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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
K Le Guennec, O Quenez, G Nicolas, D Wallon, S Rousseau, A-C Richard, J Alexander, P Paschou, C Charbonnier, C Bellenguez, B Grenier-Boley, D Lechner, M-T Bihoreau, R Olaso, A Boland, V Meyer, J-F Deleuze, P Amouyel, H M Munter, G Bourque, M Lathrop, T Frebourg, R Redon, L Letenneur, J-F Dartigues, O Martinaud, O Kalev, S Mehrabian, L Traykov, T Ströbel, I Le Ber, P Caroppo, S Epelbaum, T Jonveaux, F Pasquier, A Rollin-Sillaire, E Génin, L Guyant-Maréchal, G G Kovacs, J-C Lambert, D Hannequin, D Campion, A Rovelet-Lecrux
To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers...
December 13, 2016: Molecular Psychiatry
Claudia Ciaccio, Chiara Dordoni, Marco Ritelli, Marina Colombi
Koolen-de Vries syndrome (KdS) is a rare genetic condition characterized by typical facial dysmorphisms, cardiac and renal defects, skeletal anomalies, developmental delay, and intellectual disability of variable level. It is caused by a 440-680-kb deletion in the 17q21.31 region, encompassing CRHR1, MAPT, IMP5, STH, and KANSL1, or by an intragenic KANSL1 mutation. The majority of the patients reported are pediatric or young adults, and long-term studies able to define the prognosis of the disease are lacking...
2016: Cytogenetic and Genome Research
Marcella Zollino, Giuseppe Marangi, Emanuela Ponzi, Daniela Orteschi, Stefania Ricciardi, Serena Lattante, Marina Murdolo, Domenica Battaglia, Ilaria Contaldo, Eugenio Mercuri, Maria Chiara Stefanini, Roseline Caumes, Patrick Edery, Massimiliano Rossi, Maria Piccione, Giovanni Corsello, Matteo Della Monica, Francesca Scarano, Manuela Priolo, Mattia Gentile, Giuseppe Zampino, Raymon Vijzelaar, Omar Abdulrahman, Anita Rauch, Beatrice Oneda, Matthew A Deardorff, Sulagna C Saitta, Marni J Falk, Holly Dubbs, Elaine Zackai
BACKGROUND: The 17q21.31 deletion syndrome phenotype can be caused by either chromosome deletions or point mutations in the KANSL1 gene. To date, about 60 subjects with chromosome deletion and 4 subjects with point mutation in KANSL1 have been reported. Prevalence of chromosome deletions compared with point mutations, genotype-phenotype correlations and phenotypic variability have yet to be fully clarified. METHODS: We report genotype-phenotype correlations in 27 novel subjects with 17q21...
December 2015: Journal of Medical Genetics
Louise V Wain, Nick Shrine, Suzanne Miller, Victoria E Jackson, Ioanna Ntalla, María Soler Artigas, Charlotte K Billington, Abdul Kader Kheirallah, Richard Allen, James P Cook, Kelly Probert, Ma'en Obeidat, Yohan Bossé, Ke Hao, Dirkje S Postma, Peter D Paré, Adaikalavan Ramasamy, Reedik Mägi, Evelin Mihailov, Eva Reinmaa, Erik Melén, Jared O'Connell, Eleni Frangou, Olivier Delaneau, Colin Freeman, Desislava Petkova, Mark McCarthy, Ian Sayers, Panos Deloukas, Richard Hubbard, Ian Pavord, Anna L Hansell, Neil C Thomson, Eleftheria Zeggini, Andrew P Morris, Jonathan Marchini, David P Strachan, Martin D Tobin, Ian P Hall
BACKGROUND: Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health. METHODS: We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers...
October 2015: Lancet Respiratory Medicine
David A Koolen, Rolph Pfundt, Katrin Linda, Gea Beunders, Hermine E Veenstra-Knol, Jessie H Conta, Ana Maria Fortuna, Gabriele Gillessen-Kaesbach, Sarah Dugan, Sara Halbach, Omar A Abdul-Rahman, Heather M Winesett, Wendy K Chung, Marguerite Dalton, Petia S Dimova, Teresa Mattina, Katrina Prescott, Hui Z Zhang, Howard M Saal, Jayne Y Hehir-Kwa, Marjolein H Willemsen, Charlotte W Ockeloen, Marjolijn C Jongmans, Nathalie Van der Aa, Pinella Failla, Concetta Barone, Emanuela Avola, Alice S Brooks, Sarina G Kant, Erica H Gerkes, Helen V Firth, Katrin Õunap, Lynne M Bird, Diane Masser-Frye, Jennifer R Friedman, Modupe A Sokunbi, Abhijit Dixit, Miranda Splitt, Mary K Kukolich, Julie McGaughran, Bradley P Coe, Jesús Flórez, Nael Nadif Kasri, Han G Brunner, Elizabeth M Thompson, Jozef Gecz, Corrado Romano, Evan E Eichler, Bert B A de Vries
The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies...
May 2016: European Journal of Human Genetics: EJHG
María Moreno-Igoa, Blanca Hernández-Charro, Amaya Bengoa-Alonso, Aranzazu Pérez-Juana-del-Casal, Carlos Romero-Ibarra, Beatriz Nieva-Echebarria, María Antonia Ramos-Arroyo
BACKGROUND: Chromosome 17q21.31 microdeletion syndrome is a multisystem genomic disorder caused by a recurrent 600-kb-long deletion, or haploinsufficiency of the chromatin modifier gene KANSL1, which maps to that region. Patients with KANSL1 intragenic mutations have been reported to display the major clinical features of 17q21.31 microdeletion syndrome. However, they did not exhibit the full clinical spectrum of this disorder, which might indicate that an additional gene or genes, located in the 17q21...
2015: BMC Medical Genetics
Sylvain Meunier, Maria Shvedunova, Nhuong Van Nguyen, Leonor Avila, Isabelle Vernos, Asifa Akhtar
The evolutionary conserved NSL complex is a prominent epigenetic regulator controlling expression of thousands of genes. Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. Moreover, we identify KANSL3 as a microtubule minus-end-binding protein, revealing a new class of mitosis-specific microtubule minus-end regulators...
2015: Nature Communications
Ioannis Panagopoulos, Ludmila Gorunova, Bodil Bjerkehagen, Sverre Heim
Retroperitoneal leiomyoma is a rare benign smooth muscle tumor almost exclusively found in women and with histopathological features similar to uterine leiomyomas. The pathogenesis of retroperitoneal leiomyoma is unclear and next to nothing is known about the cytogenetics and molecular genetics of the tumor. We present here a retroperitoneal leiomyoma with a t(9;22)(q33;q12) as the sole karyotypic aberration. The translocation resulted in an EWSR1-PBX3 fusion gene in which exon 9 of EWSR1 (nucleotide 1320 accession number NM_013986 version 3) was in-frame fused to exon 5 of PBX3 (nucleotide 824 accession number NM_006195 version 5)...
2015: PloS One
G Jun, C A Ibrahim-Verbaas, M Vronskaya, J-C Lambert, J Chung, A C Naj, B W Kunkle, L-S Wang, J C Bis, C Bellenguez, D Harold, K L Lunetta, A L Destefano, B Grenier-Boley, R Sims, G W Beecham, A V Smith, V Chouraki, K L Hamilton-Nelson, M A Ikram, N Fievet, N Denning, E R Martin, H Schmidt, Y Kamatani, M L Dunstan, O Valladares, A R Laza, D Zelenika, A Ramirez, T M Foroud, S-H Choi, A Boland, T Becker, W A Kukull, S J van der Lee, F Pasquier, C Cruchaga, D Beekly, A L Fitzpatrick, O Hanon, M Gill, R Barber, V Gudnason, D Campion, S Love, D A Bennett, N Amin, C Berr, Magda Tsolaki, J D Buxbaum, O L Lopez, V Deramecourt, N C Fox, L B Cantwell, L Tárraga, C Dufouil, J Hardy, P K Crane, G Eiriksdottir, D Hannequin, R Clarke, D Evans, T H Mosley, L Letenneur, C Brayne, W Maier, P De Jager, V Emilsson, J-F Dartigues, H Hampel, M I Kamboh, R F A G de Bruijn, C Tzourio, P Pastor, E B Larson, J I Rotter, M C O'Donovan, T J Montine, M A Nalls, S Mead, E M Reiman, P V Jonsson, C Holmes, P H St George-Hyslop, M Boada, P Passmore, J R Wendland, R Schmidt, K Morgan, A R Winslow, J F Powell, M Carasquillo, S G Younkin, J Jakobsdóttir, J S K Kauwe, K C Wilhelmsen, D Rujescu, M M Nöthen, A Hofman, L Jones, J L Haines, B M Psaty, C Van Broeckhoven, P Holmans, L J Launer, R Mayeux, M Lathrop, A M Goate, V Escott-Price, S Seshadri, M A Pericak-Vance, P Amouyel, J Williams, C M van Duijn, G D Schellenberg, L A Farrer
APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls)...
January 2016: Molecular Psychiatry
Ioannis Panagopoulos, Ludmila Gorunova, Bodil Bjerkehagen, Sverre Heim
Retroperitoneal leiomyoma is a rare type of benign smooth muscle tumor almost exclusively found in women and with histopathological features similar to uterine leiomyomas. The pathogenesis of retroperitoneal leiomyoma is unclear and next to nothing is known about the cytogenetics and molecular genetics of the tumor. Here we present the first cytogenetically analyzed retroperitoneal leiomyoma. It had a t(10;17)(q22;q21) as the sole chromosomal abnormality. Using RNA-Sequencing and the 'grep' command to search the fastq files of the sequence data we found that the translocation resulted in fusion of the genes KAT6B (10q22) with KANSL1 (17q21)...
2015: PloS One
Jorge Dias, Nhuong Van Nguyen, Plamen Georgiev, Aline Gaub, Janine Brettschneider, Stephen Cusack, Jan Kadlec, Asifa Akhtar
The subunits of the nonspecific lethal (NSL) complex, which include the histone acetyltransferase MOF (males absent on the first), play important roles in various cellular functions, including transcription regulation and stem cell identity maintenance and reprogramming, and are frequently misregulated in disease. Here, we provide the first biochemical and structural insights into the molecular architecture of this large multiprotein assembly. We identified several direct interactions within the complex and show that KANSL1 acts as a scaffold protein interacting with four other subunits, including WDR5, which in turn binds KANSL2...
May 1, 2014: Genes & Development
Wen-Hann Tan, Lynne M Bird, Ronald L Thibert, Charles A Williams
Angelman syndrome (AS) is caused by a lack of expression of the maternally inherited UBE3A gene in the brain. However, about 10% of individuals with a clinical diagnosis of AS do not have an identifiable molecular defect. It is likely that most of those individuals have an AS-like syndrome that is clinically and molecularly distinct from AS. These AS-like syndromes can be broadly classified into chromosomal microdeletion and microduplication syndromes, and single-gene disorders. The microdeletion/microduplication syndromes are now easily identified by chromosomal microarray analysis and include Phelan–McDermid syndrome (chromosome 22q13...
April 2014: American Journal of Medical Genetics. Part A
Adrian Mc Cormack, Juliet Taylor, Leah Te Weehi, Donald R Love, Alice M George
Concurrent cryptic microdeletion and microduplication syndromes have recently started to reveal themselves with the advent of microarray technology. Analysis has shown that low-copy repeats (LCRs) have allowed chromosome regions throughout the genome to become hotspots for nonallelic homologous recombination to take place. Here, we report a case of a 7.5-year-old girl who manifests microcephaly, developmental delay, and mild dysmorphic features. Microarray analysis identified a microduplication in chromosome 17q21...
2014: Case Reports in Genetics
Kenichi Yoshida, Tsutomu Toki, Yusuke Okuno, Rika Kanezaki, Yuichi Shiraishi, Aiko Sato-Otsubo, Masashi Sanada, Myoung-ja Park, Kiminori Terui, Hiromichi Suzuki, Ayana Kon, Yasunobu Nagata, Yusuke Sato, RuNan Wang, Norio Shiba, Kenichi Chiba, Hiroko Tanaka, Asahito Hama, Hideki Muramatsu, Daisuke Hasegawa, Kazuhiro Nakamura, Hirokazu Kanegane, Keiko Tsukamoto, Souichi Adachi, Kiyoshi Kawakami, Koji Kato, Ryosei Nishimura, Shai Izraeli, Yasuhide Hayashi, Satoru Miyano, Seiji Kojima, Etsuro Ito, Seishi Ogawa
Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples...
November 2013: Nature Genetics
Karyn Meltz Steinberg, Francesca Antonacci, Peter H Sudmant, Jeffrey M Kidd, Catarina D Campbell, Laura Vives, Maika Malig, Laura Scheinfeldt, William Beggs, Muntaser Ibrahim, Godfrey Lema, Thomas B Nyambo, Sabah A Omar, Jean-Marie Bodo, Alain Froment, Michael P Donnelly, Kenneth K Kidd, Sarah A Tishkoff, Evan E Eichler
The 17q21.31 inversion polymorphism exists either as direct (H1) or inverted (H2) haplotypes with differential predispositions to disease and selection. We investigated its genetic diversity in 2,700 individuals, with an emphasis on African populations. We characterize eight structural haplotypes due to complex rearrangements that vary in size from 1.08-1.49 Mb and provide evidence for a 30-kb H1-H2 double recombination event. We show that recurrent partial duplications of the KANSL1 gene have occurred on both the H1 and H2 haplotypes and have risen to high frequency in European populations...
July 1, 2012: Nature Genetics
Linda M Boettger, Robert E Handsaker, Michael C Zody, Steven A McCarroll
Structurally complex genomic regions are not yet well understood. One such locus, human chromosome 17q21.31, contains a megabase-long inversion polymorphism, many uncharacterized copy-number variations (CNVs) and markers that associate with female fertility, female meiotic recombination and neurological disease. Additionally, the inverted H2 form of 17q21.31 seems to be positively selected in Europeans. We developed a population genetics approach to analyze complex genome structures and identified nine segregating structural forms of 17q21...
August 2012: Nature Genetics
Marcella Zollino, Daniela Orteschi, Marina Murdolo, Serena Lattante, Domenica Battaglia, Chiara Stefanini, Eugenio Mercuri, Pietro Chiurazzi, Giovanni Neri, Giuseppe Marangi
The chromosome 17q21.31 deletion syndrome is a genomic disorder characterized by highly distinctive facial features, moderate-to-severe intellectual disability, hypotonia and friendly behavior. Here, we show that de novo loss-of-function mutations in KANSL1 (also called KIAA1267) cause a full del(17q21.31) phenotype in two unrelated individuals that lack deletion at 17q21.31. These findings indicate that 17q21.31 deletion syndrome is a monogenic disorder caused by haploinsufficiency of KANSL1.
June 2012: Nature Genetics
David A Koolen, Jamie M Kramer, Kornelia Neveling, Willy M Nillesen, Heather L Moore-Barton, Frances V Elmslie, Annick Toutain, Jeanne Amiel, Valérie Malan, Anne Chun-Hui Tsai, Sau Wai Cheung, Christian Gilissen, Eugene T P Verwiel, Sarah Martens, Ton Feuth, Ernie M H F Bongers, Petra de Vries, Hans Scheffer, Lisenka E L M Vissers, Arjan P M de Brouwer, Han G Brunner, Joris A Veltman, Annette Schenck, Helger G Yntema, Bert B A de Vries
We show that haploinsufficiency of KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome, a multisystem disorder characterized by intellectual disability, hypotonia and distinctive facial features. The KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16 (H4K16) acetylation. RNA sequencing studies in cell lines derived from affected individuals and the presence of learning deficits in Drosophila melanogaster mutants suggest a role for KANSL1 in neuronal processes...
June 2012: Nature Genetics
Andy Itsara, Lisenka E L M Vissers, Karyn Meltz Steinberg, Kevin J Meyer, Michael C Zody, David A Koolen, Joep de Ligt, Edwin Cuppen, Carl Baker, Choli Lee, Tina A Graves, Richard K Wilson, Robert B Jenkins, Joris A Veltman, Evan E Eichler
Recurrent deletions have been associated with numerous diseases and genomic disorders. Few, however, have been resolved at the molecular level because their breakpoints often occur in highly copy-number-polymorphic duplicated sequences. We present an approach that uses a combination of somatic cell hybrids, array comparative genomic hybridization, and the specificity of next-generation sequencing to determine breakpoints that occur within segmental duplications. Applying our technique to the 17q21.31 microdeletion syndrome, we used genome sequencing to determine copy-number-variant breakpoints in three deletion-bearing individuals with molecular resolution...
April 6, 2012: American Journal of Human Genetics
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