Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Distinct Signaling Pathways Regulate Transformation and Inhibition of Skeletal Muscle Differentiation by Oncogenic Ras

Expression of oncogenic Ras in 23A2 skeletal myoblasts is sufficient to induce both a transformed phenotype and a differentiation-defective phenotype, but the signaling pathways activated by oncogenic Ras in these cells and their respective contribution to each phenotype have not been explored. In this study, we investigated MAP kinase activity in control 23A2 myoblasts and in 23A2 myoblasts rendered differentiation-defective by the stable expression of an oncogenic (G12V)Ha-ras gene (Ras9 cells). The MAP kinase immunoprecipitated from Ras9 cells was 30-40% more active than that from control 23A2 cells. To establish if this elevated MAP kinase activity is essential to the maintenance of the oncogenic Ras-induced phenotype, we utilized the selective MAP kinase kinase 1 (MEK1) inhibitor, PD 098059. PD 098059 decreased the MAP kinase activity in Ras9 cells to the level found in 23A2 cells. PD 098059 did not affect the ability of 23A2 myoblasts to differentiate. PD 098059 reverted the transformed morphology of Ras9 cells but did not restore the ability of these cells to express the muscle-specific myosin heavy chain gene or to form muscle fibers. Treatment with PD 098059 also did not affect the ability of oncogenic Ha-Ras to establish a non-myogenic phenotype in C3H10T1/2 cells co-expressing MyoD. These results demonstrate that the activation of MAP kinase is necessary for the transformed morphology of Ras9 cells but is not required by oncogenic Ras to establish or to maintain a differentiation-defective phenotype. While these data do not rule out the possibility that constitutive signaling by MEK1 or MAP kinase could inhibit myoblast differentiation, they clearly demonstrate that other pathways activated by oncogenic Ras are sufficient to inhibit differentiation

Reciprocal fusion transcripts of two novel Zn-finger genes in a female with absence of the corpus callosum, ocular colobomas and a balanced translocation between chromosomes 2p24 and 9q32.

We have identified a female patient with a complex phenotype that includes complete agenesis of the corpus callosum, bilateral periventricular nodular heterotopia, and bilateral chorioretinal and iris colobomas. Karyotype analysis revealed an apparently balanced, reciprocal, de novo chromosome translocation t(2;9)(p24;q32). Physical mapping of the translocation breakpoint by fluorescence in situ hybridization and PCR analysis led to the identification of two novel, ubiquitously expressed, Zn-finger-encoding transcripts that are disrupted in this patient. Unexpectedly, the rearrangement produced in-frame reciprocal fusion transcripts, making genotype-phenotype correlation difficult

Dosage Changes of a Segment at 17p13.1 Lead to Intellectual Disability and Microcephaly as a Result of Complex Genetic Interaction of Multiple Genes

Submitted by Nuzia Santos ([email protected]) on 2015-07-23T15:53:22Z No. of bitstreams: 1 Dosage Changes of a Segment at 17p13.1 Lead.pdf: 1645159 bytes, checksum: e83119eec1267cdcf9dc571d78ff4028 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-07-23T15:53:32Z (GMT) No. of bitstreams: 1 Dosage Changes of a Segment at 17p13.1 Lead.pdf: 1645159 bytes, checksum: e83119eec1267cdcf9dc571d78ff4028 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-07-23T16:05:33Z (GMT) No. of bitstreams: 1 Dosage Changes of a Segment at 17p13.1 Lead.pdf: 1645159 bytes, checksum: e83119eec1267cdcf9dc571d78ff4028 (MD5)Made available in DSpace on 2015-07-23T16:05:33Z (GMT). No. of bitstreams: 1 Dosage Changes of a Segment at 17p13.1 Lead.pdf: 1645159 bytes, checksum: e83119eec1267cdcf9dc571d78ff4028 (MD5) Previous issue date: 2014Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA /Fundação Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Belo Horizonte, MG, BrazilDuke University. Center for Human Disease Modeling.Durham, NC, USAWashington University . Division of Genetics and Genomic Medicine. Department of Pediatrics. St Louis, MO, USADuke University. Center for Human Disease Modeling.Durham, NC, USABaylor College of Medicine. Department of Pediatrics. Houston, TX, USA/ Texas Children’s Hospital. Houston, TX , USABaylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA /Baylor College of Medicine. Department of Pediatrics. Houston, TX, USA/ Texas Children’s Hospital. Houston, TX , USAVejle Hospital. Clinical Genetics Department. Vejle, DenmarkVejle Hospital. Clinical Genetics Department. Vejle, DenmarkUniversidade de São Paulo. Instituto de Biociencias. Departamento de Genetica e Evolução Biologica. Sao Paulo, SP, BrazilUniversidade de São Paulo. Instituto de Biociencias. Departamento de Genetica e Evolução Biologica. Sao Paulo, SP, BrazilTexas Oncology. Austin, TX, USASpecially for Children. Austin, TX, USAPhoenix Children’s Hospital. Phoenix, AZ, USAPhoenix Children’s Hospital. Phoenix, AZ, USABaylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USAUniversidade de São Paulo. Instituto de Biociencias. Departamento de Genetica e Evolução Biologica. Sao Paulo, SP, BrazilDuke University. Center for Human Disease Modeling. Durham, NC, USAThe 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO

A partial <it>MECP2</it> duplication in a mildly affected adult male: a putative role for the 3' untranslated region in the <it>MECP2</it> duplication phenotype

<p>Abstract</p> <p>Background</p> <p>Duplications of the X-linked <it>MECP2</it> gene are associated with moderate to severe intellectual disability, epilepsy, and neuropsychiatric illness in males, while triplications are associated with a more severe phenotype. Most carrier females show complete skewing of X-inactivation in peripheral blood and an apparent susceptibility to specific personality traits or neuropsychiatric symptoms.</p> <p>Methods</p> <p>We describe the clinical phenotype of a pedigree segregating a duplication of <it>MECP2</it> found on clinical array comparative genomic hybridization. The position, size, and extent of the duplication were delineated in peripheral blood samples from affected individuals using multiplex ligation-dependent probe amplification and fluorescence <it>in situ</it> hybridization, as well as targeted high-resolution oligonucleotide microarray analysis and long-range PCR. The molecular consequences of the rearrangement were studied in lymphoblast cell lines using quantitative real-time PCR, reverse transcriptase PCR, and western blot analysis.</p> <p>Results</p> <p>We observed a partial <it>MECP2</it> duplication in an adult male with epilepsy and mild neurocognitive impairment who was able to function independently; this phenotype has not previously been reported among males harboring gains in <it>MECP2</it> copy number. The same duplication was inherited by this individual’s daughter who was also affected with neurocognitive impairment and epilepsy and carried an additional copy-number variant. The duplicated segment involved all four exons of <it>MECP2</it>, but excluded almost the entire 3' untranslated region (UTR)<it>,</it> and the genomic rearrangement resulted in a <it>MECP2</it>-<it>TEX28</it> fusion gene mRNA transcript. Increased expression of <it>MECP2</it> and the resulting fusion gene were both confirmed; however, western blot analysis of lysates from lymphoblast cells demonstrated increased MeCP2 protein without evidence of a stable fusion gene protein product.</p> <p>Conclusion</p> <p>The observations of a mildly affected adult male with a <it>MECP2</it> duplication and paternal transmission of this duplication are unique among reported cases with a duplication of <it>MECP2</it>. The clinical and molecular findings imply a minimal critical region for the full neurocognitive expression of the <it>MECP2</it> duplication syndrome, and suggest a role for the 3′ UTR in mitigating the severity of the disease phenotype.</p