Delineating the psychiatric and behavioral phenotype of recurrent 2q13 deletions and duplications

Abstract

Recurrent deletions and duplications at the 2q13 locus have been associated with developmental delay (DD) and dysmorphisms. We aimed to undertake detailed clinical characterization of individuals with 2q13 copy number variations (CNVs), with a focus on behavioral and psychiatric phenotypes. Participants were recruited via the Unique chromosomal disorder support group, U.K. National Health Service Regional Genetics Centres, and the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database. A review of published 2q13 patient case reports was undertaken to enable combined phenotypic analysis. We present a new case series of 2q13 CNV carriers (21 deletion, 4 duplication) and the largest ever combined analysis with data from published studies, making a total of 54 deletion and 23 duplication carriers. DD/intellectual disabilities was identified in the majority of carriers (79% deletion, 70% duplication), although in the new cases 52% had an IQ in the borderline or normal range. Despite the median age of the new cases being only 9 years, 64% had a clinical psychiatric diagnosis. Combined analysis found attention deficit hyperactivity disorder (ADHD) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self‐injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence, and a high rate of childhood psychiatric diagnoses—particularly ADHD. We have further characterized the clinical phenotype related to imbalances of the 2q13 region and identified it as a region of interest for the neurobiological investigation of ADHD.

2q13 microdeletion syndrome: report on a newborn with additional features expanding the phenotype

“…The cytogenetic band 2q13 is enriched in clusters of highly homologous sequences, which facilitate the occurrence of deletions and/or duplications, quite recurrent in size and breakpoints (Hladilkowa, 2015). Among these rearrangements, a recurrent 1.71 Mb deletion is associated with a congenital syndrome (around 50 patients reported to date) manifesting with variable phenotype, which includes psychomotor development disabilities, mild craniofacial dysmorphisms and CHD, and currently defined as 2q13 deletion or microdeletion syndrome (Wolfe, 2018;Guivarch, 2018).…”

“…TMEM87B (transmembrane protein 87B) is likely related with developmental delays, autism spectrum disorders (ASDs), and other psychiatric phenotypes as well as CHD (Guivarch, 2018;Yu, 2016;Russell, 2014), and its defect may be consistent with the neurological (generalized hypotonia and feeding difficulties) and cardiac findings of our patient. Disruption of ACOXL (acyl-CoA oxidase like, affecting fatty acid metabolism) (Wolfe, 2018;Yu, 2012) andBCL2L11 (BCL2 like 11, which encodes an antiapoptotic protein expressed in the frontal cortex and in the cerebellum, thus increasing apoptosis and the correlated risk of ASDs) (Sheikh, 2010) may contribute to neurodevelopmental and ASD phenotypes of these subjects (Wolfe, 2018;Yu, 2012). ANAPC1 (anaphase promoting complex subunit 1), a neurodevelopmental facilitator mainly expressed in the brain and the lymphoid organs, and MERTK (MER proto-oncogene, tyrosine kinase) are candidate genes for the psychosis phenotype of 2q13 CNV carriers (Wolfe, 2018).…”

“…In recent years, chromosomal microarray analysis (CMA) allowed the identification of a growing number of chromosomal imbalances within the human genome (Wolfe, 2018). These copy number variations (CNVs, defined as a greater than 1 kb segment of DNA that has variable copy number as compared to normal reference genome) include deletions and duplications (Yu, 2012), and involve single or multiple genes (Wolfe, 2018). CNVs may be either benign, or associated with diseases (Yu, 2012).…”

“…Some regions of the genome are flanked by highly homologous sequences (segmental duplications, SDs, also known as low copy repeats) (Rudd, 2009). They are prone to mismatching and, then, to recurrent CNVs, some of which cause clinically recognizable phenotypes (i.e., Angelman, Prader-Willi, Smith-Magenis and Williams-Beuren syndromes) (Wolfe, 2018;Hladilkowa, 2015). The 2q13 region contains clusters of such SDs, which facilitate recurrent deletions and/or duplications.…”

“…These imbalances are less described than those affecting other chromosomes (Hladilkowa, 2015). A recurrent pathogenic 1.71 Mb microdeletion is reported to date in around 50 patients (Wolfe, 2018). Their clinical phenotype is variable for the occurrence of mild (in the majority of cases) dysmorphic features, macro-or microcephaly, neurodevelopmental delay/behavior disorder (including hypotonia, impairment in fine and global motor skills, autism spectrum disorder, attention deficit and hyperactivity disorder), as well as congenital heart disease (CHD, the most frequent anomaly) and other congenital defects (i.e.…”