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https://www.readbyqxmd.com/read/28213671/exome-analysis-of-smith-magenis-like-syndrome-cohort-identifies-de-novo-likely-pathogenic-variants
#1
Seth I Berger, Carla Ciccone, Karen L Simon, May Christine Malicdan, Thierry Vilboux, Charles Billington, Roxanne Fischer, Wendy J Introne, Andrea Gropman, Jan K Blancato, James C Mullikin, William A Gahl, Marjan Huizing, Ann C M Smith
Smith-Magenis syndrome (SMS), a neurodevelopmental disorder characterized by dysmorphic features, intellectual disability (ID), and sleep disturbances, results from a 17p11.2 microdeletion or a mutation in the RAI1 gene. We performed exome sequencing on 6 patients with SMS-like phenotypes but without chromosomal abnormalities or RAI1 variants. We identified pathogenic de novo variants in two cases, a nonsense variant in IQSEC2 and a missense variant in the SAND domain of DEAF1, and candidate de novo missense variants in an additional two cases...
February 17, 2017: Human Genetics
https://www.readbyqxmd.com/read/28211987/10-year-old-female-with-intragenic-kansl1-mutation-no-kansl1-related-intellectual-disability-and-preserved-verbal-intelligence
#2
Colleen Keen, Carole Samango-Sprouse, Holly Dubbs, Elaine H Zackai
Koolen-de Vries Syndrome (KdVS), also referred to as 17q21.31 microdeletion syndrome, is caused by haploinsufficiency of the KANSL1 gene. This genetic disorder is associated with a clinical phenotype including facial dysmorphism, developmental delay, and friendly disposition, as well as mild-to-moderate intellectual disability. We present the case of a 10 year 8 month old female with KdVS due to a de novo intragenic KANSL1 mutation. At this time, she does not present with intellectual disability, and her verbal intelligence is relatively preserved, although she has perceptual deficits, developmental dyspraxia, and severe speech disorder...
March 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28211977/1q21-3-deletion-involving-gatad2b-an-emerging-recurrent-microdeletion-syndrome
#3
Thipwimol Tim-Aroon, Natini Jinawath, Weerin Thammachote, Praweena Sinpitak, Anchalee Limrungsikul, Chaiyos Khongkhatithum, Duangrurdee Wattanasirichaigoon
GATAD2B gene is involved in chromatin modification and transcription activity. Loss-of-function mutations of GATAD2B have recently been defined to cause a recognizable syndrome with intellectual disability (ID). Human TPM3 gene encoding thin filament protein is associated with myopathies. Both genes are located on chromosome 1q21.3. We herein report an infant with feeding difficulty, developmental delay, hypotonia, and dysmorphic features including small palpebral fissures, telecanthus, sparse hair and eyebrow, cup-shaped ears, and clinodactyly...
March 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28211971/atypical-angelman-syndrome-due-to-a-mosaic-imprinting-defect-case-reports-and-review-of-the-literature
#4
Anna Le Fevre, Jasmin Beygo, Cheryl Silveira, Benjamin Kamien, Jill Clayton-Smith, Alison Colley, Karin Buiting, Tracy Dudding-Byth
Angelman syndrome (AS) is characterized by severe intellectual disability, limited, or absent speech and a generally happy demeanor. The four known etiological mechanisms; deletions, uniparental disomy, imprinting defects, and UBE3A mutation all affect expression of the UBE3A gene at 15q11-q13. An atypical phenotype is seen in individuals who are mosaic for a chromosome 15q11-q13 imprinting defect on the maternal allele. These patients present with a milder phenotype, often with hyperphagia and obesity or non-specific intellectual disability...
March 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28211887/germline-mutations-predisposing-to-diffuse-large-b-cell-lymphoma
#5
REVIEW
O C Leeksma, N F de Miranda, H Veelken
Genetic studies of diffuse large B-cell lymphomas (DLBCLs) in humans have revealed numerous targets of somatic mutations and an increasing number of potentially relevant germline alterations. The latter often affect genes involved in DNA repair and/or immune function. In general, defects in these genes also predispose to other conditions. Knowledge of these mutations can lead to disease-preventing measures in the patient and relatives thereof. Conceivably, these germline mutations will be taken into account in future therapy of the lymphoma...
February 17, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28211606/nrf2-a-novel-therapeutic-target-in-fragile-x-syndrome-is-modulated-by-nnz2566
#6
Robert M J Deacon, Michael J Hurley, Camila Martínez Rebolledo, Mike Snape, Francisco J Altimiras, Leandro Farías, Michael Pino, Rodolfo Biekofsky, Larry Glass, Patricia Cogram
Fragile X-associated disorders are a family of genetic conditions resulting from the partial or complete loss of fragile X mental retardation protein (FMRP). Among these disorders is fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism. Progress in basic neuroscience has led to identification of molecular targets for treatment in FXS; however, there is a gap in translation to targeted therapies in humans. The present study introduces a novel therapeutic target for FXS: nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor known to induce expression of over 100 cytoprotective genes...
February 17, 2017: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/28207852/tetraspanin-6-a-novel-regulator-of-hippocampal-synaptic-transmission-and-long-term-plasticity
#7
Isabel H Salas, Zsuzsanna Callaerts-Vegh, Amaia M Arranz, Francesc X Guix, Rudi D'Hooge, José A Esteban, Bart De Strooper, Carlos G Dotti
Tetraspanins (Tspan) are transmembrane proteins with important scaffold and signalling functions. Deletions of Tetraspanin 6 (Tspan6) gene, a member of the tetraspanin family, have been reported in patients with Epilepsy Female-restricted with Mental Retardation (EFMR). Interestingly, mutations in Tspan7, highly homologous to Tspan6, are associated with X-linked intellectual disability, suggesting that these two proteins are important for cognition. Considering recent evidences showing that Tspan7 plays a key role in synapse development and AMPAR trafficking, we initiated the study of Tspan6 in synaptic function using a Tspan6 knock out mouse model...
2017: PloS One
https://www.readbyqxmd.com/read/28203608/modeling-fragile-x-syndrome-in-neurogenesis-an-unexpected-phenotype-and-a-novel-tool-for-future-therapies
#8
Barbara Bardoni, Maria Capovilla, Enzo Lalli
FMRP is an RNA-binding protein involved in synaptic translation. Its absence causes a form of intellectual disability, the Fragile X syndrome (FXS). Small neuroanatomical abnormalities, present both in human and mouse FMRP-deficient brains, suggest a subtle critical role of this protein in neurogenesis. Stable depletion of FMRP has been obtained in a mouse embryonic stem cell line Fmr1 (shFmr1 ES) that does not display morphological alterations, but an abnormal expression of a subset of genes mainly involved in neuronal differentiation and maturation...
2017: Neurogenesis (Austin, Tex.)
https://www.readbyqxmd.com/read/28199897/real-world-utility-of-whole-exome-sequencing-with-targeted-gene-analysis-for-focal-epilepsy
#9
Piero Perucca, Ingrid E Scheffer, A Simon Harvey, Paul A James, Sebastian Lunke, Natalie Thorne, Clara Gaff, Brigid M Regan, John A Damiano, Michael S Hildebrand, Samuel F Berkovic, Terence J O'Brien, Patrick Kwan
OBJECTIVE: Driven by advances in genomic technology and reduction in costs, next-generation sequencing (NGS) is venturing into routine clinical care. The 'real-world' clinical utility of NGS remains to be determined in focal epilepsies, which account for 60% of all epilepsies and for which the importance of genetic factors is just beginning to emerge. We investigated the diagnostic yield and management implications of whole exome sequencing (WES)-based screening of selected genes in the routine care of common focal epilepsies suspected to have a genetic basis...
February 7, 2017: Epilepsy Research
https://www.readbyqxmd.com/read/28195318/biallelic-loss-of-function-variants-in-dock3-cause-muscle-hypotonia-ataxia-and-intellectual-disability
#10
Katherine L Helbig, Cameron Mroske, Divya Moorthy, Samin A Sajan, Milen Velinov
DOCK3 encodes the dedicator of cytokinesis 3 protein, a member of the DOCK180 family of proteins that are characterized by guanine nucleotide exchange factor activity. DOCK3 is expressed exclusively in the central nervous system and plays an important role in axonal outgrowth and cytoskeleton reorganization. Dock3 knockout mice exhibit motor deficiencies with abnormal ataxic gait and impaired learning. We report two siblings with biallelic loss-of-function variants in DOCK3. Diagnostic whole exome sequencing and chromosomal microarray were performed on a proband with severe intellectual disability, hypotonia, and ataxic gait...
February 14, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28191890/refining-the-role-of-de-novo-protein-truncating-variants-in-neurodevelopmental-disorders-by-using-population-reference-samples
#11
Jack A Kosmicki, Kaitlin E Samocha, Daniel P Howrigan, Stephan J Sanders, Kamil Slowikowski, Monkol Lek, Konrad J Karczewski, David J Cutler, Bernie Devlin, Kathryn Roeder, Joseph D Buxbaum, Benjamin M Neale, Daniel G MacArthur, Dennis P Wall, Elise B Robinson, Mark J Daly
Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9,246 families with autism spectrum disorder, intellectual disability, or developmental delay, we found that ∼1/3 of de novo variants are independently present as standing variation in the Exome Aggregation Consortium's cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further used a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes containing the observed signal of associated de novo protein-truncating variants (PTVs) in neurodevelopmental disorders...
February 13, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28191889/targeted-sequencing-identifies-91-neurodevelopmental-disorder-risk-genes-with-autism-and-developmental-disability-biases
#12
Holly A F Stessman, Bo Xiong, Bradley P Coe, Tianyun Wang, Kendra Hoekzema, Michaela Fenckova, Malin Kvarnung, Jennifer Gerdts, Sandy Trinh, Nele Cosemans, Laura Vives, Janice Lin, Tychele N Turner, Gijs Santen, Claudia Ruivenkamp, Marjolein Kriek, Arie van Haeringen, Emmelien Aten, Kathryn Friend, Jan Liebelt, Christopher Barnett, Eric Haan, Marie Shaw, Jozef Gecz, Britt-Marie Anderlid, Ann Nordgren, Anna Lindstrand, Charles Schwartz, R Frank Kooy, Geert Vandeweyer, Celine Helsmoortel, Corrado Romano, Antonino Alberti, Mirella Vinci, Emanuela Avola, Stefania Giusto, Eric Courchesne, Tiziano Pramparo, Karen Pierce, Srinivasa Nalabolu, David G Amaral, Ingrid E Scheffer, Martin B Delatycki, Paul J Lockhart, Fereydoun Hormozdiari, Benjamin Harich, Anna Castells-Nobau, Kun Xia, Hilde Peeters, Magnus Nordenskjöld, Annette Schenck, Raphael A Bernier, Evan E Eichler
Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100)...
February 13, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28183735/new-insights-into-the-regulatory-function-of-cyfip1-in-the-context-of-wave-and-fmrp-containing-complexes
#13
Sabiha Abekhoukh, H Bahar Sahin, Mauro Grossi, Samantha Zongaro, Thomas Maurin, Irene Madrigal, Daniele Kazue-Sugioka, Annick Raas-Rothschild, Mohamed Doulazmi, Pilar Carrera, Andrea Stachon, Steven Scherer, Maria Rita Drula Do Nascimento, Alain Trembleau, Ignacio Arroyo, Szatmari Peter, Isabel M Smith, Montserrat Milà, Adam C Smith, Angela Giangrande, Isabelle Caillé, Barbara Bardoni
CYtoplasmic FMRP Interacting Protein 1 (CYFIP1) is a candidate gene for intellectual disability (ID), autism, schizophrenia and epilepsy. It is a member of a family of proteins that is very conserved during evolution, sharing high homology with dCYFIP, its Drosophila homolog. CYFIP1 interacts with the Fragile X Mental Retardation Protein (FMRP), whose absence causes the Fragile X Syndrome, and with the translation initiation factor eIF4E. It is a member of the WAVE Regulatory Complex (WRC), thus representing a link between translational regulation and actin cytoskeleton...
February 9, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28182669/a-de-novo-loss-of-function-grin2a-mutation-associated-with-childhood-focal-epilepsy-and-acquired-epileptic-aphasia
#14
Kai Gao, Anel Tankovic, Yujia Zhang, Hirofumi Kusumoto, Jin Zhang, Wenjuan Chen, Wenshu XiangWei, Gil H Shaulsky, Chun Hu, Stephen F Traynelis, Hongjie Yuan, Yuwu Jiang
OBJECTIVE: N-methyl-D-aspartate receptors (NMDAR) subunit GRIN2A/GluN2A mutations have been identified in patients with various neurological diseases, such as epilepsy and intellectual disability / developmental delay (ID/DD). In this study, we investigated the phenotype and underlying molecular mechanism of a GRIN2A missense mutation identified by next generation sequencing on idiopathic focal epilepsy using in vitro electrophysiology. METHODS: Genomic DNA of patients with epilepsy and ID/DD were sequenced by targeted next-generation sequencing within 300 genes related to epilepsy and ID/DD...
2017: PloS One
https://www.readbyqxmd.com/read/28181389/novel-lins1-missense-mutation-in-a-family-with-non-syndromic-intellectual-disability
#15
Jayesh Sheth, Gyan Ranjan, Krati Shah, Riddhi Bhavsar, Frenny Sheth
Newer sequencing technologies decipher molecular variations and increase the knowledge of pathogenesis of complex diseases like intellectual disability (ID), affecting 2-3% of the population. We report a novel family with a missense mutation in LINS1 as a cause for non-syndromic ID. Clinical exome sequencing for ID related genes carried out for a male with dysmorphism, mutism, and cognitive delay was uninformative. Subsequently, "pathogenic" and "likely pathogenic" variants associated with other inherited disorders were searched for as secondary findings...
February 9, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28180184/a-gain-of-function-mutation-in-the-grik2-gene-causes-neurodevelopmental-deficits
#16
Yomayra F Guzmán, Keri Ramsey, Jacob R Stolz, David W Craig, Mathew J Huentelman, Vinodh Narayanan, Geoffrey T Swanson
OBJECTIVE: To identify inherited or de novo mutations associated with a suite of neurodevelopmental abnormalities in a 10-year-old patient displaying ataxia, motor and speech delay, and intellectual disability. METHODS: We performed whole-exome sequencing of the proband and her parents. A pathogenic gene variant was identified as damaging based on sequence conservation, gene function, and association with disorders having similar phenotypic profiles. Functional characterization of the mutated protein was performed in vitro using a heterologous expression system...
February 2017: Neurology. Genetics
https://www.readbyqxmd.com/read/28180026/chromosomal-microarrays-understanding-genetics-of-neurodevelopmental-disorders-and-congenital-anomalies
#17
REVIEW
Jill A Rosenfeld, Ankita Patel
Chromosomal microarray (CMA) testing, used to identify DNA copy number variations (CNVs), has helped advance knowledge about genetics of human neurodevelopmental disease and congenital anomalies. It has aided in discovering new CNV syndromes and uncovering disease genes. It has discovered CNVs that are not fully penetrant and/or cause a spectrum of phenotypes, including intellectual disability, autism, schizophrenia, and dysmorphisms. Such CNVs can pose challenges to genetic counseling. They also have helped increase knowledge of genetic risk factors for neurodevelopmental disease and raised awareness of possible shared etiologies among these variable phenotypes...
March 2017: Journal of Pediatric Genetics
https://www.readbyqxmd.com/read/28180024/ciliopathies-genetics-in-pediatric-medicine
#18
REVIEW
Machteld M Oud, Ideke J C Lamers, Heleen H Arts
Ciliary disorders, which are also referred to as ciliopathies, are a group of hereditary disorders that result from dysfunctional cilia. The latter are cellular organelles that stick up from the apical plasma membrane. Cilia have important roles in signal transduction and facilitate communications between cells and their surroundings. Ciliary disruption can result in a wide variety of clinically and genetically heterogeneous disorders with overlapping phenotypes. Because cilia occur widespread in our bodies many organs and sensory systems can be affected when they are dysfunctional...
March 2017: Journal of Pediatric Genetics
https://www.readbyqxmd.com/read/28176767/intragenic-fmr1-disease-causing-variants-a-significant-mutational-mechanism-leading-to-fragile-x-syndrome
#19
Angélique Quartier, Hélène Poquet, Brigitte Gilbert-Dussardier, Massimiliano Rossi, Anne-Sophie Casteleyn, Vincent des Portes, Claire Feger, Elsa Nourisson, Paul Kuentz, Claire Redin, Julien Thevenon, Anne-Laure Mosca-Boidron, Patrick Callier, Jean Muller, Gaetan Lesca, Frédéric Huet, Véronique Geoffroy, Salima El Chehadeh, Matthieu Jung, Benoit Trojak, Stéphanie Le Gras, Daphné Lehalle, Bernard Jost, Stéphanie Maury, Alice Masurel, Patrick Edery, Christel Thauvin-Robinet, Bénédicte Gérard, Jean-Louis Mandel, Laurence Faivre, Amélie Piton
Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5'-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c...
February 8, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28173649/-a-novel-mutation-in-kcnb1-gene-in-a-child-with-neuropsychiatric-comorbidities-with-both-intellectual-disability-and-epilepsy-and-review-of-literature
#20
P Miao, J Peng, C Chen, N Gai, F Yin
Objective: To explore the association between the phenotype and KCNB1 gene mutation. Method: Clinical information including physical features, laboratory and genetic data of one patient of mental retardation with refractory epilepsy from Department of Pediatrics, Xiangya Hospital in January 2016 was analyzed. This patient was discovered to have KCNB1 gene mutations through whole exome sequencing. Relevant information about KCNB1 gene mutation was searched and collected from Pubmed, CNKI, Human Gene Mutation Database(HGMD) and Online Mendelian Inheritance in Man(OMIM)...
February 2, 2017: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
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