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Gilles Maussion, Cristiana Cruceanu, Jill A Rosenfeld, Scott C Bell, Fabrice Jollant, Jin Szatkiewicz, Ryan L Collins, Carrie Hanscom, Ilaria Kolobova, Nicolas Menjot de Champfleur, Ian Blumenthal, Colby Chiang, Vanessa Ota, Christina Hultman, Colm O'Dushlaine, Steve McCarroll, Martin Alda, Sebastien Jacquemont, Zehra Ordulu, Christian R Marshall, Melissa T Carter, Lisa G Shaffer, Pamela Sklar, Santhosh Girirajan, Cynthia C Morton, James F Gusella, Gustavo Turecki, Dimitri J Stavropoulos, Patrick F Sullivan, Stephen W Scherer, Michael E Talkowski, Carl Ernst
We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11...
October 19, 2016: American Journal of Medical Genetics. Part A
Christopher C Angelakos, Adam J Watson, W Timothy O'Brien, Kyle S Krainock, Thomas Nickl-Jockschat, Ted Abel
Sleep disturbances and hyperactivity are prevalent in several neurodevelopmental disorders, including autism spectrum disorders (ASDs) and attention deficit-hyperactivity disorder (ADHD). Evidence from genome-wide association studies indicates that chromosomal copy number variations (CNVs) are associated with increased prevalence of these neurodevelopmental disorders. In particular, CNVs in chromosomal region 16p11.2 profoundly increase the risk for ASD and ADHD, disorders that are more common in males than females...
October 14, 2016: Autism Research: Official Journal of the International Society for Autism Research
Franziska Degenhardt, Barbara Heinemann, Jana Strohmaier, Marvin A Pfohl, Ina Giegling, Andrea Hofmann, Kerstin U Ludwig, Stephanie H Witt, Michael Ludwig, Andreas J Forstner, Margot Albus, Sibylle G Schwab, Margitta Borrmann-Hassenbach, Leonard Lennertz, Michael Wagner, Per Hoffmann, Dan Rujescu, Wolfgang Maier, Sven Cichon, Marcella Rietschel, Markus M Nöthen
Duplications in 16p11.2 are a risk factor for schizophrenia (SCZ). Using genetically modified zebrafish, Golzio and colleagues identified KCTD13 within 16p11.2 as a major driver of the neuropsychiatric phenotype observed in humans. The aims of the present study were to explore the role of KCTD13 in the development of SCZ and to provide a more complete picture of the allelic architecture at this risk locus. The exons of KCTD13 were sequenced in 576 patients. The mutations c.6G>T and c.598G>A were identified in one patient each...
September 23, 2016: Psychiatric Genetics
Kate Wolfe, André Strydom, Deborah Morrogh, Jennifer Carter, Peter Cutajar, Mo Eyeoyibo, Angela Hassiotis, Jane McCarthy, Raja Mukherjee, Dimitrios Paschos, Nagarajan Perumal, Stephen Read, Rohit Shankar, Saif Sharif, Suchithra Thirulokachandran, Johan H Thygesen, Christine Patch, Caroline Ogilvie, Frances Flinter, Andrew McQuillin, Nick Bass
Chromosomal copy-number variations (CNVs) are a class of genetic variants highly implicated in the aetiology of neurodevelopmental disorders, including intellectual disabilities (ID), schizophrenia and autism spectrum disorders (ASD). Yet the majority of adults with idiopathic ID presenting to psychiatric services have not been tested for CNVs. We undertook genome-wide chromosomal microarray analysis (CMA) of 202 adults with idiopathic ID recruited from community and in-patient ID psychiatry services across England...
September 21, 2016: European Journal of Human Genetics: EJHG
J A Anguera, A N Brandes-Aitken, C E Rolle, S N Skinner, S S Desai, J D Bower, W E Martucci, W K Chung, E H Sherr, E J Marco
Assessing cognitive abilities in children is challenging for two primary reasons: lack of testing engagement can lead to low testing sensitivity and inherent performance variability. Here we sought to explore whether an engaging, adaptive digital cognitive platform built to look and feel like a video game would reliably measure attention-based abilities in children with and without neurodevelopmental disabilities related to a known genetic condition, 16p11.2 deletion. We assessed 20 children with 16p11.2 deletion, a genetic variation implicated in attention deficit/hyperactivity disorder and autism, as well as 16 siblings without the deletion and 75 neurotypical age-matched children...
2016: Translational Psychiatry
Joanna Lazier, Deborah Fruitman, Julie Lauzon, Francois Bernier, Bob Argiropoulos, Judy Chernos, Oana Caluseriu, Rebecca Simrose, Mary Ann Thomas
OBJECTIVES: To examine the diagnostic performance of array comparative genomic hybridization (CGH) for fetal cardiac anomalies in two medium-sized Canadian prenatal genetics clinics. METHODS: We prospectively recruited 22 pregnant women with fetal structural cardiac anomalies, normal rapid aneuploidy detection, and FISH for 22q11.2 testing for array CGH analysis. RESULTS: One case had an 8p deletion that was also visible on karyotype and included the GATA4 gene, which has been associated with congenital heart disease...
July 2016: Journal of Obstetrics and Gynaecology Canada: JOGC, Journal D'obstétrique et Gynécologie du Canada: JOGC
Toshiyuki Yamamoto, Keiko Shimojima, Yumiko Ondo, Katsumi Imai, Pin Fee Chong, Ryutaro Kira, Mitsuhiro Amemiya, Akira Saito, Nobuhiko Okamoto
Next-generation sequencing (NGS) is widely used for the detection of disease-causing nucleotide variants. The challenges associated with detecting copy number variants (CNVs) using NGS analysis have been reported previously. Disease-related exome panels such as Illumina TruSight One are more cost-effective than whole-exome sequencing (WES) because of their selective target regions (~21% of the WES). In this study, CNVs were analyzed using data extracted through a disease-related exome panel analysis and the eXome Hidden Markov Model (XHMM)...
2016: Human Genome Variation
Jeroen Breckpot, Marieke Vercruyssen, Eddy Weyts, Sean Vandevoort, Greet D'Haenens, Griet Van Buggenhout, Lore Leempoels, Elise Brischoux-Boucher, Lionel Van Maldergem, Alessandra Renieri, Maria Antonietta Mencarelli, Carla D'Angelo, Veronica Mericq, Mariette J Hoffer, Maithé Tauber, Catherine Molinas, Claudia Castiglioni, Nathalie Brison, Joris R Vermeesch, Marina Danckaerts, Pascal Sienaert, Koenraad Devriendt, Annick Vogels
BACKGROUND: Catatonia is a motor dysregulation syndrome co-occurring with a variety of psychiatric and medical disorders. Response to treatment with benzodiazepines and electroconvulsive therapy suggests a neurobiological background. The genetic etiology however remains largely unexplored. Copy Number Variants (CNV), known to predispose to neurodevelopmental disorders, may play a role in the etiology of catatonia. METHODS: This study is exploring the genetic field of catatonia through CNV analysis in a cohort of psychiatric patients featuring intellectual disability and catatonia...
September 2016: European Journal of Medical Genetics
Stephen J Mosca, Lisa Marie Langevin, Deborah Dewey, A Micheil Innes, Anath C Lionel, Christian C Marshall, Stephen W Scherer, Jillian S Parboosingh, Francois P Bernier
BACKGROUND: Developmental coordination disorder is a common neurodevelopment disorder that frequently co-occurs with other neurodevelopmental disorders including attention-deficit hyperactivity disorder (ADHD). Copy-number variations (CNVs) have been implicated in a number of neurodevelopmental and psychiatric disorders; however, the proportion of heritability in developmental coordination disorder (DCD) attributed to CNVs has not been explored. OBJECTIVE: This study aims to investigate how CNVs may contribute to the genetic architecture of DCD...
August 3, 2016: Journal of Medical Genetics
Xander Nuttle, Giuliana Giannuzzi, Michael H Duyzend, Joshua G Schraiber, Iñigo Narvaiza, Peter H Sudmant, Osnat Penn, Giorgia Chiatante, Maika Malig, John Huddleston, Chris Benner, Francesca Camponeschi, Simone Ciofi-Baffoni, Holly A F Stessman, Maria C N Marchetto, Laura Denman, Lana Harshman, Carl Baker, Archana Raja, Kelsi Penewit, Nicolette Janke, W Joyce Tang, Mario Ventura, Lucia Banci, Francesca Antonacci, Joshua M Akey, Chris T Amemiya, Fred H Gage, Alexandre Reymond, Evan E Eichler
Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution...
August 11, 2016: Nature
Konrad Rawlik, Amy Rowlatt, Albert Tenesa
Understanding how genetic variation affects intermediate phenotypes, like DNA methylation or gene expression, and how these in turn vary with complex human disease provides valuable insight into disease etiology. However, intermediate phenotypes are typically tissue and developmental stage specific, making relevant phenotypes difficult to assay. Assembling large case-control cohorts, necessary to achieve sufficient statistical power to assess associations between complex traits and relevant intermediate phenotypes, has therefore remained challenging...
October 2016: Genetics
Takuma Morita, Narikazu Uzawa, Kaoru Mogushi, Jun Sumino, Chieko Michikawa, Ken-Ichiro Takahashi, Kunihiro Myo, Toshiyuki Izumo, Kiyoshi Harada
Primary tumor (PT) heterogeneity can significantly affect the genetic profile of clones at metastatic sites. To understand the mechanisms underlying metastasis, we compared the genetic profile of paired PT and metastatic lymph node (MLN) samples obtained from patients with oral tongue squamous cell carcinoma (OTSCC). Large-scale genetic profiling was performed on paired PT-MLN samples obtained from 10 OTSCC patients using high-density single-nucleotide polymorphism microarrays. We compared the genetic profile of PT and MLN OTSCC samples to identify common and specific copy number alterations and copy-neutral loss-of-heterozygosity (CN-LOH)...
December 2016: Genes, Chromosomes & Cancer
Ella J Wilkins, Alison D Archibald, Margaret A Sahhar, Susan M White
Chromosomal microarray is an increasingly utilized diagnostic test, particularly in the pediatric setting. However, the clinical significance of copy number variants detected by this technology is not always understood, creating uncertainties in interpreting and communicating results. The aim of this study was to explore parents' experiences of an uncertain microarray result for their child. This research utilized a qualitative approach with a phenomenological methodology. Semi-structured interviews were conducted with nine parents of eight children who received an uncertain microarray result for their child, either a 16p11...
July 13, 2016: American Journal of Medical Genetics. Part A
Kyle J Steinman, Sarah J Spence, Melissa B Ramocki, Monica B Proud, Sudha K Kessler, Elysa J Marco, LeeAnne Green Snyder, Debra D'Angelo, Qixuan Chen, Wendy K Chung, Elliott H Sherr
Chromosome 16p11.2 deletions and duplications are among the most frequent genetic etiologies of autism spectrum disorder (ASD) and other neurodevelopmental disorders, but detailed descriptions of their neurologic phenotypes have not yet been completed. We utilized standardized examination and history methods to characterize a neurologic phenotype in 136 carriers of 16p11.2 deletion and 110 carriers of 16p11.2 duplication-the largest cohort to date of uniformly and comprehensively characterized individuals with the same 16p copy number variants (CNVs)...
July 13, 2016: American Journal of Medical Genetics. Part A
Katherine D Blizinsky, Blanca Diaz-Castro, Marc P Forrest, Britta Schürmann, Anthony P Bach, Maria Dolores Martin-de-Saavedra, Lei Wang, John G Csernansky, Jubao Duan, Peter Penzes
The architecture of dendritic arbors contributes to neuronal connectivity in the brain. Conversely, abnormalities in dendrites have been reported in multiple mental disorders and are thought to contribute to pathogenesis. Rare copy number variations (CNVs) are genetic alterations that are associated with a wide range of mental disorders and are highly penetrant. The 16p11.2 microduplication is one of the CNVs most strongly associated with schizophrenia and autism, spanning multiple genes possibly involved in synaptic neurotransmission...
July 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
Aaron M Schuh, Jacob D Taylor, Esperanza E Font-Montgomery, Aneesh K Tosh
A 17-year-old mixed race male has been followed in our adolescent clinic for severe obesity, dysmorphic features, and behavioral issues. Among other interventions, he has received symptomatic treatment for hypertension, insulin resistance, and attention deficit hyperactivity disorder. Genetic investigation identified a 16p11.2 microdeletion, commonly associated with severe obesity and developmental delay. We present the clinical history, treatment, and implications for this patient.
July 9, 2016: International Journal of Adolescent Medicine and Health
Rayapadi G Swetha, Sudha Ramaiah, Anand Anbarasu
FUS (fused in sarcoma) gene encodes the RNA binding protein FUS. This gene is mapped to chromosome 16p11.2. The FUS protein binds with Karyopherineβ2 (Kapβ2) through its proline/tyrosine-nuclear localization signal (PY-NLS) that helps in the localization of FUS protein within the nucleus. Arginine residue in 521 position (R521) of PY-NLS plays a vital role in the binding of FUS protein with Kapβ2. Mutations in this position (R521C and R521H) are the most predominant mutations associated with Amyotrophic lateral sclerosis (ALS)...
July 5, 2016: Journal of Biomolecular Structure & Dynamics
Jocelyn J LeBlanc, Charles A Nelson
BACKGROUND: Duplication and deletion of the chromosomal region 16p11.2 cause a broad range of impairments, including intellectual disability, language disorders, and sensory symptoms. However, it is unclear how changes in 16p11.2 dosage affect cortical circuitry during development. The aim of this study was to investigate whether the visual evoked potential (VEP) could be used as a noninvasive quantitative measure of cortical processing in children with 16p11.2 copy number variation. METHODS: Pattern-reversal VEPs were successfully recorded in 19 deletion carriers, 9 duplication carriers, and 13 typically developing children between the ages of 3 and 14 years...
2016: Molecular Autism
Malgorzata I Srebniak, Laura J C M van Zutven, Florence Petit, Sonia Bouquillon, Ilse P J van Heel, Maarten F C M Knapen, Jerome M J Cornette, Andreas Kremer, Diane Van Opstal, Karin E M Diderich
BACKGROUND: Chromosome 6q duplication syndrome is a chromosome abnormality associated with characteristic phenotypic features such as intellectual disability (ID), short stature, feeding difficulties, microcephaly, dysmorphic features (prominent forehead, downslanting palpebral fissures, flat nasal bridge, tented upper lip, micrognathia, short webbed neck) and joint contractures. Only a few cases of pure partial 6q trisomy have been published and the severity of the phenotype seems to depend on the breakpoint position...
2016: Molecular Cytogenetics
J Chen, V D Calhoun, N I Perrone-Bizzozero, G D Pearlson, J Sui, Y Du, J Liu
Schizophrenia (SZ) and bipolar disorder (BD) are known to share genetic risks. In this work, we conducted whole-genome scanning to identify cross-disorder and disorder-specific copy number variants (CNVs) for these two disorders. The Database of Genotypes and Phenotypes (dbGaP) data were used for discovery, deriving from 2416 SZ patients, 592 BD patients and 2393 controls of European Ancestry, as well as 998 SZ patients, 121 BD patients and 822 controls of African Ancestry. PennCNV and Birdsuite detected high-confidence CNVs that were aggregated into CNV regions (CNVRs) and compared with the database of genomic variants for confirmation...
2016: Translational Psychiatry
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