High Incidence of Copy Number Variants in Adults with Intellectual Disability and Co-morbid Psychiatric Disorders

Behavior Genetics https://doi.org/10.1007/s10519-018-9902-6 ORIGINAL RESEARCH High Incidence of Copy Number Variants in Adults with Intellectual Disability and Co-morbid Psychiatric Disorders Marina Viñas‑Jornet1,2 · Susanna Esteba‑Castillo3 · Neus Baena1 · Núria Ribas‑Vidal3 · Anna Ruiz1 · David Torrents‑Rodas3 · Elisabeth Gabau4 · Elisabet Vilella5 · Lourdes Martorell5 · Lluís Armengol6 · Ramon Novell3 · Míriam Guitart1 Received: 9 May 2017 / Accepted: 10 May 2018 © The Author(s) 2018 Abstract A genetic analysis of unexplained mild-moderate intellectual disability and co-morbid psychiatric or behavioural disorders is not systematically conducted in adults. A cohort of 100 adult patients affected by both phenotypes were analysed in order to identify the presence of copy number variants (CNVs) responsible for their condition identifying a yield of 12.8% of pathogenic CNVs (19% when including clinically recognizable microdeletion syndromes). Moreover, there is a detailed clinical description of an additional 11% of the patients harbouring possible pathogenic CNVs—including a 7q31 deletion (IMMP2L) in two unrelated patients and duplications in 3q29, 9p24.2p24.1 and 15q14q15.1—providing new evidence of its contribution to the phenotype. This study adds further proof of including chromosomal microarray analysis (CMA) as a mandatory test to improve the diagnosis in the adult patients in psychiatric services. Keywords Adult patients · Behavioural disorders · Copy number variants · Intellectual disability · Psychiatric disorders Introduction Edited by Michael Lyons. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10519-018-9902-6) contains supplementary material, which is available to authorized users. * Míriam Guitart 1 Genetics lab, UDIAT-centre diagnostic. Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí I3PT. Universitat Autònoma de Barcelona, C/Parc Tauli,1, 08208 Sabadell, Barcelona, Spain 2 Cellular Biology, Physiology and Immunology Department, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain 3 Mental Health and Intellectual Disability Specialized Service, Institut Assistència Sanitària (IAS), Parc Hospitalari Martí i Julià, Girona, Spain 4 Pediatry‑Clinical Genetics Service, Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí I3PT. Universitat Autònoma de Barcelona, Sabadell, Spain 5 Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, CIBERSAM, Reus, Spain 6 Research and Development Department, qGenomics Laboratory, Barcelona, Spain Intellectual disability (ID) is a complex and multifactorial disorder that includes both intellectual and adaptive functioning deficits in the conceptual, social and practical domains with onset during the developmental period. This disorder affects approximately 1–3% of the general population, and between 10 and 40% of people with ID also present with mental illness or behavioural disorders (Cooper et al. 2007; Lowe et al. 2007; Morgan et al. 2008). The diagnostic categories of these mental disorders are based on the symptoms (Stein et al. 2013), but there is considerable clinical heterogeneity and overlap with different psychiatric categories (Burmeister et al. 2008). Indeed, the boundaries of the diagnostic categories can be blurred when the patients’ symptoms are not clearly expressed. The diagnosis of a psychiatric disorder in subjects with ID can be difficult, and most symptoms tend to be attributed to the ID. For this reason, the co-occurrence of both entities is usually overlooked (Costello and Bouras 2006). Copy number variants (CNVs) are a source of human genetic variation and have been described as an important genomic cause of human disease (Iafrate et al. 2004; Sebat et al. 2004). Screening of ID patient cohorts via 13 Vol.:(0123456789) Behavior Genetics chromosomal microarray analysis (CMA) has led to the characterization of new syndromes, such as 8q21.11 deletion syndrome (OMIM: 614230) and 19p13.3 microdeletion/microduplication syndrome (Dolan et al. 2010; Orellana et al. 2015). Additionally, there is evidence that CNVs can predispose individuals to the development of psychiatric disorders, such as the autism spectrum disorders (ASDs) (Marshall et al. 2008; Hedges et al. 2012), schizophrenia (SQZ) (Kirov et al. 2012; Xu et al. 2008), bipolar disorder (Green et al. 2015) and attention-deficit/hyperactive disorder (ADHD) (Jarick et al. 2014; Ramos-Quiroga et al. 2014). Numerous CNV loci have been recurrently observed across ID and various neuropsychiatric phenotypes, such as the16p11.2 and NRXN1 deletions, both of which are associated with ID, SQZ and ASD. These findings suggest that ID and psychiatric disorders may share genetic susceptibility factors (Guilmatre et al. 2009). A large proportion of the adult population affected by ID lacks a genetic diagnosis. Some of these adult patients have never received a diagnostic assessment; alternatively, in some cases the assessment is completed without finding an explanation for the ID possibly due to the use of less advanced technologies than are currently available. At present, there is little knowledge of the genetics of ID and comorbid psychiatric disorder in adults. Nevertheless, CMA and whole exome sequencing could shed light on the genetic diagnoses in adults with idiopathic ID (Baker et al. 2012; Posey et al. 2016; Taylor et al. 2010; Wolfe et al. 2016). Here, we report the genetic analysis of 100 adult patients affected by ID and psychiatric and/or behavioural disorders. The main purpose of this study is to investigate the contribution of putative pathogenic CNVs among patients with ID and comorbid psychiatric/behavioural disorders. Materials and methods Participants This study was designed prospectively. Cognitive, psychiatric and behavioural evaluation was performed by psychiatric Table 1  Cognitive, psychiatric and behavioural measures tests Clinical evaluation: cognitive, behavioural, psychiatric and dysmorphic measures Different tests were administered to all participants to identify the presence of ID and establish its severity level, as well as to identify the presence of a psychiatric and/or behavioural disorder (Table 1). The presence of a behavioural disorder not necessarily related to a mental disorder was defined according to (Emerson 1995) as “culturally abnormal behaviour of such intensity, frequency or duration that the physical safety of the person or others is placed in serious jeopardy, or behaviour which is likely to seriously limit or deny them access to ordinary community facilities”. A family history of ID, psychiatric or behavioural disorders was also recorded. Dysmorphic features were classified into five categories as follows: craniofacial, limbs, cutaneous, genital and body Measures Tests Cognitive – K-BIT-II (Kauffman Brief Intelligence Test-II) – ABS-RC2 first part (Ad (...truncated)