianu, Bree Lawson, Nicolas Girerd, Patrick Allimant, David Kenizou, Marine Kinnel, Beatrice Morisset, Ines Harzallah, Didier Bresson, L. Jacquemin, Clemence Perrin, Stéphane Zuily, BOZEC, Erwan, Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Service Hématologie, Mulhouse, Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], and French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT )

Subjects
medicine.medical_specialty, Aorta, Coronavirus disease 2019 (COVID-19), Endothelium, business.industry, Disease, 030204 cardiovascular system & hematology, medicine.disease, Thrombosis, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Endothelial activation, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030220 oncology & carcinogenesis, Internal medicine, Concomitant, medicine.artery, medicine, Cardiology, Cardiology and Cardiovascular Medicine, business, Hospital stay
Abstract

International audience; We describe a patient with coronavirus disease 2019 (COVID-19) and multiple concomitant thromboses occurring on the 9th day of hospital stay. Thromboses were found in distinct zones of the aorta, as well as in the renal, humeral, and pulmonary arteries. The extensive biological workup performed following this catastrophic thrombotic syndrome found no evidence for underlying prothrombotic disease. In light of current evidence regarding endothelium abnormalities related to COVID-19, this extreme case of catastrophic thrombotic syndrome suggests that COVID-19 can induce severe arterial thrombosis following intense endothelial activation.

Published
2021
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15. Screening of the duplication 24 pb of ARX gene in Moroccan patients with X-linked Intellectual Disability

Author

Zeineb Zian, Renaud Touraine, Naima Ghailani Nourouti, Amina Barakat, Kaoutar Ben Makhlouf, Ines Harzallah, Mohcine Bennani Mechita, and Yousra Benmakhlouf

Subjects
0301 basic medicine, Male, X-linked intellectual disability, Population, lcsh:Medicine, 030105 genetics & heredity, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Exon, 0302 clinical medicine, Intellectual Disability, Intellectual disability, Gene duplication, medicine, Humans, Genetic Testing, lcsh:Science (General), education, lcsh:QH301-705.5, Gene, Genetics, Homeodomain Proteins, Mutation, education.field_of_study, lcsh:R, Genes, Homeobox, Duplication 24 pb, General Medicine, medicine.disease, Research Note, Nonsyndromic ID, Morocco, lcsh:Biology (General), dup, ARX, 030217 neurology & neurosurgery, lcsh:Q1-390, Transcription Factors
Abstract

Objective Intellectual Disability (ID) represents a neuropsychiatric disorder, which its etiopathogenesis remains insufficiently understood. Mutations in the Aristaless Related Homeobox gene (ARX) have been identified to cause syndromic and nonsyndromic (NS-ID). The most recurrent mutation of this gene is a duplication of 24pb, c.428-451dup. Epidemiological and genetic studies about ID in the Moroccan population remain very scarce, and none study is carried out on the ARX gene. This work aimed to study c.428–451dup (24 bp) mutation in the exon 2 of the ARX gene in 118 males’ Moroccan patients with milder NS-ID to evaluate if the gene screening is a good tool for identifying NS-ID. Results Our mutational analysis did not show any dup(24pb) in our patients. This is because based on findings from previous studies that found ARX mutations in 70% of families with NS-ID, and in most cases, 1.5–6.1% of individuals with NS-ID have this duplication. Since 1/118 = 0.0084 (0.84%) is not much different from 1.5%, then it is reasonable that this could a sample size artifact. A complete screening of the entire ARX gene, including the five exons, should be fulfilled. Further investigations are required to confirm these results.

Published
2020

16. Comparison of Point-of-Care and Classical Immunoassays for the Monitoring Infliximab and Antibodies Against Infliximab in IBD

Author

Anne-Emmanuelle Berger, Yara Nasser, Xavier Roblin, Ines Harzallah, Stéphane Paul, and Remi Labetoulle

Subjects
0301 basic medicine, Comparative Effectiveness Research, medicine.medical_specialty, Physiology, medicine.drug_class, Point-of-Care Systems, Enzyme-Linked Immunosorbent Assay, Monoclonal antibody, Gastroenterology, Antibodies, 03 medical and health sciences, 0302 clinical medicine, Gastrointestinal Agents, Internal medicine, Adalimumab, medicine, Humans, Point of care, Immunoassay, Gastrointestinal agent, biology, medicine.diagnostic_test, Tumor Necrosis Factor-alpha, business.industry, Inflammatory Bowel Diseases, Infliximab, 030104 developmental biology, biology.protein, Trough level, 030211 gastroenterology & hepatology, France, Drug Monitoring, Antibody, business, medicine.drug
Abstract

The primary objective is to assess whether the POC assays to measure infliximab residual trough level in the serum of IBD patients were non-inferior to the ELISA techniques available on the market, and to determine which of them was the most robust. The second is to compare three different ELISA kits for monitoring anti-infliximab antibodies (ATI). The assays were carried out on patients’ sera using four ELISA kits from four different suppliers (three with a monoclonal antibody and one polyclonal) and two rapid techniques provided by BUHLMANN (Quantum Blue®) and R-Biopharm (Ridaquick) for monitoring infliximab levels. ATI were measured by three ELISA sets (Grifols, Theradiag, and R-Biopharm) which have different positivity limits and different units. We measured infliximab residual level and ATI in the serum of 90 IBD patients (85 treated with infliximab and five with adalimumab). All of the infliximab assays were very well correlated when analyzed with Spearman nonparametric correlation (0.93 ≤ r ≤ 0.99), and the two POC assays were also excellently correlated (r = 0.98). The ATI monitoring kits revealed a correlation ranging from 0.73 to 0.96 when comparing positive and negative patients. When normalizing the quantitative values between the different ELISA tests (expressed arbitrarily by using multiples of the positivity limits defined by each supplier), the Spearman r coefficient ranged from 0.81 to 0.93. The available evidence allows us to conclude that all of the infliximab monitoring assays correlate well and may be used for IFX monitoring; albeit variations in measured IFX concentration among different assays remain present, these assays could be interchangeable. The ATI monitoring techniques are all capable of detecting ATI-positive patients, but because of the difference in the positivity limits and the measurement units, it is better to follow a patient rate with one definite kit.

Published
2018
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17. Identification of TSC1 or TSC2 mutation limited to the tumor in three cases of solitary subependymal giant cell astrocytoma using next-generation sequencing technology

Author

Nathalie Streichenberger, Fabienne Giuliano, Ines Harzallah, Martine Fohlen, Renaud Touraine, Marc Polivka, Linda Pons, and Georg Dorfmüller

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Technology, Somatic cell, Astrocytoma, medicine.disease_cause, Germline, Tuberous Sclerosis Complex 1 Protein, 03 medical and health sciences, Tuberous sclerosis, Exon, 0302 clinical medicine, Germline mutation, Tuberous Sclerosis Complex 2 Protein, medicine, Humans, Retrospective Studies, Mutation, Subependymal giant cell astrocytoma, business.industry, High-Throughput Nucleotide Sequencing, General Medicine, medicine.disease, nervous system diseases, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, Cancer research, Neurology (clinical), TSC1, business, 030217 neurology & neurosurgery
Abstract

Subependymal giant-cell astrocytomas (SEGAs) are low grade intraventricular tumors typically found in patients with tuberous sclerosis complex (TSC). The occurrence of SEGA in non TSC patients is very rare and from a genetic point of view these so-called solitary SEGA are thought to result either from somatic mutations in one of the TSC genes (TSC1 or TSC2) limited to the tumor, or be part of a “forme fruste” of TSC with somatic mosaicism. We report on three new cases of solitary SEGA with germline and somatic mutation analysis. We retrospectively analyzed TSC genes in three patients with a solitary SEGA using next-generation sequencing technique. In the three patients, a somatic mutation of TSC1 or TSC2 was found only in the tumor cells: one patient had a TSC1 heterozygote mutation, involving the natural acceptor splicing site of intron 15 (c.1998-1G > A (p.?). Two patients had a TSC2 mutation located in the canonical splicing donor site of intron 5 (c.599 + 1G > A) in 70% of the alleles in one patient and in exon 9: c.949_955dup7 (p.V319DfxX21) in 25 of the alleles in the second patient. No other TSC mutations were found in patient’s blood or tumor and those identified mutations were absent in blood DNA from parents and siblings. We therefore conclude that solitary SEGA can occur with a TSC1 or TSC2 mutation limited to the tumor in patients without TSC.

Published
2019

18. Factor IX assays in treated hemophilia B patients

Author

Claire, Pouplard, Emmanuelle, Jeanpierre, Dominique, Lasne, Véronique, Le Cam Duchez, Valérie, Eschwege, Claire, Flaujac, Hubert, Galinat, Ines, Harzallah, Valérie, Proulle, Motalib, Smahi, Frédéric, Sobas, Catherine, Ternisien, Pierre, Toulon, Sophie, Voisin, Christophe, Nougier, Annelise, Voyer, Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Microbiologie Clinique [AP-HP Hôpital Necker-Enfants Malades], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier de Versailles André Mignot (CHV), Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Laboratoire de Microbiologie [GHR Mulhouse Sud-Alsace, Mulhouse], Groupe hospitalier de la région de Mulhouse Sud-Alsace (GHRMSA), Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CH eaubonne montmorency, Hospices Civils de Lyon (HCL), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Pasteur [Nice] (CHU), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours, Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
030213 general clinical medicine, medicine.medical_specialty, Gastroenterology, Hemophilia B, Factor IX, 03 medical and health sciences, Collaborative group, 0302 clinical medicine, Internal medicine, medicine, Humans, In patient, Monitoring, Physiologic, Plasma samples, medicine.diagnostic_test, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, Prognosis, 3. Good health, Hemorrhagic diseases, Coagulation, MESH: Blood Chemical Analysis/methods, Blood Coagulation Tests/methods, Monitoring, Physiologic/methods, Blood Coagulation Tests, Chronometric assays, Blood Chemical Analysis, medicine.drug, Partial thromboplastin time, Chromogenic assays
Abstract

International audience; Replacement therapy with plasma-derived or recombinant FIX (pdFIX or rFIX) concentrates is the standard of treatment in patients with hemophilia B. The method predominantly used for measuring factor IX (FIX:C) levels is the one-stage clotting assay (OSA) but this method depends on the activated partial thromboplastin time (APTT) reagent and the coagulation analyzer used, and wide variations in the measurements of FIX recovery have been reported with some factor concentrates. The French study group on the biology of hemorrhagic diseases (a collaborative group of the GFHT and MHEMO network), presents a review of the literature and proposals for the monitoring of FIX:C levels in treated hemophilia B patients. The use of OSA calibrated with a plasma reference tested against the current FIX WHO International Standard is recommended for the monitoring of patients treated with pdFIX or rFIX. Chromogenic substrate assays (CSA) are adequate for the monitoring of patients treated with Rixubis®, but data available for Benefix® are currently too limited. For extended half-life rFIX (EHL-rFIX), large discordances in the FIX:C levels measured were evidenced, depending on the method and reagents used. Great attention is therefore required for measuring FIX:C levels by OSA in patients substituted by EHL-rFIX. Commercial kits for CSA are not equivalent, and although potentially useful, they are not validated for all EHL-rFIX. Most of recent studies reported data obtained with spiked plasmas, which deserve to be confirmed on plasma samples collected in treated patients.

Published
2019
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19. Risk estimation of uniparental disomy of chromosome 14 or 15 in a fetus with a parent carrying a non‐homologous Robertsonian translocation. Should we still perform prenatal diagnosis?

Author

Sébastien Schmitt, Philippe Vago, Marie-Laure Maurin, Gregory Egea, Denise Molina Gomes, Emmanuelle Haquet, Marine Lebrun, Jacques Puechberty, François Vialard, Olivier Pichon, Perrine Malzac, Philippe Jonveaux, Martine Doco-Fenzy, Paul Kuentz, Sandra Chantot-Bastaraud, Kamran Moradkhani, Jean-Paul Bonnefont, Caroline Janel, Jean-Michel Dupont, Pierre Boisseau, Jean-Pierre Siffroi, Cédric Le Caignec, Anne-Laure Fauret-Amsellem, Damien Sanlaville, Chantal Missirian, Carole Goumy, Agnès Guichet, Marie-Christine Manca-Pellissier, Renaud Touraine, Laurence Cuisset, Pascale Saugier-Veber, Nicolas Gruchy, Houda Hamdi-Rozé, Bénédicte Duban-Bedu, Bruno Delobel, N. Joye, Isabelle Creveaux, Ines Harzallah, Frédéric Bilan, Philippe Gosset, Marie-Pierre Audrézet, Laboratoire de cytogénétique [CHU Nantes] (Service de génétique médicale), Centre hospitalier universitaire de Nantes (CHU Nantes), Depatment Biochemical Genetics, Université Paris Descartes - Paris 5 (UPD5), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Gatonero SA, Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), CHU Pontchaillou [Rennes], Service d'histologie, embryologie et cytogénétique [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de cytogénétique prénatale [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Assistance Publique - Hôpitaux de Marseille (APHM), Espace éthique méditerranéen, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Génétique, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire de génétique chromosomique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Service de parasitologie et mycologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire de Biochimie, Université d'Auvergne - Clermont-Ferrand I (UdA), CHU Clermont-Ferrand, Histologie Embryologie Cytogénétique, Université d'Auvergne - Clermont-Ferrand I (UdA)-Faculté de Médecine, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Les Hôpitaux Universitaires de Strasbourg (HUS), Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Centre de Génétique Chromosomique, Génétique Médicale, CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Département de biologie de la reproduction et de gynécologie [CHIPS, Poissy], Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], CHI Poissy-Saint-Germain, Gamètes, implantation, gestation (GIG), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Saint-Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), GHICL-Hôpital Saint Vincent de Paul, Hôpital Saint Vincent de Paul-GHICL, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biologie de la Reproduction, and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Robertsonian translocation, Chromosomal translocation, Prenatal diagnosis, 030105 genetics & heredity, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, medicine.disease_cause, Risk Assessment, Translocation, Genetic, Miscarriage, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Prenatal Diagnosis, medicine, Humans, Genetics (clinical), Retrospective Studies, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 15, Fetus, 030219 obstetrics & reproductive medicine, Obstetrics, business.industry, Obstetrics and Gynecology, Chromosome, Uniparental Disomy, medicine.disease, Uniparental disomy, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Female, business
Abstract

International audience; Objective: Uniparental disomy (UPD) testing is currently recommended during pregnancy in fetuses carrying a balanced Robertsonian translocation (ROB) involving chromosome 14 or 15, both chromosomes containing imprinted genes. The overall risk that such a fetus presents a UPD has been previously estimated to be around ~0.6‐0.8%. However, because UPD are rare events and this estimate has been calculated from a number of studies of limited size, we have reevaluated the risk of UPD in fetuses for whom one of the parents was known to carry a nonhomologous ROB (NHROB).Method: We focused our multicentric study on NHROB involving chromosome 14 and/or 15. A total of 1747 UPD testing were performed in fetuses during pregnancy for the presence of UPD(14) and/or UPD(15).Result: All fetuses were negative except one with a UPD(14) associated with a maternally inherited rob(13;14).Conclusion: Considering these data, the risk of UPD following prenatal diagnosis of an inherited ROB involving chromosome 14 and/or 15 could be estimated to be around 0.06%, far less than the previous estimation. Importantly, the risk of miscarriage following an invasive prenatal sampling is higher than the risk of UPD. Therefore, we do not recommend prenatal testing for UPD for these pregnancies and parents should be reassured.

Published
2019
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