title: Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction.
abstract: Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin-related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS-overlapping features. The phenotype of our patients is very broad, whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counseling and risk prediction.
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.|Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Parenti
authors.affiliation: Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Gervasini
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Pozojevic
authors.affiliation: Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: K S
authors.initials: KS
authors.lastname: Wendt
authors.affiliation: Faculté de Médecine, Institut de Génétique et Développement de Rennes, UMR6290-CNRS, Rennes, France.
authors.forename: E
authors.initials: E
authors.lastname: Watrin
authors.affiliation: Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Azzollini
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Braunholz
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Buiting
authors.affiliation: U.O.S. Genetica Clinica Pediatrica, Clinica Pediatrica Fondazione MBBM, A.O. S.Gerardo, Monza, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cereda
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Engels
authors.affiliation: Clinical Genetics Unit, Department of Obstetrics and Pediatrics, IRCCS S. Maria Nuova Hospital, Reggio Emilia, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Garavelli
authors.affiliation: The Center for Medical Genetics GENESIS Poznan, Poland.
authors.forename: R
authors.initials: R
authors.lastname: Glazar
authors.affiliation: Department of Pediatrics, University Hospital Linköping, Linköping, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Graffmann
authors.affiliation: Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Larizza
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: H J
authors.initials: HJ
authors.lastname: Lüdecke
authors.affiliation: U.O.S. Genetica Clinica Pediatrica, Clinica Pediatrica Fondazione MBBM, A.O. S.Gerardo, Monza, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mariani
authors.affiliation: Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Masciadri
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, Medical School, University of Zaragoza, CIBERER-GCV and ISS-Aragon, Zaragoza, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Pié
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, Medical School, University of Zaragoza, CIBERER-GCV and ISS-Aragon, Zaragoza, Spain.|Unidad de Genetica Clınica, Servicio de Pediatrıa, Hospital Clınico Universitario "Lozano Blesa", CIBERER-GCV and ISS-Aragon, Zaragoza, Spain.
authors.forename: F J
authors.initials: FJ
authors.lastname: Ramos
authors.affiliation: Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Russo
authors.affiliation: U.O.S. Genetica Clinica Pediatrica, Clinica Pediatrica Fondazione MBBM, A.O. S.Gerardo, Monza, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Selicorni
authors.affiliation: Department of Clinical Genetics, University Hospital Linköping, Linköping, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Stefanova
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: T M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Division of Experimental Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine, University of Lübeck, Lübeck, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Werner
authors.affiliation: Department and Clinic of Pediatrics, Hematooncology, Oncology and Endocrinology, Medical University of Gdańsk, Gdańsk, Poland.|Department of General Nursing, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Wierzba
authors.affiliation: Birth Defects Unit, Department of Pediatrics, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Zampino
authors.affiliation: Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
authors.forename: F J
authors.initials: FJ
authors.lastname: Kaiser
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D003635:De Lange Syndrome / Q000235:genetics* / Q000473:pathology; D005145:Face / Q000002:abnormalities*; D005146:Facial Asymmetry / Q000235:genetics* / Q000473:pathology; D019066:Facies; D005260:Female; D005817:Genetic Counseling; D005838:Genotype; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA / Q000379:methods; D017386:Sequence Homology, Amino Acid; D012720:Severity of Illness Index; D049951:X Chromosome Inactivation
chemical_list: D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases
keywords: Cornelia de Lange syndrome; HDAC8; X-inactivation; cohesin; mosaicism