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1. Evidence for high breakpoint variability in 46, XX, SRY‐positive testicular disorder and frequent ARSE deletion that may be associated with short stature

Author

Céline Capron, Louis Januel, Gaëlle Vieville, Sylvie Jaillard, Paul Kuentz, Gaëlle Salaun, Gwenaël Nadeau, Patrice Clement, Marie Pierre Brechard, Bérénice Herve, Jean Michel Dupont, Nicolas Gruchy, Pascal Chambon, Fatma Abdelhedi, Eric Dahlen, Philippe Vago, Radu Harbuz, Ingrid Plotton, Charles Coutton, Marc‐Antoine Belaud‐Rotureau, Caroline Schluth‐Bolard, François Vialard, CHI Poissy-Saint-Germain, Hospices Civils de Lyon (HCL), Pôle Couple-Enfant, Département de Génétique et Procréation, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Clermont-Ferrand, Centre Hospitalier Métropole Savoie [Chambéry], Laboratoire Clément, Partenaires INRAE, Hôpital Saint-Joseph [Marseille], GHU AP-HP Centre Université de Paris, Service de Génétique [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), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Rouen, Hedi Chaker Hospital [Sfax], Faculté de médecine - Faculty of Medicine [Sfax, Tunisie] (FMS), Université de Sfax - University of Sfax, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), and École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Male, chromosomal rearrangement, 46, XX Testicular Disorders of Sex Development, Urology, Endocrinology, Diabetes and Metabolism, XX SRY-positive male syndrome, arylsulfatase E gene, Testicular Diseases, replication-based mechanisms, Translocation, Genetic, PRKX, short stature, Endocrinology, Reproductive Medicine, Humans, Protein Kinases, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Arylsulfatases
Abstract

International audience; The translocation of SRY onto one of the two X chromosomes results in a 46,XX testicular disorder of sex development; this is supposedly due to non-allelic homologous recombination between the protein kinase X gene (PRKX) and the inverted protein kinase Y pseudogene (PRKY). Although 46,XX SRY-positive men are infertile, the literature data indicate that some of these individuals are of short stature (relative to the general population). We sought to determine whether short stature was linked to additional, more complex chromosomal rearrangements.Twelve laboratories gathered detailed clinical, anthropomorphic, cytogenetic and genetic data (including chromosome microarray (CMA) data) on patients with 46,XX SRY-positive male syndrome.SRY was present (suggesting a der(X)t(X;Y)) in 34 of the 38 cases (89.5%). When considering only the 20 patients with CMA data, we identified several chromosomal rearrangements and breakpoints - especially on the X chromosome. In the five cases for whom the X chromosome breakpoint was located in the pseudoautosomal (PAR) region, there was partial duplication of the derivate X chromosome. In contrast, in the 15 cases for whom the breakpoint was located downstream of the pseudoautosomal region, part of the derivate X chromosome had been deleted (included the arylsulfatase E (ARSE) gene in 11 patients). For patients with vs. without ARSE deletion, the mean height was respectively 167.7 ± 4.5 and 173.1 ± 4.0 cm; this difference was not statistically significant (p = 0.1005).Although 46,XX SRY-positive male syndromes were mainly due to imbalanced crossover between the X and Y chromosome during meiosis, the breakpoints differed markedly from one patient to another (especially on the X chromosome); this suggests the presence of a replication-based mechanism for recombination between non-homologous sequences. In some patients, the translocation of SRY to the X chromosome was associated with ARSE gene deletion, which might have led to short stature. With a view to explaining this disorder of sex development, whole exome sequencing could be suggested for SRY-negative patients. This article is protected by copyright. All rights reserved.

Published
2022
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2. 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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3. Xq22.3q23 microdeletion harboring TMEM164 and AMMECR1 genes: Two case reports confirming a recognizable phenotype with short stature, midface hypoplasia, intellectual delay, and elliptocytosis

Author

Renaud Touraine, Véronique Adouard, Pierre-Simon Jouk, Véronique Satre, Radu Harbuz, Claire Vettier, Claire Barro, Charles Coutton, Francis Ramond, Julien Thevenon, Brice Poreau, and Klaus Dieterich

Subjects
Male, Nephritis, Hereditary, Short stature, Contiguous gene syndrome, Craniofacial Abnormalities, Elliptocytosis, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Alport syndrome, Child, Genetics (clinical), Exome sequencing, Chromosomes, Human, X, business.industry, Elliptocytosis, Hereditary, Membrane Proteins, Proteins, Genetic Diseases, X-Linked, AMMECR1, Prognosis, medicine.disease, Chromosome Deletion, medicine.symptom, business, Haploinsufficiency
Abstract

The AMME syndrome defined as the combination of Alport syndrome, intellectual disability, midface hypoplasia, and elliptocytosis (AMME) is known to be a contiguous gene syndrome associated with microdeletions in the region Xq22.3q23. Recently, using exome sequencing, missense pathogenic variants in AMMECR1 have been associated with intellectual disability, midface hypoplasia, and elliptocytosis. In these cases, AMMECR1 gene appears to be responsible for most of the clinical features of the AMME syndrome except for Alport syndrome. In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array-CGH involving TMEM164 and AMMECR1 genes and SNORD96B small nucleolar RNA for one patient, inherited from their mothers. These original cases further confirm that most specific AMME features are ascribed to AMMECR1 haploinsufficiency. These cases reporting the smallest microdeletions encompassing AMMECR1 gene provide new evidence for involvement of AMMECR1 in the AMME phenotype and permit to discuss a phenotype related to AMMECR1 haploinsufficiency: developmental delay/intellectual deficiency, midface hypoplasia, midline defect, deafness, and short stature.

Published
2019
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4. Genomic duplication in the 19q13.42 imprinted region identified as a new genetic cause of intrauterine growth restriction

Author

Pierre-Simon Jouk, Patrick Lorès, Gaëlle Vieville, Véronique Satre, Radu Harbuz, Aurélie Truffot, Graciane Petre, Daniel Vaiman, Pierre F. Ray, Hervé Sartelet, Aminata Touré, François Berger, Brice Poreau, Sandrine Brandeis, Florence Amblard, Guillaume Martinez, Marie Bidart, Françoise Devillard, Charles Coutton, BrainTech Laboratory [CHU Grenoble Alpes - Inserm U1205], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Université Grenoble Alpes (UGA), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), BrainTech Laboratory [CHU Grenoble Alpes - Inserm U1205] (Brain Tech Lab ), CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Adult, 0301 basic medicine, [SDV]Life Sciences [q-bio], Biopsy, Intrauterine growth restriction, Biology, Ultrasonography, Prenatal, Epigenesis, Genetic, Genomic Imprinting, 03 medical and health sciences, Pregnancy, Gene Duplication, Placenta, Gene duplication, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Allele, Gene, ComputingMilieux_MISCELLANEOUS, Genetic Association Studies, reproductive and urinary physiology, Genetics (clinical), Fetus, Fetal Growth Retardation, Microarray analysis techniques, medicine.disease, Immunohistochemistry, Neoplasm Proteins, DNA-Binding Proteins, 030104 developmental biology, medicine.anatomical_structure, embryonic structures, Female, Genomic imprinting, Chromosomes, Human, Pair 19
Abstract

We report findings from a male fetus of 26 weeks' gestational age with severe isolated intrauterine growth restriction (IUGR). Chromosomal microarray analysis (CMA) on amniotic fluid cells revealed a 1.06-Mb duplication in 19q13.42 inherited from the healthy father. This duplication contains 34 genes including ZNF331, a gene encoding a zinc-finger protein specifically imprinted (paternally expressed) in the placenta. Study of the ZNF331 promoter by methylation-specific-multiplex ligation-dependent probe amplification showed that the duplicated allele was not methylated in the fetus unlike in the father's genome, suggesting both copies of the ZNF331 gene are expressed in the fetus. The anti-ZNF331 immunohistochemical analysis confirmed that ZNF331 was expressed at higher levels in renal and placental tissues from this fetus compared to controls. Interestingly, ZNF331 expression levels in the placenta have previously been reported to inversely correlate with fetal growth parameters. The original observation presented in this report showed that duplication of ZNF331 could be a novel genetic cause of isolated IUGR and underlines the usefulness of CMA to investigate the genetic causes of isolated severe IUGR.

Published
2018
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5. A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH

Author

François Vialard, Eva Pipiras, Pascale Kleinfinger, Dominique Martin-Coignard, Marie Catty, Elisabeth Flori, Emilie Landais, Mylène Valduga, Marie-France Portnoï, Aline Receveur, Agnès Choiset, Ghislaine Plessis, Nathalie Le Meur, Audrey Basinko, Justine Besseau-Ayasse, James Lespinasse, Radu Harbuz, Céline Poirsier, Martine Doco-Fenzy, Pascaline Letard, Caroline Schluth-Bolard, Anne Bazin, Jérôme Toutain, Fabienne Prieur, Florence Amblard, Cédric Le Caignec, Tiffany Busa, Marie Christine de Blois, Melanie Jimenez, Patrick Callier, Chantal Missirian, Céline Pebrel-Richard, Paul Kuentz, Catherine Yardin, François Cartault, Hakima Lallaoui, Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), UVSQ - Département de maïeutique (UVSQ Maïeutique), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), 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), CHU Bordeaux [Bordeaux], 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), 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 universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Génétique moléculaire et génétique épidémiologique, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Laboratoire de cytogénétique et génétique moléculaire [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Service de génétique, Centre hospitalier Félix Guyon, Bellepierre, Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), CHU Clermont-Ferrand, Service de Génétique et d'Embryologie Médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service d'histologie, embryologie et cytogénétique [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Service d'Histologie, cytologie, cytogénétique, biologie cellulaire [CHU Limoges], CHU Limoges, Activité Motrice et Adaptation PsychoPhysiologique (AMAPP), Université d'Orléans (UO), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Service Histologie-embryologie-cytogénétique, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Laboratoire Pasteur Cerba, Laboratoire de Cytogénétique, CHI Poissy-Saint-Germain, Service de gynécologie et obstétrique [CHI Poissy-Saint Germain], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), 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), Institut Pasteur [Paris] (IP)-Laboratoire CERBA [Saint Ouen l'Aumône], 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 Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Association des Cytogénéticiens de Langue Française, Gamètes, implantation, gestation (GIG), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Institut Pasteur [Paris]-Laboratoire CERBA [Saint Ouen l'Aumône], Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [Bondy]

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, 22q11 Deletion Syndrome, Adolescent, [SDV]Life Sciences [q-bio], Population, Article, 03 medical and health sciences, Intellectual disability, Genetics, medicine, Humans, Genetic Testing, Child, education, ComputingMilieux_MISCELLANEOUS, In Situ Hybridization, Fluorescence, Genetics (clinical), Comparative Genomic Hybridization, Fetus, education.field_of_study, business.industry, Incidence (epidemiology), Infant, Newborn, Cytogenetics, Infant, Microdeletion syndrome, medicine.disease, 3. Good health, 030104 developmental biology, Child, Preschool, Cohort, Paternal Inheritance, Female, France, business, Comparative genomic hybridization
Abstract

Although 22q11.2 deletion syndrome (22q11.2DS) is the most recurrent human microdeletion syndrome associated with a highly variable phenotype, little is known about the condition's true incidence and the phenotype at diagnosis. We performed a multicenter, retrospective analysis of postnatally diagnosed patients recruited by members of the Association des Cytogénéticiens de Langue Française (the French-Speaking Cytogeneticists Association). Clinical and cytogenetic data on 749 cases diagnosed between 1995 and 2013 were collected by 31 French cytogenetics laboratories. The most frequent reasons for referral of postnatally diagnosed cases were a congenital heart defect (CHD, 48.6%), facial dysmorphism (49.7%) and developmental delay (40.7%). Since 2007 (the year in which array comparative genomic hybridization (aCGH) was introduced for the routine screening of patients with intellectual disability), almost all cases have been diagnosed using FISH (96.1%). Only 15 cases (all with an atypical phenotype) were diagnosed with aCGH; the deletion size ranged from 745 to 2904 kb. The deletion was inherited in 15.0% of cases and was of maternal origin in 85.5% of the latter. This is the largest yet documented cohort of patients with 22q11.2DS (the most commonly diagnosed microdeletion) from the same population. French cytogenetics laboratories diagnosed at least 108 affected patients (including fetuses) per year from among a national population of ∼66 million. As observed for prenatal diagnoses, CHDs were the most frequently detected malformation in postnatal diagnoses. The most common CHD in postnatal diagnoses was an isolated septal defect.

Published
2015
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6. Association of structural and numerical anomalies of chromosome 22 in a patient with syndromic intellectual disability

Author

Alain Kitzis, Radu Harbuz, Brigitte Gilbert-Dussardier, Frédéric Bilan, Rania Naoufal, Dominique Couet, and Marine Legendre

Subjects
0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, Chromosomes, Human, Pair 22, Developmental Disabilities, Chromosome Disorders, Trisomy, 030105 genetics & heredity, Biology, Trisomy 22, 03 medical and health sciences, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Language Development Disorders, Genetics (clinical), In Situ Hybridization, Fluorescence, Chromosome Aberrations, Comparative Genomic Hybridization, medicine.diagnostic_test, Mosaicism, General Medicine, Uniparental Disomy, medicine.disease, Hypotonia, Uniparental disomy, 030104 developmental biology, Karyotyping, Speech delay, medicine.symptom, Chromosome Deletion, Chromosome 22, Fluorescence in situ hybridization
Abstract

Array comparative genomic hybridization (aCGH) is now widely adopted as a first-tier clinical diagnostic test for patients with developmental delay (DD)/intellectual disability (ID), autism spectrum disorders, and multiple congenital anomalies. Nevertheless, classic karyotyping still has its impact in diagnosing genetic diseases, particularly mosaic cases. We report on a 30 year old patient with syndromic intellectual disability, a 22q13.2 microdeletion and mosaic trisomy 22. The patient had the following clinical features: intrauterine growth retardation at birth, hypotonia, cryptorchidism, facial asymmetry, enophthalmus, mild prognathism, bifid uvula, hypoplastic upper limb phalanges, DD including speech delay, and ID. Whole genome aCGH showed a de novo 1 Mb interstitial heterozygous deletion in 22q13.2, confirmed by fluorescence in situ hybridization in all cells examined. Moreover, 18% cells had an extra chromosome 22 suggesting a trisomy 22 mosaicism. Almost all 22q13 deletions published so far have been terminal deletions with variable sizes (100 kb to over 9 Mb). Very few cases of interstitial 22q13.2 deletions were reported. In its mosaic form, trisomy 22 is compatible with life, and there are about 20 reports in the literature. It has a variable clinical presentation: growth restriction, dysmorphic features, cardiovascular abnormalities, hemihyperplasia, genitourinary tract anomalies and ID. Neurodevelopmental outcome ranges from normal to severe DD. The patient presents clinical features that are common to both the interstitial 22q13 deletion and the mosaic trisomy 22; characteristics related to the interstitial deletion alone and others explained solely by the mosaic trisomy. Our case points out the role of conventional cytogenetic tools in mosaic cases that could be missed by microarray technology. We therefore suggest the combination of both conventional and molecular karyotyping in the investigation of certain genetic diseases.

Published
2016

7. Identification of a new recurrent Aurora kinase C mutation in both European and African men with macrozoospermia

Author

Catherine Poirot, François Vialard, Agnès Guichet, Jean Pierre Soulie, Florence Lestrade, Pierre-Simon Jouk, Christophe Arnoult, Joël Lunardi, Nathalie Rives, Pascale May-Panloup, Sylviane Hennebicq, Véronique Satre, Charles Coutton, Chema Triki, J. Rollet, Raoudha Zouari, Béatrice Dorphin, Ghaya Merdassi, Pierre F. Ray, Brigitte Benzacken, Farid Abada, Michael G. B. Blum, Isabelle Koscinski, Valérie Mitchell, Laeticia Hesters, Mariem Ben Khelifa, Radu Harbuz, Leila Keskes, Stéphane Viville, AGeing and IMagery (AGIM), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Clinique de la reproduction les Jasmins, 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), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie de la Reproduction, Labo FIV, Centre Hospitalier Universitaire d'Angers (CHU Angers), Centre of Reproductive Medicine and Prenatal Diagnosis (CMRDP), entre of Reproductive Medicine and Prenatal Diagnosis (CMRDP), Unité de Procréation médicalement Assistée, hôpital Aziza Othmana, Département de Biologie de la Reproduction, CHI Poissy-Saint-Germain, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biology of Reproduction Unit, Paris, France, Université Pierre et Marie Curie - Paris 6 (UPMC), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Clinique de Promotion des Sciences de la Reproduction [Tunis] (CPSR), Polyclinique les Jasmins [Tunis], Département de biologie de la reproduction et de gynécologie [CHIPS, Poissy], Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], and Dynamiques Cellulaire, Tissulaire & Microscopie fonctionnelle (TIMC-IMAG-DyCTiM)

Subjects
Adult, Male, Infertility, Tunisia, Mutant, Protein Serine-Threonine Kinases, Biology, Cohort Studies, 03 medical and health sciences, Exon, 0302 clinical medicine, Aurora Kinases, Meiotic spindle assembly checkpoint, medicine, Humans, Aurora Kinase C, Crossing Over, Genetic, Allele, Genetic Association Studies, Infertility, Male, Retrospective Studies, 030304 developmental biology, Genetics, 0303 health sciences, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], 030219 obstetrics & reproductive medicine, Rehabilitation, Obstetrics and Gynecology, Heterozygote advantage, Exons, medicine.disease, Spermatozoa, Founder Effect, Pedigree, 3. Good health, Morocco, Reproductive Medicine, Codon, Nonsense, Algeria, Mutation, Mutation (genetic algorithm), Sperm Head, France, Founder effect
Abstract

International audience; STUDY QUESTION: Can we identify new sequence variants in the aurora kinase C gene (AURKC) of patients with macrozoospermia and establish a genotype-phenotype correlation? SUMMARY ANSWER: We identified a new non-sense mutation, p.Y248*, that represents 13% of all mutant alleles. There was no difference in the phenotype of individuals carrying this new mutation versus the initially described and main mutation c.144delC. WHAT IS KNOWN ALREADY: The absence of a functional AURKC gene causes primary infertility in men by blocking the first meiotic division and leading to the production of tetraploid large-headed spermatozoa. We previously demonstrated that most affected men were of North African origin and carried a homozygous truncating mutation (c.144delC). STUDY DESIGN, SIZE, DURATION: This is a retrospective study carried out on patients consulting for infertility and described as having >5% large-headed spermatozoa. A total of 87 patients are presented here, 43 patients were published previously and 44 are new patients recruited between January 2008 and December 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients consulted for primary infertility in fertility clinics in France (n = 44), Tunisia (n = 30), Morocco (n = 9) or Algeria (n = 4). Sperm analysis was carried out in the recruiting fertility clinics and all molecular analyses were performed at Grenoble teaching hospital. DNA was extracted from blood or saliva and the seven AURKC exons were sequenced. RT-PCR was carried out on transcripts extracted from leukocytes from one patient homozygous for p.Y248*. Microsatellite analysis was performed on all p.Y248* patients to evaluate the age of this new mutation. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a new non-sense mutation, p.Y248*, in 10 unrelated individuals of European (n = 4) and North African origin (n = 6). We show that this new variant represents 13% of all mutant alleles and that the initially described c.144delC variant accounts for almost all of the remaining mutated alleles (85.5%). No mutated transcripts could be detected by RT-PCR suggesting a specific degradation of the mutant transcripts by non-sense mediated mRNA decay. A rare variant located in the 3' untranslated region was found to strictly co-segregate with p.Y248*, demonstrating a founding effect. Microsatellite analysis confirmed this linkage and allowed us to estimate a mutational age of between 925 and 1325 years, predating the c.144delC variant predicted by the same method to have arisen 250-650 years ago. Patients with no identified AURKC mutation (n = 15) have significantly improved parameters in terms of vitality and concentration of normal spermatozoa, and a decreased rate of spermatozoa with a large head and multiple flagella (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Despite adherence to the World Health Organization guidelines, large variations in most characteristic sperm parameters were observed, even for patients with the same homozygous mutation. We believe that is mainly related to inter-laboratory variability in sperm parameter scoring. This prevented us from establishing clear-cut values to indicate a need for molecular analysis of patients with macrozoospermia. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms yet again the importance of AURKC mutations in the aetiology of macrozoospermia. Although a large majority of patients are of North African origin, we have now identified European patients carrying a new non-sense mutation indicating that a diagnosis of absence of a functional AURKC gene should not be ruled out for non-Magrebian individuals. Indirect evidence indicates that AURKC might be playing a role in the meiotic spindle assembly checkpoint (SAC) during meiosis. We postulate that heterozygous men might have a more relaxed SAC leading to a more abundant sperm production and a reproductive advantage. This could be the reason for the rapid accumulation of the two AURKC mutations we observe in North African individuals. STUDY FUNDING/COMPETING INTEREST(S): None of the authors have any competing interest. This work is part of the project 'Identification and Characterization of Genes Involved in Infertility (ICG2I)' funded by the programme GENOPAT 2009 from the French Research Agency (ANR).

Published
2012
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8. A Recurrent Deletion of DPY19L2 Causes Infertility in Man by Blocking Sperm Head Elongation and Acrosome Formation

Author

Marrakchi Ouafi, Isabelle Koscinski, Ghaya Merdassi, B. Sèle, Fethi Zhioua, François Vialard, Stéphane Viville, Raoudha Zouari, Thérèse Schweitzer, Mariem Ben Khelifa, Radu Harbuz, Mounir Makni, Lazhar Halouani, Charles Coutton, Christophe Arnoult, Nathalie Sermondade, Pierre-Simon Jouk, Amel Zhioua, Virginie Pierre, Véronique Satre, Mahmoud Kharouf, Jessica Escoffier, Chema Triki, Yorgos Nikas, Pierre F. Ray, Habib Latrous, Sylviane Hennebicq, Joël Lunardi, Farid Abada, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, AGeing and IMagery (AGIM), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Clinique de la reproduction les Jasmins, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Procréation médicalement Assistée, hôpital Aziza Othmana, Athens Innovative Microscopy, Département de Biologie de la Reproduction, CHI Poissy-Saint-Germain, Service de Biologie de la Reproduction, CHU Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre of Reproductive Medicine and Prenatal Diagnosis (CMRDP), entre of Reproductive Medicine and Prenatal Diagnosis (CMRDP), Histologie Embriologie Cytogénétique CECOS, Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'assistance médicale à la procréation, Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Rhône-Alpes Region - CIBLE 2009 program, Roux-Buisson, Nathalie, Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Clinique de Promotion des Sciences de la Reproduction [Tunis] (CPSR), Polyclinique les Jasmins [Tunis], Département de biologie de la reproduction et de gynécologie [CHIPS, Poissy], and Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy]

Subjects
Male, Infertility, DNA Copy Number Variations, Genetic Linkage, Non-allelic homologous recombination, Reproductive technology, Biology, Male infertility, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Report, Genetics, medicine, Homologous chromosome, Humans, Genetics(clinical), Family, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Acrosome, Infertility, Male, Genetics (clinical), Globozoospermia, 030304 developmental biology, 0303 health sciences, Jordan, 030219 obstetrics & reproductive medicine, Homozygote, Membrane Proteins, medicine.disease, Pedigree, 3. Good health, Genetic Loci, Sperm Head, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Gene Deletion
Abstract

International audience; An increasing number of couples require medical assistance to achieve a pregnancy, and more than 2% of the births in Western countries now result from assisted reproductive technologies. To identify genetic variants responsible for male infertility, we performed a whole-genome SNP scan on patients presenting with total globozoospermia, a primary infertility phenotype characterized by the presence of 100% round acrosomeless spermatozoa in the ejaculate. This strategy allowed us to identify in most patients (15/20) a 200 kb homozygous deletion encompassing only DPY19L2, which is highly expressed in the testis. Although there was no known function for DPY19L2 in humans, previous work indicated that its ortholog in C. elegans is involved in cell polarity. In man, the DPY19L2 region has been described as a copy-number variant (CNV) found to be duplicated and heterozygously deleted in healthy individuals. We show here that the breakpoints of the deletions are located on a highly homologous 28 kb low copy repeat (LCR) sequence present on each side of DPY19L2, indicating that the identified deletions were probably produced by nonallelic homologous recombination (NAHR) between these two regions. We demonstrate that patients with globozoospermia have a homozygous deletion of DPY19L2, thus indicating that DPY19L2 is necessary in men for sperm head elongation and acrosome formation. A molecular diagnosis can now be proposed to affected men; the presence of the deletion confirms the diagnosis of globozoospermia and assigns a poor prognosis for the success of in vitro fertilization.

Published
2011
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9. Refining the regulatory region upstream of SOX9 associated with 46,XX testicular disorders of Sex Development (DSD)

Author

Rakia Bhouri, Alain Kitzis, Anu Bashamboo, Ken McElreavey, Frédéric Bilan, Capucine Hyon, Matthieu Peycelon, Brigitte Gilbert-Dussardier, Mathilde Sibony, Radu Harbuz, Sandra Rojo, X. Piguel, Jean-Pierre Siffroi, Nicolas Perrot, Sandra Chantot-Bastaraud, Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Tenon [AP-HP], Institut Pasteur [Paris] (IP), Service Endocrinologie [CHU Poitiers], Génétique du Développement humain - Human developmental genetics, We thank Joelle Bignon-Topalovic for technical assistance, Support for this work was provided by the Agence Nationale de la Recherche-GIS Institut des Maladies Rares (K.M.), March of Dimes Foundation Research Grant 1-FY07-490 (to K.M.), EuroDSD in the European Community’sSeventh Framework Programme FP7/2007–2013 under Grant 201444 (to K.M. and A.B.), European Project: 201444,EC:FP7:HEALTH,FP7-HEALTH-2007-A,EURODSD(2008), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de génétique et embryologie médicales [CHU Trousseau], 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 Radiologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pathologie [CHU Tenon], Institut Pasteur [Paris], Génétique du développement humain, HAL-UPMC, Gestionnaire, Investigation of the molecular pathogenesis and pathophysiology of Disorders of Sex Development (DSD) - EURODSD - - EC:FP7:HEALTH2008-05-01 - 2011-10-31 - 201444 - VALID, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Male, Gonad, Testicular Disorder, CNV, Disorders of Sex Development, [SDV.GEN] Life Sciences [q-bio]/Genetics, SOX9, Regulatory Sequences, Nucleic Acid, Biology, Regulatory region, 03 medical and health sciences, MESH: SOX9 Transcription Factor, SOX9 gene, Gene duplication, Genetics, medicine, XX DSD, Humans, MESH: Chromosome Aberrations, MESH: Regulatory Sequences, Nucleic Acid, Disorders of sex development, Gene, Genetics (clinical), 030304 developmental biology, regulatory element, Chromosome Aberrations, Azoospermia, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, 030305 genetics & heredity, SOX9 Transcription Factor, medicine.disease, MESH: Male, medicine.anatomical_structure, duplication, MESH: Disorders of Sex Development
Abstract

International audience; Disorders of Sex Development (DSD) are a heterogeneous group of disorders affecting gonad and/or genito-urinary tract development and usually the endocrine-reproductive system. A genetic diagnosis is made in only around 20% of these cases. The genetic causes of 46,XX-SRY negative testicular DSD as well as ovotesticular DSD are poorly defined. Duplications involving a region located ∼600 kb upstream of SOX9, a key gene in testis development, were reported in several cases of 46,XX DSD. Recent studies have narrowed this region down to a 78 kb interval that is duplicated or deleted respectively in 46,XX or 46,XY DSD. We identified three phenotypically normal patients presenting with azoospermia and 46,XX testicular DSD. Two brothers carried a 83.8 kb duplication located ∼600 kb upstream of SOX9 that overlapped with the previously reported rearrangements. This duplication refines the minimal region associated with 46,XX-SRY negative DSD to a 40.7-41.9 kb element located ∼600 kb upstream of SOX9. Predicted enhancer elements and evolutionary-conserved binding sites for proteins known to be involved in testis determination are located within this region.

Published
2015
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10. Absent CNKSR2 causes seizures and intellectual, attention, and language deficits

Author

Andrea K, Vaags, Sarah, Bowdin, Mary-Lou, Smith, Brigitte, Gilbert-Dussardier, Katja S, Brocke-Holmefjord, Katia, Sinopoli, Cindy, Gilles, Tove B, Haaland, Catherine, Vincent-Delorme, Emmanuelle, Lagrue, Radu, Harbuz, Susan, Walker, Christian R, Marshall, Gunnar, Houge, Vera M, Kalscheuer, Stephen W, Scherer, and Berge A, Minassian

Subjects
Adult, Male, Heterozygote, Language Disorders, Adolescent, Electroencephalography, Middle Aged, Neuropsychological Tests, Pedigree, Attention Deficit Disorder with Hyperactivity, Seizures, Intellectual Disability, Humans, Female, Age of Onset, Child, Adaptor Proteins, Signal Transducing
Abstract

Synaptic function is central to brain function. Understanding the synapse is aided by studies of patients lacking individual synaptic proteins. Common neurological diseases are genetically complex. Their understanding is likewise simplified by studies of less common monogenic forms. We detail the disease caused by absence of the synaptic protein CNKSR2 in 8 patients ranging from 6 to 62 years old. The disease is characterized by intellectual disability, attention problems, and abrupt lifelong language loss following a brief early childhood epilepsy with continuous spike-waves in sleep. This study describes the phenotype of CNKSR2 deficiency and its involvement in systems underlying common neurological disorders.

Published
2014

11. Osteogenesis imperfecta, tricho-dento-osseous syndrome and intellectual disability: a familial case with 17q21.33-q22 (COL1A1 and DLX3) deletion and 7q32.3-q33 duplication resulting from a reciprocal interchromosomal insertion

Author

Alain Kitzis, Valérie Charraud, Brigitte Gilbert-Dussardier, Radu Harbuz, Frédéric Bilan, and Dominique Couet

Subjects
Male, Candidate gene, Biology, Collagen Type I, Tricho-Dento-Osseous Syndrome, Craniofacial Abnormalities, Young Adult, Intellectual Disability, Intellectual disability, Gene duplication, Chromosome Duplication, Genetics, medicine, Humans, Gene, Genetics (clinical), In Situ Hybridization, Fluorescence, Sequence Deletion, Homeodomain Proteins, Comparative Genomic Hybridization, DLX3, Syndrome, Middle Aged, Osteogenesis Imperfecta, medicine.disease, Pedigree, Chromosome 17 (human), Collagen Type I, alpha 1 Chain, Mutagenesis, Insertional, Phenotype, Osteogenesis imperfecta, Dental Enamel Hypoplasia, Female, Hair Diseases, Chromosomes, Human, Pair 7, Chromosomes, Human, Pair 17, Transcription Factors
Abstract

We report on a 22-year-old woman with features of osteogenesis imperfecta (OI), tricho-dento-osseous (TDO) syndrome and intellectual disability. Whole genome oligonucleotide microarray analysis revealed a copy number gain of 3 Mb in 7q32.3-q33 and a loss of 3.4 Mb in 17q21.33-q22. FISH analysis showed that the third copy of 7q32 was inserted into the long arm of one chromosome 17, exactly in the region 17q21.33-q22 that was deleted. The maternal uncle presented with clinical features similar to the proposita and had the same chromosomal anomalies. The mother of the proposita and two other family members were balanced carriers of this rearrangement, interpreted as an interchromosomal reciprocal insertion. Reciprocal insertion/four-break rearrangement is a very rare chromosomal event. The deleted region on chromosome 17 contains 39 genes, including COL1A1 and DLX3 involved in OI and TDO syndrome respectively. The CACNA1G gene on the deleted segment of chromosome 17 may be a good candidate gene to explain the intellectual impairment. © 2013 Wiley Periodicals, Inc.

Published
2012

12. A new AURKC mutation causing macrozoospermia: implications for human spermatogenesis and clinical diagnosis.: A NEW AURKC MUTATION CAUSING MACROZOOSPERMIA

Author

Mariem Ben Khelifa, Radu Harbuz, Raoudha Zouari, Lazhar Halouani, Pierre F. Ray, Christophe Arnoult, Joël Lunardi, AGeing and IMagery (AGIM), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), Clinique de la reproduction les Jasmins, INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire de biochimie et génétique moléculaire, CHU Grenoble-CHU Grenoble, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, and This work is part of the project 'Identification and Characterization of Genes Involved in Infertility (ICG2I)' funded by the program GENOPAT 2009 from the French Research Agency (ANR). This work was also funded in part by program CIBLE 2009 from the Rhône- Alpes Région.

Subjects
Male, Embryology, DNA Mutational Analysis, MESH: Base Sequence, medicine.disease_cause, Polymerase Chain Reaction, Male infertility, Exon, 0302 clinical medicine, Aurora Kinases, Aurora Kinase C, MESH: DNA Mutational Analysis, MESH: Heterozygote, Genetics, 0303 health sciences, Mutation, 030219 obstetrics & reproductive medicine, MESH: Spermatozoa, Obstetrics and Gynecology, Exons, Spermatozoa, 3. Good health, Pedigree, Meiosis, MESH: Tunisia, MESH: Spermatogenesis, Heterozygote, MESH: Mutation, Tunisia, Sequence analysis, MESH: Pedigree, Molecular Sequence Data, Biology, MESH: Infertility, Male, Protein Serine-Threonine Kinases, MESH: Protein-Serine-Threonine Kinases, Article, 03 medical and health sciences, medicine, Humans, Spermatogenesis, Molecular Biology, Gene, Infertility, Male, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Siblings, Heterozygote advantage, MESH: Polymerase Chain Reaction, Cell Biology, medicine.disease, Molecular biology, MESH: Male, MESH: Siblings, MESH: Meiosis, Reproductive Medicine, MESH: Exons, Developmental Biology
Abstract

International audience; The presence of close to 100% large-headed multi-tailed spermatozoa in the ejaculate has been described as a rare phenotype of male infertility with a very poor prognosis. We demonstrated previously that most cases were caused by a homozygous mutation (c.144delC) in the Aurora Kinase C gene (AURKC) leading to the absence or the production of a non-functional protein. AURKC deficiency in these patients blocked meiosis and resulted in the production of tetraploid spermatozoa unsuitable for fertilization. We describe here the study of two brothers presenting with large-headed spermatozoa. Molecular analysis of the AURKC gene was carried out in two brothers presenting with a typical large-headed spermatozoa phenotype. Both affected brothers were heterozygous for the c.144delC mutation. After complete sequencing of the gene a new heterozygous variant, c.436-2A>G, was identified in both patients. This mutation is located in the acceptor consensus splice site of exon 5. AURKC transcripts were extracted from one of the patient's leukocytes and reverse transcription polymerase chain reaction could be realized showing the presence of a truncated transcript indicating that c.436-2A>G leads to the skipping of exon 5. These results indicate that AURKC molecular analysis of patients with large-headed spermatozoa should not be stopped in the absence of a homozygous recurrent mutation on exon 3 but complete sequence analysis should be performed. This diagnosis is important as the identification of AURKC mutations in patients indicates that all spermatozoa will be chromosomally abnormal and that ICSI should not be attempted.

Published
2011
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13. Identification of new FOXP3 mutations and prenatal diagnosis of IPEX syndrome

Author

Christine Francannet, Mariem Benkhelifa, Stéphanie Boulet, Pierre-Simon Jouk, Pierre F. Ray, Isabelle Creveaux, Joël Lunardi, Radu Harbuz, James Lespinasse, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, Département de Gynécologie Obstétrique, CH Chambéry, Unité de Génétique Médicale, Hôtel-Dieu-CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I (UdA), Laboratoire de Biochimie, Université d'Auvergne - Clermont-Ferrand I (UdA), RFMQ, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie-CHU Grenoble-faculté de médecine-pharmacie, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), ARCHAMPS, VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Département de génétique et procréation

Subjects
Male, Pediatrics, MESH: Sequence Analysis, DNA, Disease, MESH: Intestinal Diseases, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, MESH: Reverse Transcriptase Polymerase Chain Reaction, IPEX, Enteropathy, MESH: Syndrome, MESH: Genetic Variation, Polyendocrinopathies, Autoimmune, Genetics (clinical), 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, MESH: Infant, Newborn, immunological disorder, Obstetrics and Gynecology, Forkhead Transcription Factors, Genetic Diseases, X-Linked, Syndrome, 3. Good health, 030220 oncology & carcinogenesis, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.medical_specialty, FOXP3, Prenatal diagnosis, Prenatal care, 03 medical and health sciences, Male pregnancy, MESH: Polyendocrinopathies, Autoimmune, MESH: Forkhead Transcription Factors, MESH: RNA, medicine, MESH: Genetic Diseases, X-Linked, Humans, Point Mutation, Neonatology, MESH: Prenatal Diagnosis, 030304 developmental biology, MESH: Point Mutation, prenatal diagnosis, MESH: Humans, business.industry, Infant, Newborn, Genetic Variation, Sequence Analysis, DNA, IPEX syndrome, medicine.disease, mutations, MESH: Male, Intestinal Diseases, Immunology, RNA, business, MESH: Female
Abstract

Objective Molecular diagnosis and prenatal care of two pregnant women at risk of transmitting immunodysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome. Methods FOXP3 coding sequence and exon boundaries were analyzed in the two consultants and family members. Non-invasive sex determination and specific prenatal diagnosis was realized. Results Following sequence analysis a new FOXP3 mutation was identified in each consultant. Sex diagnosis realized by amplification of Y sequences from the plasma of the two mothers revealed a male and a female fetus, respectively. Prenatal diagnosis showed that the male fetus was unaffected. The baby is now born and healthy. Subsequent ultrasound examinations confirmed the sex in the second pregnancy but unfortunately led to the diagnosis of a 69,XXX triploidy. The pregnancy was thus interrupted. Conclusion Two new FOXP3 mutations were identified and prenatal diagnosis could be proposed. Due to the rarity of the disease, clinical diagnosis is often considered with delay. Both patients reported here were already pregnant at the beginning of the genetic investigation and one had previously interrupted a male pregnancy for lack of diagnosis. When faced with children with severe refractory diarrhea, clinicians should entertain the possibility of IPEX. Copyright © 2010 John Wiley & Sons, Ltd.

Published
2010
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14. The Aurora Kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population

Author

Mohamed Zahi, Marie-Christine Jacob, Sellama Nadifi, François Vialard, Yorgos Nikas, Raoudha Zouari, Abdelaziz Sefiani, Pierre-Simon Jouk, Hanane Bellayou, Nadia Prisant, Abdelali Zoghmar, Marie Roberte Guichaoua, Delphine Martinez, Klaus Dieterich, Joël Lunardi, Mehrdad Noruzinia, Mahmoud Kharouf, Sylviane Hennebicq, Stéphane Viville, Denise Escalier, Radu Harbuz, Isabelle Koscinski, Jacqueline Lornage, Pierre F. Ray, B. Sèle, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Clinique de Promotion des Sciences de la Reproduction [Tunis] (CPSR), Polyclinique les Jasmins [Tunis], Laboratoire de Cytogénétique, CHI Poissy-Saint-Germain, Laboratoire de Génétique et Pathologie Moléculaire, Faculté de Médecine et Pharmacie Casablanca, Assistance médicale à la procréation, Biologie de reproduction - Stérilité [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Médecine de la Reproduction, Laboratoire de biologie de la reproduction, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service de Biologie de la Reproduction, CHU Strasbourg, Department of Hematology, Tarbiat Modares University [Tehran], Département de génétique médicale, Institut National d'Hygiène, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre privé de Fécondation in vitro, RFMQ, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant-Hôpital Couple-Enfant, Laboratoire d'Immunocytologie, EFS, Bases moléculaires et cellulaires des maladies génétiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Athens Innovative Microscopy, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), ARCHAMPS, Clinique de la reproduction les Jasmins, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Département de génétique et procréation, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Roux-Buisson, Nathalie

Subjects
Male, MESH: Tissue Donors, DNA Mutational Analysis, MESH: Africa, Northern, MESH: Flow Cytometry, Nucleic Acid Denaturation, medicine.disease_cause, Oogenesis, 0302 clinical medicine, Africa, Northern, Aurora Kinases, Aurora Kinase C, MESH: DNA Mutational Analysis, Chromatography, High Pressure Liquid, Genetics (clinical), Genetics, 0303 health sciences, education.field_of_study, Mutation, 030219 obstetrics & reproductive medicine, MESH: Spermatozoa, Exons, General Medicine, Flow Cytometry, Spermatozoa, Tissue Donors, Meiosis, Meiotic cytokinesis, Female, MESH: Spermatogenesis, Infertility, MESH: Mutation, Population, Black People, MESH: Nucleic Acid Denaturation, Protein Serine-Threonine Kinases, Biology, Models, Biological, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Spermatogenesis, education, MESH: Chromatography, High Pressure Liquid, Molecular Biology, 030304 developmental biology, MESH: Humans, MESH: Models, Biological, MESH: Fertility, medicine.disease, MESH: Male, MESH: Meiosis, Fertility, MESH: African Continental Ancestry Group, MESH: Exons, MESH: Female
Abstract

International audience; Infertility concerns a minimum of 70 million couples worldwide. An important proportion of cases is believed to have a genetic component, yet few causal genes have been identified so far. In a previous study, we demonstrated that a homozygous mutation (c.144delC) in the Aurora Kinase C (AURKC) gene led to the production of large-headed polyploid multi-flagellar spermatozoa, a primary infertility phenotype mainly observed in North Africans. We now want to estimate the prevalence of the defect, to improve our understanding of AURKC physiopathology in spermatogenesis and assess its implication in oogenesis. A carrier frequency of 1/50 was established from individuals from the Maghrebian general population, comparable to that of Y-microdeletions, thus far the only known recurrent genetic event altering spermatogenesis. A total of 62 patients were genotyped, all who had a typical phenotype with close to 100% large-headed spermatozoa were homozygously mutated (n = 32), whereas no AURKC mutations were detected in the others. Two homozygous females were identified; both were fertile indicating that AURKC is not indispensible in oogenesis. Previous FISH results had showed a great chromosomal heterogeneity in these patient's spermatozoa. We demonstrate here by flow cytometry that all spermatozoa have in fact a homogeneous 4C DNA content and are thus all blocked before the first meiotic division. Our data thus indicate that a functional AURKC protein is necessary for male meiotic cytokinesis while its absence does not impair oogenesis.

Published
2009
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