Date Published: March 31, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Kate Wolfe, Andrew McQuillin, Viola Alesi, Elise Boudry Labis, Peter Cutajar, Bruno Dallapiccola, Maria Lisa Dentici, Anne Dieux‐Coeslier, Benedicte Duban‐Bedu, Tina Duelund Hjortshøj, Himanshu Goel, Sara Loddo, Deborah Morrogh, Anne‐Laure Mosca‐Boidron, Antonio Novelli, Laurence Olivier‐Faivre, Jennifer Parker, Michael J. Parker, Christine Patch, Anna L. Pelling, Thomas Smol, Zeynep Tümer, Olivier Vanakker, Arie van Haeringen, Clémence Vanlerberghe, Andre Strydom, David Skuse, Nick Bass.
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.
Chromosomal microarray analysis technologies have led to the discovery of chromosomal imbalances across the human genome. These imbalances, or copy number variations (CNVs), comprise deletions or duplications affecting single or multiple genes on sections of the chromosome. CNVs occur as part of natural variation and can be benign in nature. Typically, it is the rare CNVs, occurring in less than 1% of the population, that are enriched in individuals with neurodevelopmental and neuropsychiatric phenotypes (Iyer & Girirajan, 2015). Several challenges, however, remain in CNV interpretation. CNVs frequently display reduced penetrance, meaning not everyone with the CNV displays the disease phenotype, and/or variable expressivity, whereby the severity of the phenotype differs between CNV carriers (Rosenfeld, Coe, Eichler, Cuckle, & Shaffer, 2013).
CNVs at the 2q13 locus are rare in the population, can be observed in healthy controls and transmitted from unaffected parents. Despite this, multiple studies have now shown that CNVs at 2q13 are risk factors for DD and dysmorphisms. This study represents the largest ever case series of 2q13 patients, comprising detailed phenotypic data for 25 new cases and combined analysis in 77 individuals, refining our understanding of the phenotypic associations of CNVs at the 2q13 locus.
In the largest study of 2q13 CNVs to date, we present detailed phenotypic data for 25 new 2q13 deletion and duplication carriers. Combining this with previous literature yields a total of 54 deletion and 23 duplication carriers, enabling a refined understanding of the phenotypic associations of CNVs at the 2q13 locus. Combined analysis predominantly supports existing literature on an increased rate of developmental, medical, and dysmorphic phenotypes. Psychiatric investigations reveal that the majority of deletion and duplication carriers have been clinically diagnosed with a psychiatric disorder, with a particularly high incidence of ADHD. This could have important implications for psychiatric screening upon clinical diagnosis of 2q13 CNVs, and further investigation of this region may have some relevance to understanding the neurobiology of ADHD.