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

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.

Introduction

Catatonia is a motor dysregulation syndrome characterized by alternation of excessive and reduced mobility, often in association with speech abnormalities. It should be considered in any patient with marked deterioration in psychomotor function and overall responsiveness (movement, speech, self-care, skills). Prevalence estimates of catatonia among psychiatric patients range from 7.6 to 38% (Fink, 2009, Taylor and Fink, 2003). Although common and severe, catatonia remains poorly recognized. There have been efforts to enhance early diagnosis, as reflected by changes in catatonia classification in DSM-5, where it appears as a distinct clinical-diagnostic entity (Tandon et al., 2013). A clinical diagnosis of catatonia is based on the presence of at least 3 of the following DSM-5 criteria: catalepsy, waxy flexibility, stupor, agitation, mutism, negativism, posturing, mannerisms, stereotypy, grimacing, echolalia or echopraxia. Symptoms may present in different combinations and co-occur with a variety of other psychiatric or medical conditions (Daniels, 2009). This clinical heterogeneity hampers early recognition and treatment, which are important as catatonia is sometimes associated with autonomic symptoms, that can be life threatening.

Regardless of the comorbid pathology, there is a unique response to treatment with benzodiazepines, zolpidem and electroconvulsive therapy (ECT), suggesting a biological etiology separate from other psychiatric disorders (Dhossche et al., 2010, Javelot et al., 2015). Benzodiazepines and ECT are agonists of the inhibitory function of the GABA-A receptor complex. Their therapeutic effect on catatonia suggests a dysfunctional neurotransmission as the underlying neurobiological mechanism. A possible genetic etiology underlying disrupted synaptic transmission in the development of catatonia, is supported by the occurrence of catatonic symptoms in patients with Prader-Willi Syndrome (PWS) (Dhossche and Bouman, 1997, Poser and Trutia, 2015). PWS is caused by the lack of expression of genes on the paternally derived 15q11q13 chromosomal segment, including a set of genes coding for particular subunits of the GABA_A receptor, namely GABRB3, GABRA5 and GABRG3, which encode the β3, α5, and γ3 subunits, respectively (Coghlan et al., 2012). This has led to the assumption that altered inhibitory GABAergic neurotransmission may underlay catatonia in PWS (Dhossche et al., 2005). In addition to this GABAergic hypothesis, excess glutamate or hyperactivity of glutamate receptors such as the N-Methyl-D-Aspartate receptor (NMDAR), seem to be involved as well, as catatonic symptoms in selected cases resolve by treatment with the NMDA antagonist Amantadine (Northoff et al., 1999). The beneficial effects of NMDA antagonists on catatonia are ascribed to recovery of GABA-A function in brain regions that were previously GABA-A deficient due to NMDA hyperactivity (Carroll et al., 2007).

Despite the evidence of a role of disturbed neurotransmission involving different synaptic receptors, studies on the genetic etiology of catatonia are scarce. Three studies reported familial transmission with anticipation and parent-of-origin effect in periodic catatonia (Beckmann et al., 1996, Stober et al., 1995, Stober et al., 1998). The same research group reported linkage of periodic catatonia to 15q15 and 22q13 (Stober et al., 2000). Whereas the causative gene for catatonia on 15q15 remains obscure, catatonia related to 22q13 has been attributed to loss of one functional copy of the SHANK3 gene, as loss-of-function mutations and deletions affecting this gene were found in catatonic patients with intellectual disability and comorbid psychiatric disease (Serret et al., 2015). In addition, catatonia has been recurrently found in association with Down syndrome (Ghaziuddin et al., 2015) and the 22q11 deletion syndrome (Faedda et al., 2015).

More recent genomic technologies such as chromosomal microarray and massive parallel sequencing may help to identify other chromosomal regions and genes playing a role in the etiology of this motor dysregulation disorder. In this study, we performed copy number analysis in 15 adults with intellectual disability and catatonia to identify chromosomal deletions and duplications predisposing to this psychiatric disorder.