Copy number variation analysis in adults with catatonia confirms haploinsufficiency of SHANK3 as a predisposing factor

• Published in: European journal of medical genetics 2016-09, Vol.59 (9), p.436-443
• Main Authors: Breckpot, Jeroen, Vercruyssen, Marieke, Weyts, Eddy, Vandevoort, Sean, D'Haenens, Greet, Van Buggenhout, Griet, Leempoels, Lore, Brischoux-Boucher, Elise, Van Maldergem, Lionel, Renieri, Alessandra, Mencarelli, Maria Antonietta, D'Angelo, Carla, Mericq, Veronica, Hoffer, Mariette J, Tauber, Maithé, Molinas, Catherine, Castiglioni, Claudia, Brison, Nathalie, Vermeesch, Joris R, Danckaerts, Marina, Sienaert, Pascal, Devriendt, Koenraad, Vogels, Annick
• Format: Article
• Language: English
• Subjects: 14q11.2 duplication; Adolescent; Catatonia; Catatonia - genetics; Child; Child, Preschool; Chromosome Aberrations; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 22; DNA Copy Number Variations; Female; Genetic Predisposition to Disease; Haploinsufficiency - genetics; Humans; Intellectual Disability - genetics; Male; Medical Education; Middle Aged; Nerve Tissue Proteins - genetics; Psychiatric disorder; SHANK3; SUPT16H; Young Adult
• ISSN: 1769-7212; 1878-0849
• DOI: 10.1016/j.ejmg.2016.08.003

Abstract Background Catatonia is a motor dysregulation syndrome co-occurring with a variety of psychiatric and medical disorders. Response to treatment with benzodiazepines and electroconvulsive therapy suggests a neurobiological background. The genetic etiology however remains largely unexplored. Copy Number Variants (CNV), known to predispose to neurodevelopmental disorders, may play a role in the etiology of catatonia. Methods This study is exploring the genetic field of catatonia through CNV analysis in a cohort of psychiatric patients featuring intellectual disability and catatonia. Fifteen adults admitted to a psychiatric inpatient unit and diagnosed with catatonia were selected for array Comparative Genomic Hybridization analysis at 200 kb resolution. We introduced a CNV interpretation algorithm to define detected CNVs as benign, unclassified, likely pathogenic or causal with regard to catatonia. Results Co-morbid psychiatric diagnoses in these patients were autism, psychotic or mood disorders. Eight patients were found to carry rare CNVs, which could not be classified as benign, comprising 6 duplications and 2 deletions. Microdeletions on 22q13.3, considered causal for catatonia, were detected in 2 patients. Duplications on 16p11.2 and 22q11.2 were previously implicated in psychiatric disorders, but not in catatonia, and were therefore considered likely pathogenic. Driven by the identification of a rare 14q11.2 duplication in one catatonic patient, additional patients with overlapping duplications were gathered to delineate a novel susceptibility locus for intellectual disability and psychiatric disorders on 14q11.2, harboring the gene SUPT16H . Three remaining variants respectively on 2q36.1, 16p13.13 and 17p13.3 were considered variants of unknown significance. Conclusion The identification of catatonia-related copy number changes in this study, underscores the importance of genetic research in patients with catatonia. We confirmed that 22q13.3 deletions, affecting the gene SHANK3 , predispose to catatonia, and we uncover 14q11.2 duplications as a novel susceptibility factor for intellectual and psychiatric disorders.