High rate of disease-related copy number variations in childhood onset schizophrenia

Abstract

Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, epilepsy, intellectual disability (ID) and schizophrenia. Childhood onset schizophrenia (COS), defined as onset before the age of 13 years, is a rare and severe form of the disorder, with more striking array of prepsychotic developmental disorders and abnormalities in brain development. Because of the well-known phenotypic variability associated with pathogenic CNVs, we conducted whole genome genotyping to detect CNVs and then focused on a group of 46 rare CNVs that had well-documented risk for adult onset schizophrenia (AOS), autism, epilepsy and/or ID. We evaluated 126 COS probands, 69 of which also had a healthy full sibling. When COS probands were compared with their matched related controls, significantly more affected individuals carried disease-related CNVs (P = 0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (P<0.0001). A total of 15 (11.9%) subjects exhibited at least one such CNV and four of these subjects (26.7%) had two. Five of 15 (4.0% of the sample) had a 2.5–3 Mb deletion mapping to 22q11.2, a rate higher than that reported for adult onset (0.3–1%) (P<0.001) or autism spectrum disorder and, indeed, the highest rate reported for any clinical population to date. For one COS subject, a duplication found at 22q13.3 had previously only been associated with autism, and for four patients CNVs at 8q11.2, 10q22.3, 16p11.2 and 17q21.3 had only previously been associated with ID. Taken together, these findings support the well-known pleiotropic effects of these CNVs suggesting shared abnormalities early in brain development. Clinically, broad CNV-based population screening is needed to assess their overall clinical burden.

Gene Dosage in the Dysbindin Schizophrenia Susceptibility Network Differentially Affect Synaptic Function and Plasticity

“…Second, genotype-to-phenotype correlations observed in a BLOC-1 trait following a gene pair analysis better predict, although not precisely, how other traits may respond. These findings provide a perspective to the complexity and predictability of synaptic phenotypes derived from copy number variation associated to human neurodevelopmental disorders (Stefansson et al, 2009Bassett et al, 2010Malhotra and Sebat, 2012;Moreno-De-Luca et al, 2013;Ahn et al, 2014). Dominant and recessive fly traits associated with mutations affecting BLOC-1 complexes support the dosage balance hypothesis, which predicts that mutations affecting genes encoding different subunits of a protein complex may confer distinct phenotypes and inheritance mechanisms (Veitia et al, 2008;Birchler and Veitia, 2012).…”

Genome-wide Purification of Extrachromosomal Circular DNA from Eukaryotic Cells

“…Studies of eccDNAs in germline cells could be used to measure germline mutation rates and assess sperm quality, for example in livestock. Thus, Circle-Seq has the potential to yield insights into the rate at which genetic variation arises in the form of copy number variation, and lead to a novel understanding of diseases that involve gene copynumber variation [38][39][40] .…”

Common polygenic variation and risk for childhood-onset schizophrenia

“…We previously documented that COS patients, compared with their healthy siblings and with adult-onset patients (AOS), carry significantly more rare chromosomal copy number variations, spanning large genomic regions (4100 kb) (Ahn et al 2014). Here, we interrogated the contribution of common polygenic variation to the genetic susceptibility for schizophrenia.…”