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Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses (SMI), including schizophrenia (SZ) and bipolar disorder (BP). Recent research suggests genetic links to several cognitive phenotypes in both SMI and in the general population. Our goal in this study was to identify potential genomic signatures of cognitive functioning in veterans with severe mental illness and compare them to previous findings for cognition across different populations. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and functional capacity measures among SZ and BP patients. In conjunction with the VA Million Veteran Program, 3,959 European American (1,095 SZ, 2,864 BP) and 2,601 African American (1,095 SZ, 2,864 BP) patients were genotyped using a custom Affymetrix Axiom Biobank array. We performed a genome-wide association study of global cognitive functioning, constructed polygenic scores for SZ and cognition in the general population, and examined genetic correlations with 2,626 UK Biobank traits. Although no single locus attained genome-wide significance, observed allelic effects were strongly consistent with previous studies. We observed robust associations between global cognitive functioning and polygenic scores for cognitive performance, intelligence, and SZ risk. We also identified significant genetic correlations with several cognition-related traits in UK Biobank. In a diverse cohort of U.S. veterans with SZ or BP, we demonstrate broad overlap of common genetic effects on cognition in the general population, and find that greater polygenic loading for SZ risk is associated with poorer cognitive performance.

Foci of papillary or follicular thyroid carcinoma are frequently noted in thyroidectomy specimens of anaplastic thyroid carcinoma (ATC). However, whether ATCs evolve from these co-existing well-differentiated thyroid carcinomas (WDTCs) has not been well-understood. To investigate the progression of ATC in patients with co-existing WDTCs, five ATC tumors with co-existing WDTCs and matching normal tissues were whole-exome sequenced. After mapping the somatic alteration landscape, evolutionary lineages were constructed by sub-clone analysis. Though each tumor harbored at least some unique private mutations, all five ATCs demonstrated numerous overlapping mutations with matched WDTCs. Clonal analysis further demonstrated that each ATC/WDTC pair shared a common ancestor, with some pairs diverging early in their evolution and others in which the ATC seems to arise directly from a sub-clone of the WDTC. Though the precise lineal relationship remains ambiguous, based on the genetic relationship, our study clearly suggests a shared origin of ATC and WDTC.

Objective: Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous and overlapping clinical features often allocate patients into the boundary of the two conditions, complicating accurate diagnosis and appropriate medical interventions. Therefore, we investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions. Methods: We screened novel genetic factors from 34 RTT-like patients without MECP2 mutations, which account for ∼90% of RTT cases, by whole exome sequencing. The biological function of the discovered variants was assessed in cell culture and Xenopus tropicalis models. Results: We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model. Interpretation: GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated GABA signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. This article is protected by copyright. All rights reserved.

Background Alterations in stress-related gene expression may play a role in stress-related drinking and the risk of alcohol dependence. Methods Microarrays were used to measure changes in gene expression in peripheral blood in nonsmoking, social drinking subjects exposed to 3 types of personalized imagery: neutral, stressful (but not alcohol related), and alcohol-related cues. Gene expression was measured at baseline, immediately after, and 1 hour after stimulus presentation. Subjects were allowed to drink up to 750 cc of beer in a “taste test” following stimulus presentation in each imagery condition, and the amount of beer consumed was recorded. Gene-expression levels were compared in 2 groups of nonsmoking subjects (n = 11/group): heavy drinkers (HD; defined as regular alcohol use over the past year of at least 8 standard drinks per week for women and at least 15 standard drinks per week for men), and moderate drinkers (MD; defined as up to 7 standard drinks per week for women and 14 standard drinks per week for men). Expression of microRNA-10a (miR-10a) and microRNA-21 (miR-21) was assessed by quantitative real-time polymerase chain reaction. Results After correction for multiple testing (false discovery rate 1.3-fold in the HD group, but not the MD group, following exposure to stress. No changes were observed for any of these genes in either group following exposure to neutral or alcohol-related imagery. Pathway analysis suggested that many of these genes, form part of the transactivation responsive (TAR)-RNA-binding protein (TRBP)-associated complex and are positively regulated by miR-10a and miR-21. Expression of both miR-10a and miR-21 was up-regulated following psychological stress in HD, but not MD subjects; however, the differences between groups were not statistically significant. Expression levels of both microRNAs was correlated (miR-10a, R2 = 0.59, miR-21 R2 = 0.57) with amount drunk in HD, but not MD subjects. Conclusions Expression of miR-10a, miR-21, and several of their target genes is regulated by acute psychological stress and is correlated with stress-induced drinking in a laboratory setting. Alterations in miRNA expression may be one mechanism linking psychological stress with changes in gene expression and increased alcohol intake in binge/HD.

The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.

Neuroacanthocytoses are neurodegenerative disorders marked by phenotypic and genetic heterogeneity. There are several associated genetic loci, and many defects, including gene deletions and insertions, and missense, nonsense, and splicing mutations, have been found spread over hundreds of kilobases of genomic DNA. In some cases, specific diagnosis is unclear, particularly in the early stages of disease or when there is an atypical presentation. Determination of the precise genetic defect allows assignment of the diagnosis and permits carrier detection and genetic counseling. The objective of this report was to utilize exome sequencing for genetic diagnosis in the neuroacanthocytosis syndromes. Genomic DNA from 2 patients with clinical features of chorea-acanthocytosis was subjected to targeted exon capture. Captured DNA was subjected to ultrahigh throughput next-generation sequencing. Sequencing data were assembled, filtered against known human variant genetic databases, and results were analyzed. Both patients were compound heterozygotes for mutations in the VPS13A gene, the gene associated with chorea-acanthocytosis. Patient 1 had a 4-bp deletion that removes the 5′ donor splice site of exon 58 and a nucleotide substitution that disrupts the 5′ donor splice site of exon 70. Patient 2 had a dinucleotide deletion in exon 16 and a dinucleotide insertion in exon 33. No mutations were identified in the XK, PANK2, or JPH3 gene loci. Exome sequencing is a valuable diagnostic tool in the neuroacanthocytosis syndromes. These studies may provide a better understanding of the function of the associated proteins and provide insight into the pathogenesis of these disorders. © 2011 Movement Disorder Society

Beech RD, Lowthert L, Leffert JJ, Mason PN, Taylor MM, Umlauf S, Lin A, Lee JY, Maloney K, Muralidharan A, Lorberg B, Zhao H, Newton SS, Mane S, Epperson CN, Sinha R, Blumberg H, Bhagwagar Z. Increased peripheral blood expression of electron transport chain genes in bipolar depression. Bipolar Disord 2010: 12: 813–824. © 2010 The Authors.Journal compilation © 2010 John Wiley & Sons A/S. Objective: To identify specific genetic pathways showing altered expression in peripheral blood of depressed subjects with bipolar disorder (BPD). Methods: Illumina Sentrix BeadChip (Human-6v2) microarrays containing >48,000 transcript probes were used to measure levels of gene expression in peripheral blood from 20 depressed subjects with BPD and in 15 healthy control subjects. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to confirm a subset of these differences. Results: A total of 1,180 genes were differentially expressed between subjects with BPD and healthy controls (fold-change >1.3, false discovery rate-corrected p

Current techniques to define gastric neoplasia are limited but molecular genetic signatures can categorize tumors and provide biological rationale for predicting clinical behavior. We identified three gene signatures: Chromogranin A (CgA), MAGE-D2 (adhesion), and MTA1 (metastasis) that define gastrointestinal (GI) carcinoids and hypothesize that their expression can delineate gastric neoplasia. This strategy provides a molecular basis to define neuroendocrine gastric carcinoids (GCs), neuronal stromal tumors (GISTs), or epithelial cell (gastric adenocarcinomas [GCAs])-derived tumors.Total RNA was isolated from 38 GCs: Type I/II (n = 7), Type III/IV (n = 6), GISTs (n = 12), GCAs (n = 13), and normal mucosa (n = 12). Quantitative reverse transcriptase polymerase chain reaction (Q RT-PCR) gene expression was quantified against glyseraldehyde-3-phosphate dehydrogenase (GAPDH) and CgA and MTA1 protein expression levels were analyzed by immunohistochemical analyses of a gastric neoplasia microarray.CgA was elevated in Type I/II (10-fold; P.01) and Type III/IV (100-fold, P.005), decreased in GISTs (100-fold, P.03), and unchanged in GCAs. MAGE-D2 was 5-10-fold elevated (P.05) in Type III/IV, GISTs, and GCAs but not in Type I/II tumors. MTA1 (5-fold, P.01) was elevated in GCs (Type III/IVI/II, P.05), in GISTs (4-fold, P.05), and GCAs. CgA protein levels were elevated in GCs (P.005) but not in GISTs and GCAs. MTA1 levels were elevated in all tumors (P.02) compared with normal, and especially with tumor invasion (P.05).CgA discriminates GCs from other gastric neoplasms; overexpression of MAGE-D2 and MTA1 differentiate Type III/IV from Type I/II GCs. GISTs share similar expression patterns with Type III/IV GCs but have decreased CgA. MTA1 is a marker of tumor invasion.

In science and medicine there are occasional major advances that facilitate transformations of a field. The application of next-generation massively parallel sequencing technologies coupled with powerful computational approaches to discover genes for Mendelian disorders is arguably such a major advance [Biesecker, 2010]. Just three years ago, the strategy of exome sequencing (ES) followed by discrete filtering was introduced and shown to be a potential approach to identify the genes underlying Mendelian conditions [Choi et al., 2009; Ng et al., 2010; Ng et al., 2009]. Since then, ES and whole genome sequencing (WGS) [Lupski et al., 2010] have been used to explain the cause of dozens of disorders [Bamshad et al., 2011; Claudia Gonzaga-Jauregui, 2012; Gilissen et al., 2011] including those transmitted as X-linked, autosomal recessive [Bilguvar and et al., 2010], and autosomal dominant traits [Choi et al. 2011]; as well as phenotypes caused by de novo dominant mutations [Choate et al. 2010; O'Roak et al. 2011; Vissers et al. 2010] and somatic mosaicism [Lindhurst et al. 2011]. Given the technical and analytical improvements expected over the next several years, the application of ES/WGS-based strategies will enable the identification of the genes underlying a very large fraction of all known Mendelian disorders for which the genetic basis is not yet known — at a small fraction of the current cost for discovery per disorder. Based on these advances, exploring all Mendelian disorders should become an imperative for the worldwide human genetics community. The discoveries made through such exploration would be of enormous service to families, and will provide novel entry points to investigate the mechanisms underlying disease development. Such an effort would, however, be very ambitious, requiring an unprecedented degree of cooperation and coordination in the field of medical genetics and the assistance of patients and families from around the world. A global initiative to explore all Mendelian conditions is now emerging. The initiative, which includes the International Rare Diseases Research Consortium, the Finding of Rare Disease Genes (FORGE) in Canada, and centers in Europe, East Asia and elsewhere, will establish the necessary collaborative framework and physical infrastructure to achieve this goal. In the United States, the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) have partnered to support this effort at three Centers for Mendelian Genomics (CMGs): the Center for Mendelian Genomics at the University of Washington; the Center for Mendelian Disorders at Yale University; and the Baylor-Johns Hopkins Center for Mendelian Genomics at Baylor College of Medicine and the Johns Hopkins University. The CMGs have four major goals: (1) to ascertain samples for all Mendelian disorders for which the genetic basis is not yet understood from clinicians and investigators around the world by developing a ‘public list’ of samples and by coordinating submissions to the NIH program with those of other international programs; (2) to improve the efficiency of the sequencing pipeline and quality of exome and genome data through ongoing technology innovation; (3) to determine the genetic basis for as many Mendelian conditions as possible; and (4) to disseminate methods and data to facilitate gene discovery by investigators working independently across the globe. The CMGs will study disorders with age of onset across the entire lifespan including well-delineated, known Mendelian phenotypes as well as novel phenotypes thought to be Mendelian on the basis of their segregation patterns in families. Initially, the “public list” will be a catalog of collected DNA samples, organized by condition, that have entered the sequencing pipeline at any one of the CMGs. Next, this list will expand to include all of the Mendelian disorders for which the CMGs have solicited DNA samples, sequencing status, and the results obtained to date. Since the availability of a sufficient number of samples from clinically well-characterized cases and families will be critical to the discovery of genes for all Mendelian disorders, one aim of the public list is to facilitate coordination of sample collection and implementation of ES among clinicians and researchers around the world. Ultimately, the CMGs aim to develop the list into a comprehensive community resource that provides information on samples that are available worldwide for concerted disease gene discovery efforts. With this introduction, we would like to engage the medical genetics community to join with us and collaborate with the CMGs by submitting information about familial conditions, adding samples to the effort from individuals or families with rare Mendelian disorders to stimulate collaborations and eventually new insights. Since many of these conditions are rare, and often with locus heterogeneity, multiple investigators will need to contribute samples from individuals and families with the same diagnosis to improve chances for finding and validating candidate genes and variants. Following sequencing and analysis, the CMGs will return the results to the submitters, and will collaborate with investigators to facilitate further analysis, functional studies, and, ultimately publication. Results will be provided to the collaborating investigators as soon as possible. Collaborating investigators will have data exclusivity for a minimum of six months to ensure ample time to conduct follow up studies and prepare manuscripts for publication. The development of a public list will ensure transparency and facilitate communications about progress within and beyond the medical genetics community; this list will soon be accessible via the CMG website (http://mendelian.org). While the workflow will vary among CMGs, several key common practices across the CMGs will enable high-quality data production and analysis with partnering contributors. Phenotypic information associated with each sample and family will be collected and evaluated to increase diagnostic precision, identify phenotypic features that clarify genetic heterogeneity and aid in the identification of previously unrecognized disorders. DNA samples will be genotyped using low-cost, genome-wide marker arrays to provide a unique profile for sample tracking, to identify copy number variation (CNVs) and to provide genetic information for subsequent analysis of sequence variations (large and small insertion-deletions) underlying these conditions. These approaches, when applied to well-characterized pedigrees, will aid in finding the genomic intervals shared among all (or nearly all) cases, and reduce the genomic search space and speed the subsequent identification of candidate gene(s) by the collaborating investigators [Sobreira et al., 2010]. The success of this effort will require collaboration at an unprecedented scale in the field of human genetics. The CMGs and their global partners welcome partnering scientists and clinicians with samples or families affected with a Mendelian condition to collaborate with us by submitting inquiries to gro.nailednem@lednemg. The CMGs have partnered with Wiley-Liss and the American Journal of Medical Genetics (AJMG) to advertise in each issue to its worldwide readership of clinical and medical geneticists. The corresponding author of each manuscript accepted by the Journal will be provided with information about the CMGs. This is a welcome and important partnership since the AJMG is a well-known forum for the delineation of new syndromes and for reporting the description of novel rare, Mendelian conditions. Similarly, the Online Mendelian Inheritance in Man (OMIM; www.OMIM.org) catalog will provide a means for quickly disseminating summaries of newly discovered genes for known Mendelian disorders and adding newly delineated disorders to the OMIM catalog. We welcome the possibilities for other scientists, international journals and websites to link to the CMG site (http://mendelian.org). We ask clinicians and scientists to collaborate with us by submitting cases and families. The key drivers for the CMGs are to serve the scientific community and the individuals and families with rare diseases by improving knowledge about these rare conditions. By making specific diagnoses and exploring on a genome level the relationships between sequence variation and phenotype, collaboratively we can achieve more comprehensive pre-symptomatic or carrier screening. Additionally, the knowledge obtained from these efforts could initiate the exploration of new and/or improved therapeutics for these conditions. The CMG mechanism will eliminate significant financial and technical barriers for clinicians who wish to gain deeper understanding of genetic disorders and will catalyze interactions across the worldwide biomedical community to utilize these genotype/phenotype correlations to drive a deeper understanding of the biology of disease. The application of powerful new genomic approaches in genetics will provide an unprecedented view into the molecular basis of many, if not most, unexplained Mendelian phenotypes. The CMG will provide the community with access to production infrastructure, bioinformatics support, and analytical expertise. The challenge to the human genetics community is to help initiate this new phase of medical genomics and take advantage of this new opportunity by providing the resources for such studies that obviously cannot occur without finding and characterizing the patients and their families. Please contact us at gro.nailednem@lednemg or through the web portals of the individual centers with questions or with samples to submit.