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1. Deep intronic variation in splicing regulatory element of the ERCC8 gene associated with severe but long-term survival Cockayne syndrome

Author

Cathy Obringer, Audrey Schalk, Nadège Calmels, Jamel Chelly, Géraldine Greff, Hélène Dollfus, Nathalie Drouot, and Vincent Laugel

Subjects
Male, 0301 basic medicine, Microcephaly, Biology, medicine.disease_cause, Article, Cockayne syndrome, 03 medical and health sciences, Exon, Genetics, medicine, Humans, Child, Cockayne Syndrome, Cells, Cultured, Genetics (clinical), Mutation, Infant, Splicing regulatory element, medicine.disease, Introns, DNA Repair Enzymes, 030104 developmental biology, ERCC8, RNA Splice Sites, ERCC6, Transcription Factors, Minigene
Abstract

Cockayne syndrome is an autosomal recessive multisystem disorder characterized by intellectual disability, microcephaly, severe growth failure, sensory impairment, peripheral neuropathy, and cutaneous sensitivity. This rare disease is linked to disease-causing variations in the ERCC6 (CSB) and ERCC8 (CSA) genes. Various degrees of severity have been described according to age at onset and survival, without any clear genotype-phenotype correlation. All types of nucleotide changes have been observed in CS genes, including splice variations mainly affecting the splice site consensus sequences. We report here the case of two brothers from a consanguineous family presenting a severe but long-term survival phenotype of Cockayne syndrome. We identified in the patients a homozygous deep intronic nucleotide variation causing the insertion of a cryptic exon in the ERCC8 (CSA) transcript, by modifying intronic regulatory elements important for exon definition. The pathogenesis of the nucleotide variant NG_009289.1(NM_000082.3):c.173+1119G>C was validated in vitro with a reporter minigene system. To our knowledge, these are the first Cockayne patients described with this kind of disease-causing variation, though molecular mechanism underlying early onset symptoms and unexpected slow raise of progression of the disease remain to be elucidated.

Published
2018

2. Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing

Author

Massimiliano Rossi, Boris Keren, François Feillet, Julien Tarabeux, Isabel Llano-Rivas, Florence Renaldo-Robin, Vincent Laugel, Patricia Bretones, Bérénice Doray, Marguerite Miguet, Géraldine Greff, Caroline Michot, Béatrice Digeon, Nadine Kempf, Nadège Calmels, Anne Cavau, Martine Doco-Fenzy, Claire Gasnier, Cathy Obringer, Jean-Louis Mandel, Pascal Sabouraud, Jesus Gardeazabal, Didier Bessis, Christel Depienne, Blanca Gener, Artur Mazur, Jean Muller, Sophie Julia, Geneviève Baujat, Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'endocrinologie pédiatrique, Hôpital mère enfant, Bron, CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Universitaire de Reims (CHU Reims), Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), BioCruces Research Institute, University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU)-Hospital Universitario Cruces = Cruces University Hospital, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Rzeszow University, Unité de Neurologie, Hôpital Robert Debré, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (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 Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique Humaine, Collège de France (CdF (institution)), CHU Strasbourg, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Saint-Eloi, University of the Basque Country [Bizkaia] (UPV/EHU)-Hospital Universitario Cruces = Cruces University Hospital, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Chaire Génétique Humaine, CHU Strasbourg - Hopital Civil, Laboratoire de Génétique Médicale, Université de Strasbourg - Institut National de la Santé et de la Recherche Médicale (INSERM) - Faculté de Médecine, Centre de référence maladies osseuses constitutionnelles CHU Necker, Hôpital Necker - Enfants malades, Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5), CHU Reims, CHU Félix Guyon, Université de Lorraine (UL) - Institut National de la Santé et de la Recherche Médicale (INSERM), University of the Basque Country [Bizkaia] (UPV/EHU) - Cruces University Hospital, Hôpital Purpan, Hospices Civils de Lyon / Centre hospitalier Lyon Sud (HCL), Hospices Civils de Lyon, Centre de recherche en neurosciences de Lyon, Centre National de la Recherche Scientifique (CNRS) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Claude Bernard Lyon 1 (UCBL) - Université Jean Monnet - Saint-Etienne - PRES Université de Lyon, Université Pierre et Marie Curie - Paris 6 (UPMC) - Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Pitié-Salpêtrière [APHP], Institut du Cerveau et de la Moëlle Epinière (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC) - Institut National de la Santé et de la Recherche Médicale (INSERM) - CHU Pitié-Salpêtrière [APHP] - Centre National de la Recherche Scientifique (CNRS), Service de génétique, cytogénétique, embryologie [CHU 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), and HAL UPMC, Gestionnaire

Subjects
0301 basic medicine, ERCC6, ERCC8, DNA Repair, DNA-Directed DNA Polymerase, Cockayne syndrome, Genetics(clinical), Pharmacology (medical), Poly-ADP-Ribose Binding Proteins, Genetics (clinical), Medicine(all), Genetics, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, High-Throughput Nucleotide Sequencing, Nuclear Proteins, General Medicine, 3. Good health, DNA-Binding Proteins, Phenotype, POLH, NGS, Xeroderma pigmentosum, Population, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, medicine, Humans, education, Xeroderma Pigmentosum Group D Protein, Research, DNA Helicases, xeroderma pigmentosum, medicine.disease, Endonucleases, 030104 developmental biology, DNA Repair Enzymes, Mutation, NER, ERCC2, ERCC3, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Nucleotide excision repair, Transcription Factors, ERCC5
Abstract

Background Deficient nucleotide excision repair (NER) activity causes a variety of autosomal recessive diseases including xeroderma pigmentosum (XP) a disorder which pre-disposes to skin cancer, and the severe multisystem condition known as Cockayne syndrome (CS). In view of the clinical overlap between NER-related disorders, as well as the existence of multiple phenotypes and the numerous genes involved, we developed a new diagnostic approach based on the enrichment of 16 NER-related genes by multiplex amplification coupled with next-generation sequencing (NGS). Methods Our test cohort consisted of 11 DNA samples, all with known mutations and/or non pathogenic SNPs in two of the tested genes. We then used the same technique to analyse samples from a prospective cohort of 40 patients. Multiplex amplification and sequencing were performed using AmpliSeq protocol on the Ion Torrent PGM (Life Technologies). Results We identified causative mutations in 17 out of the 40 patients (43 %). Four patients showed biallelic mutations in the ERCC6(CSB) gene, five in the ERCC8(CSA) gene: most of them had classical CS features but some had very mild and incomplete phenotypes. A small cohort of 4 unrelated classic XP patients from the Basque country (Northern Spain) revealed a common splicing mutation in POLH (XP-variant), demonstrating a new founder effect in this population. Interestingly, our results also found ERCC2(XPD), ERCC3(XPB) or ERCC5(XPG) mutations in two cases of UV-sensitive syndrome and in two cases with mixed XP/CS phenotypes. Conclusions Our study confirms that NGS is an efficient technique for the analysis of NER-related disorders on a molecular level. It is particularly useful for phenotypes with combined features or unusually mild symptoms. Targeted NGS used in conjunction with DNA repair functional tests and precise clinical evaluation permits rapid and cost-effective diagnosis in patients with NER-defects. Electronic supplementary material The online version of this article (doi:10.1186/s13023-016-0408-0) contains supplementary material, which is available to authorized users.

Published
2016

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