Genetic Veterinary science Inc

Spokane, WA, United States

Genetic Veterinary science Inc

Spokane, WA, United States
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Goldlust I.S.,Emory University | Hermetz K.E.,Emory University | Catalano L.M.,Emory University | Barfield R.T.,Emory University | And 23 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2013

Obesity is a highly heritable condition and a risk factor for other diseases, including type 2 diabetes, cardiovascular disease, hypertension, and cancer. Recently, genomic copy number variation (CNV) has been implicated in cases of early onset obesity that may be comorbid with intellectual disability. Here, we describe a recurrent CNV that causes a syndrome associated with intellectual disability, seizures, macrocephaly, and obesity. This unbalanced chromosome translocation leads to duplication of over 100 genes on chromosome 12, including the obesity candidate gene G protein β3 (GNB3). We generated a transgenic mouse model that carries an extra copy of GNB3, weighs significantly more than its wild-type littermates, and has excess intraabdominal fat accumulation. GNB3 is highly expressed in the brain, consistent with G-protein signaling involved in satiety and/or metabolism. These functional data connect GNB3 duplication and overexpression to elevated body mass index and provide evidence for a genetic syndrome caused by a recurrent CNV.

Nguyen L.S.,University of Adelaide | Kim H.-G.,Harvard University | Kim H.-G.,Georgia Regents University | Rosenfeld J.A.,Perkin Elmer Corporation | And 7 more authors.
Human Molecular Genetics | Year: 2013

The nonsense-mediated mRNA decay (NMD) pathway functions not only to degrade transcripts containing premature termination codons (PTC), but also to regulate the transcriptome. UPF3B and RBM8A, important components of NMD, have been implicated in various forms of intellectual disability (ID) and Thrombocytopenia with Absent Radius (TAR) syndrome, which is also associated with ID. To gauge the contribution of other NMD factors to ID, we performed a comprehensive search for copy number variants (CNVs) of 18 NMD genes among individuals with ID and/or congenital anomalies. We identified 11 cases with heterozygous deletions of the genomic region encompassing UPF2, which encodes for a direct interacting protein of UPF3B. Using RNA-Seq, we showed that the genome-wide consequence of reduced expression of UPF2 is similar to that seen in patients with UPF3B mutations. Out of the 1009 genes found deregulated in patients with UPF2 deletions by at least 2-fold, majority (95%) were deregulated similarly in patients with UPF3B mutations. This supports the major role of deletion of UPF2 in ID. Furthermore, we found that four other NMD genes, UPF3A, SMG6, EIF4A3 and RNPS1 are frequently deleted and/or duplicated in the patients. We postulate that dosage imbalances of these NMD genes are likely to be the causes or act as predisposing factors for neuro-developmental disorders. Our findings further emphasize the importance of NMD pathway(s) in learning and memory. © The Author 2013. Published by Oxford University Press. All rights reserved.

Hermetz K.E.,Emory University | Newman S.,Emory University | Conneely K.N.,Emory University | Martin C.L.,Emory University | And 8 more authors.
PLoS Genetics | Year: 2014

Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. For half of the rearrangements in our study, we sequenced at least one breakpoint junction. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted sequences are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a "fold-back" intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the fold-back loop. This process can lead to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes. © 2014 Hermetz et al.

Shaffer L.G.,Genetic Veterinary science Inc. | Rosenfeld J.A.,Perkin Elmer Corporation
Expert Review of Molecular Diagnostics | Year: 2013

The goal of prenatal cytogenetic testing is to provide reassurance to the couple seeking testing for their pregnancy, identify chromosome abnormalities in the fetus, if present, and provide treatments and medical management for affected babies. Cytogenetic analysis of banded chromosomes has been the standard for identifying chromosome abnormalities in the fetus for over 40 years. With chromosome analysis, whole chromosome aneuploidies and large structural rearrangements can be identified. The sequencing of the human genome has provided the resources to develop molecular tools that allow higher resolution observations of human chromosomes. The future holds the promise of sequencing that may identify chromosomal imbalances and deleterious single nucleotide variants. This review will focus on the use of genomic microarrays for the testing and identification of chromosome anomalies in prenatal diagnosis and will discuss the future directions of fetal testing. © 2013 Informa UK Ltd.

Callaway J.L.A.,Salisbury District Hospital | Shaffer L.G.,Genetic Veterinary science Inc. | Chitty L.S.,University College London | Chitty L.S.,Great Ormond Street NHS Foundation Trust | And 3 more authors.
Prenatal Diagnosis | Year: 2013

The clinical utility of microarray technologies when used in the context of prenatal diagnosis lies in the technology's ability to detect submicroscopic copy number changes that are associated with clinically significant outcomes. We have carried out a systematic review of the literature to calculate the utility of prenatal microarrays in the presence of a normal conventional karyotype. Amongst 12362 cases in studies that recruited cases from all prenatal ascertainment groups, 295/12362 (2.4%) overall were reported to have copy number changes with associated clinical significance (pCNC), 201/3090 (6.5%) when ascertained with an abnormal ultrasound, 50/5108 (1.0%) when ascertained because of increased maternal age and 44/4164 (1.1%) for all other ascertainment groups (e.g. parental anxiety and abnormal serum screening result). When additional prenatal microarray studies are included in which ascertainment was restricted to fetuses with abnormal ultrasound scans, 262/3730 (7.0%) were reported to have pCNCs. © 2013 John Wiley & Sons, Ltd.

Rosenfeld J.A.,Perkin Elmer Corporation | Coe B.P.,University of Washington | Eichler E.E.,University of Washington | Eichler E.E.,Howard Hughes Medical Institute | And 3 more authors.
Genetics in Medicine | Year: 2013

Purpose: Although an increasing number of copy-number variations are being identified as susceptibility loci for a variety of pediatric diseases, the penetrance of these copy-number variations remains mostly unknown. This poses challenges for counseling, both for recurrence risks and prenatal diagnosis. We sought to provide empiric estimates for penetrance for some of these recurrent, disease-susceptibility loci.Methods:We conducted a Bayesian analysis, based on the copy-number variation frequencies in control populations (n = 22,246) and in our database of >48,000 postnatal microarray-based comparative genomic hybridization samples. The background risk for congenital anomalies/ developmental delay/intellectual disability was assumed to be ∼5%. Copy-number variations studied were 1q21.1 proximal duplications, 1q21.1 distal deletions and duplications, 15q11.2 deletions, 16p13.11 deletions, 16p12.1 deletions, 16p11.2 proximal and distal deletions and duplications, 17q12 deletions and duplications, and 22q11.21 duplications.Results:Estimates for the risk of an abnormal phenotype ranged from 10.4% for 15q11.2 deletions to 62.4% for distal 16p11.2 deletions.Conclusion:This model can be used to provide more precise estimates for the chance of an abnormal phenotype for many copy-number variations encountered in the prenatal setting. By providing the penetrance, additional, critical information can be given to prospective parents in the genetic counseling session. © American College of Medical Genetics and Genomics.

PubMed | Genetic Veterinary science Inc., Applied Genomics, Harvard University, The Hospital for Sick Children and 8 more.
Type: | Journal: Molecular psychiatry | Year: 2016

Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts maps could uncover functionally and clinically related genes.Molecular Psychiatry advance online publication, 31 May 2016; doi:10.1038/mp.2016.84.

PubMed | McGill University, Perkin Elmer Corporation and Genetic Veterinary science Inc.
Type: Journal Article | Journal: American journal of human genetics | Year: 2014

Neurodevelopmental disorders (NDDs) are caused by mutations in diverse genes involved in different cellular functions, although therecan be crosstalk, or convergence, between molecular pathways affected by different NDDs. To assess molecular convergence, we generated human neural progenitor cell models of 9q34 deletion syndrome, caused by haploinsufficiency of EHMT1, and 18q21 deletion syndrome, caused by haploinsufficiency of TCF4. Using next-generation RNA sequencing, methylation sequencing, chromatin immunoprecipitation sequencing, and whole-genome miRNA analysis, we identified several levels of convergence. We found mRNA and miRNA expression patterns that were more characteristic of differentiating cells than of proliferating cells, and we identified CpG clusters that had similar methylation states in both models of reduced gene dosage. There was significant overlap of gene targets of TCF4 and EHMT1, whereby 8.3% of TCF4 gene targets and 4.2% of EHMT1 gene targets were identical. These data suggest that 18q21 and 9q34 deletion syndromes show significant molecular convergence but distinct expression and methylation profiles. Common intersection points might highlight the most salient features of disease and provide avenues for similar treatments for NDDs caused by different genetic mutations.

Antonacci F.,University of Bari | Dennis M.Y.,University of Washington | Huddleston J.,University of Washington | Huddleston J.,Howard Hughes Medical Institute | And 20 more authors.
Nature Genetics | Year: 2014

Recurrent deletions of chromosome 15q13.3 associate with intellectual disability, schizophrenia, autism and epilepsy. To gain insight into the instability of this region, we sequenced it in affected individuals, normal individuals and nonhuman primates. We discovered five structural configurations of the human chromosome 15q13.3 region ranging in size from 2 to 3 Mb. These configurations arose recently (â 1/40.5-0.9 million years ago) as a result of human-specific expansions of segmental duplications and two independent inversion events. All inversion breakpoints map near GOLGA8 core duplicons - a â 1/414-kb primate-specific chromosome 15 repeat that became organized into larger palindromic structures. GOLGA8-flanked palindromes also demarcate the breakpoints of recurrent 15q13.3 microdeletions, the expansion of chromosome 15 segmental duplications in the human lineage and independent structural changes in apes. The significant clustering (P = 0.002) of breakpoints provides mechanistic evidence for the role of this core duplicon and its palindromic architecture in promoting the evolutionary and disease-related instability of chromosome 15. © 2014 Nature America, Inc. All rights reserved.

Simons A.,Radboud University Nijmegen | Shaffer L.G.,Genetic Veterinary science Inc. | Hastings R.J.,University of Oxford
Cytogenetic and Genome Research | Year: 2013

The latest edition of the International System for Human Cytogenetic Nomenclature, ISCN 2013, has recently been published following a thorough revision of the 2009 issue and the incorporation of suggestions from the community by the current standing committee. This review will highlight the multiple nomenclature changes in the respective chapters of the 2013 version compared to the previous version of the ISCN published in 2009. These highlights are meant as a guide for the cytogeneticist to assist in the transition in the use of this updated nomenclature for describing cytogenetic and molecular cytogenetic findings in both clinical and research reports. © 2013 S. Karger AG, Basel.

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