Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome

Abstract

We identified a novel homozygous 15q13.3 microdeletion in a young boy, with a complex neurodevelopmental disorder characterized by severe cerebral visual impairment with additional signs of congenital stationary night blindness, congenital hypotonia with areflexia, profound intellectual disability, and refractory epilepsy. The mechanisms by which the genes in the deleted region exert their effect are unclear. In this paper, we probed the role of downstream effects of the deletions as a contributing mechanism to the molecular basis of the observed phenotype. We analyzed gene expression of lymphoblastoid cells derived from peripheral blood of the proband and his relatives to ascertain the relative effects of the homozygous and heterozygous deletions. We identified 267 genes with apparent differential expression between the proband with the homozygous deletion and 3 age-and sex-matched typically developing controls. Several of the differentially expressed genes are known to influence neurodevelopment and muscular function, and thus may contribute to the observed cognitive impairment and hypotonia. We further investigated the role of CHRNA7 by measuring TNFa modulation (a potentially important pathway in regulating synaptic plasticity). We found that the cell line with the homozygous deletion lost the ability to inhibit the activation of tumor necrosis factor-a secretion. Our findings suggest downstream genes that may have been altered by the 15q13.3 homozygous deletion, and thus contributed to the severe developmental encephalopathy of the proband. Furthermore, we show that a potentially important pathway in learning and development is affected by the deletion of CHRNA7.

Network effects of the neuropsychiatric 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons

“…While previous studies have explored the role that individual genes within the 15q13.3 microdeletion may play in neuronal dysfunction, little is known about which downstream genes and molecular mechanisms are affected and how they contribute to the associated neuropsychiatric symptoms. To date, only one study has characterized the transcriptome-wide effects of the 15q13.3 microdeletion in human tissue, and this analysis was performed in non-neuronal (lymphoblastoid) cells [15]. Current knowledge is even more limited concerning the epigenetic changes associated with this CNV.…”

“…Two other candidates genes in the deletion region are FAN1, a DNA repair nuclease that has nonsynonymous single nucleotide variants associated with both schizophrenia and autism [12,13]; and ARHGAP11B, a hominin-specific gene that increased basal progenitor cell generation in a mouse model, and that has been hypothesized to be a contributor to the evolutionary expansion of the human neocortex [14].While previous studies have explored the role that individual genes within the 15q13.3 microdeletion may play in neuronal dysfunction, little is known about which downstream genes and molecular mechanisms are affected and how they contribute to the associated neuropsychiatric symptoms. To date, only one study has characterized the transcriptome-wide effects of the 15q13.3 microdeletion in human tissue, and this analysis was performed in non-neuronal (lymphoblastoid) cells [15]. Current knowledge is even more limited concerning the epigenetic changes associated with this CNV.…”

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…Psychiatric disorders have been associated with this microdeletion syndrome, which is characterized by a 2-Mb deletion in 15q13.3 and shown to be inherited in 75% of patients with this syndrome (Masurel-Paulet et al, 2010). Although microdeletions in chromosome 15q13.3 generally encompass several genes and therefore render difficult the interpretation of the pathologic mechanisms, the identification in a smaller number of patients with homozygous microdeletion of CHRNA7 is starting to shed new light on the pathology associated with the absence of a7 nAChRs (Shinawi et al, 2009;Hoppman-Chaney et al, 2013;Le Pichon et al, 2013). Identification of the missing CHRNA7 can be performed using fluorescence in situ hybridization (FISH) analysis as illustrated in Fig.…”

Clinical and Genetic Heterogeneity of the 15q13.3 Microdeletion Syndrome

“…Therefore, other genetic factors are bound to influence the degree of clinical manifestations. A possible explanation could be an altered expression of her genes in the genome, which may have diverse effects [Le Pichon et al, 2013]. This approach has been further confirmed by Henrichsen et al [2009], who have shown that CNV regions are expressed at lower and more variable levels and modify the expression of neighboring genes.…”