A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes

Shinawi, Marwan; Schaaf, Christian P.; Bhatt, Samarth; Xia, Zhilian; Patel, Ankita; Cheung, Sau Wai; Lanpher, Brendan C.; Nagl, Sandra; Herding, Heinrich Stephan; Nevinny-Stickel, C.; Immken, LaDonna; Patel, Gayle; German, Jennifer R.; Beaudet, Arthur L.; Stankiewicz, Paweł

doi:10.1038/ng.481

Cited by 175 publications

(189 citation statements)

References 15 publications

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“…[25][26][27][28] These B2-Mb microdeletions lead to the loss of CHRNA7 and five other genes (Supplementary Figure 1a), but smaller variants that show a similar range of phenotypes remove only CHRNA7 and one other gene. 29 These observations strongly implicate the CHRNA7 region in schizophrenia and other neuropsychiatric disorders.…”

Section: Introductionmentioning

confidence: 93%

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

et al. 2012

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There is considerable evidence implicating the 15q13.3 region in neuropsychiatric disorders, with the a7 nicotinic receptor gene CHRNA7 the most plausible candidate. This region has multiple duplications and many copy number variants (CNVs). A common CNV involves a partial duplication of CHRNA7 (CHRFAM7A), which occurs in either orientation. We examined the distribution of these alternative genomic arrangements in a large cohort of psychiatric patients, their relatives and controls using the 2-bp deletion polymorphism as a marker for the orientation of CHRFAM7A. We investigated three common alleles for association with psychosis and with the P50 sensory gating deficit, which is strongly associated with psychosis and strongly linked to 15q13.3. We found significant within-family association with P50 (empirical P ¼ 0.004), which is robust to population stratification. Most of the effect came from the 2-bp deletion allele, which tags the variant of CHRFAM7A in the same orientation as CHRNA7. This allele is associated with the presence of the P50 sensory gating deficit (empirical P ¼ 0.0006). Tests comparing within-family and between-family components of association suggest considerable population stratification in the sample. We found no evidence for association with psychosis, but this may reflect lower power using this phenotype. Four out of six previous association studies found association of different psychiatric phenotypes with the same 2-bp deletion allele.

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Section: Introductionmentioning

confidence: 93%

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

et al. 2012

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“…[1][2][3][4][5][6][7][8] The phenotype varies in spectrum and severity owing to incomplete penetrance or variable expressivity. The 15q13.3 deletion is typically 1.6 Mb, harboring at least seven genes, ARHGAP11B, MTMR15, MTMR10, TRPM1, KLF13, OTUD7A, and CHRNA7.…”

Section: Introductionmentioning

confidence: 99%

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

Pichon

Kibiryeva

et al. 2013

Eur J Hum Genet

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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.

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“…This subunit has important roles in brain development and neuron differentiation and migration (Gotti et al 2009;Taly et al 2009), and its chromosomal locus was associated in humans with developmental and neurological disorders (Ben-Shachar et al 2009;Consortium 2008;Helbig et al 2009;Miller et al 2009;Sharp et al 2008;Shinawi et al 2009;Stefansson et al 2008). Despite the importance of the α7 nAChR subunit, its deficiency results in viable, anatomically normal α7-null mice (Orr-Urtreger et al 1997;Paylor et al 1998).…”

Section: Discussionmentioning

confidence: 99%

“…The nAChRs have been implicated in complex diseases affecting the nervous system, including epilepsy, schizophrenia, developmental disorders, and aging-associated neurodegenerative diseases such as AD and PD (Freedman et al 2001;Steinlein et al 1995). Several recent genome-wide association studies identified genomic alterations in the human α7 nAChR subunit gene locus in patients with schizophrenia, bipolar disorder, autism, developmental delay, and seizures (Ben-Shachar et al 2009;Consortium 2008;Helbig et al 2009;Miller et al 2009;Sharp et al 2008;Shinawi et al 2009;Stefansson et al 2008). α7 subunits can form homopentameric receptor channels, which are activated by acetylcholine (ACh) and blocked by α-bungarotoxin (αBgtx).…”

Section: Introductionmentioning

confidence: 99%

The effects of aging vs. α7 nAChR subunit deficiency on the mouse brain transcriptome: aging beats the deficiency

Kedmi

Orr-Urtreger

2010

AGE

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Aging is accompanied by expression changes in multiple genes, and the brain is one of the tissues most vulnerable to aging. Since the α7 nicotinic acetylcholine receptor (nAChR) subunit has been associated with neurodevelopmental disorders and cognitive decline during aging, we hypothesized that its absence might affect gene expression profiles in aged brains. To study whether transcriptional changes occur due to aging, α7 deficiency, or both, we analyzed whole-brain transcriptomes of young (8 weeks) and aged (2 years) α7-deficient and wild-type control mice, using Mouse Genome 430 2.0 microarray. Highly significant expression changes were detected in 47 and 1,543 genes [after Bonferroni and false discovery rate (FDR) correction] in the brains of aged mice compared to young mice, regardless of their genotype. These included genes involved in immune system function and ribosome structure, as well as genes that were previously demonstrated as differentially expressed in aging human brains. Genotype-dependent changes were detected in only three genes, Chrna7 which encodes the α7 nAChR subunit, and two closely linked genes, likely due to a "mouse background effect." Expression changes dependent on age-genotype interaction were detected in 207 genes (with a low significance threshold). Age-dependent differential expression levels were approved in all nine genes that were chosen for validation by real-time RT-PCR. Our results suggest that the robust effect of aging on brain transcription clearly overcomes the almost negligible effect of α7 nAChR subunit deletion and that germ line deficiency of this subunit has a minor effect on brain expression profile in aged mice.

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A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes

Cited by 175 publications

References 15 publications

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

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

The effects of aging vs. α7 nAChR subunit deficiency on the mouse brain transcriptome: aging beats the deficiency

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