Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction.

I Parenti, C Gervasini, J Pozojevic, K S Wendt, E Watrin, J Azzollini, D Braunholz, K Buiting, A Cereda, H Engels, L Garavelli, R Glazar, B Graffmann, L Larizza, H J Lüdecke, M Mariani, M Masciadri, J Pié, F J Ramos, S Russo, A Selicorni, M Stefanova, T M Strom, R Werner, J Wierzba, G Zampino, G Gillessen-Kaesbach, D Wieczorek, F J Kaiser

Journal: Clinical genetics 2017;89(5):564-73

PMID: 26671848

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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.

Address: 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.; Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.; Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.; Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.; Faculté de Médecine, Institut de Génétique et Développement de Rennes, UMR6290-CNRS, Rennes, France.; Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.; U.O.S. Genetica Clinica Pediatrica, Clinica Pediatrica Fondazione MBBM, A.O. S.Gerardo, Monza, Italy.; Institute of Human Genetics, University of Bonn, Bonn, Germany.; Clinical Genetics Unit, Department of Obstetrics and Pediatrics, IRCCS S. Maria Nuova Hospital, Reggio Emilia, Italy.; The Center for Medical Genetics GENESIS Poznan, Poland.; Department of Pediatrics, University Hospital Linköping, Linköping, Sweden.; Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.; 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.; 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.; Department of Clinical Genetics, University Hospital Linköping, Linköping, Sweden.; Institute of Human Genetics, Technische Universität München, Munich, Germany.; Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.; Division of Experimental Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine, University of Lübeck, Lübeck, Germany.; 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.; Birth Defects Unit, Department of Pediatrics, Università Cattolica del Sacro Cuore, Rome, Italy.; Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.

DOI: 10.1111/cge.12717

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MeSH Terms: Amino Acid Sequence, Base Sequence, Child, De Lange Syndrome, Face, Facial Asymmetry, Facies, Female, Genetic Counseling, Genotype, Histone Deacetylases, Humans, Male, Mutation, Phenotype, Repressor Proteins, Risk Factors, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Severity of Illness Index, X Chromosome Inactivation