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Hobia Gole, Raymond Chuk, David Coman
Kabuki syndrome is a clinically and genetically heterogeneous congenital malformation syndrome with protean clinical manifestations. This reflects the important epigenetic role in embryonic development of the two genes currently known to be associated with Kabuki syndrome i.e., KMT2D and KDM6A, which are responsible for Kabuki syndrome 1 and Kabuki syndrome 2, respectively. Hypoglycemia is thought to be a rare manifestation of Kabuki syndrome; however it may be under diagnosed. Herein we describe the case of a 5-year-old girl with Kabuki syndrome 2 in whom persistent hyperinsulinism was diagnosed at 4 years of age...
August 8, 2016: Clinics and Practice
Joshua J Meeks, Benedito A Carneiro, Sachin G Pai, Daniel T Oberlin, Alfred Rademaker, Kyle Fedorchak, Sohail Balasubramanian, Julia Elvin, Nike Beaubier, Francis J Giles
The genetic mechanisms associated with progression of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have not been described. We conducted selective next-generation sequencing (NGS) of HR-NMIBC and compared the genomic profiles of cancers that responded to intravesical therapy and those that progressed to muscle-invasive or advanced disease. DNA was extracted from paraffin-embedded sections from 25 HR-NMIBCs (22 with T1HG; 3 with TaHG with or without carcinoma in situ). Ten patients with HR-NMIBC developed progression (pT2+ or N+) ("progressors")...
October 14, 2016: Oncotarget
Linda M Slot, Robbert Hoogeboom, Laura A Smit, Thera A M Wormhoudt, Bart J Biemond, Monique E C M Oud, Esther J M Schilder-Tol, André B Mulder, Aldo Jongejan, Antoine H C van Kampen, Philip M Kluin, Jeroen E J Guikema, Richard J Bende, Carel J M van Noesel
Follicular lymphoma (FL) is an indolent B-cell non-Hodgkin lymphoma able to transform into germinal center-type diffuse large B-cell lymphoma. We describe four extraordinary cases of FL, which progressed to TdT(+)CD20(-) precursor B-lymphoblastic lymphoma (B-LBL). Fluorescence in situ hybridization analysis showed that all four B-LBLs had acquired a MYC translocation on transformation. Comparative genomic hybridization analysis of one case demonstrated that in addition to 26 numerical aberrations that were shared between the FL and B-LBL, deletion of CDKN2A/B and 17q11, 14q32 amplification, and copy-neutral loss of heterozygosity of 9p were gained in the B-LBL cells...
October 14, 2016: American Journal of Pathology
Jia-Jie Hao, De-Chen Lin, Huy Q Dinh, Anand Mayakonda, Yan-Yi Jiang, Chen Chang, Ye Jiang, Chen-Chen Lu, Zhi-Zhou Shi, Xin Xu, Yu Zhang, Yan Cai, Jin-Wu Wang, Qi-Min Zhan, Wen-Qiang Wei, Benjamin P Berman, Ming-Rong Wang, H Phillip Koeffler
Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about its spatial intratumoral heterogeneity (ITH) and temporal clonal evolutionary processes. To address this, we performed multiregion whole-exome sequencing on 51 tumor regions from 13 ESCC cases and multiregion global methylation profiling for 3 of these 13 cases. We found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. Half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and MTOR, among others...
October 17, 2016: Nature Genetics
Seungkyu Choi, Jai Hyang Go, Eun Kyung Kim, Hojung Lee, Won Mi Lee, Chun-Sung Cho, Kyudong Han
Extranodal natural killer (NK)/T-cell lymphoma, nasal type (NKTCL), is a malignant disorder of cytotoxic lymphocytes of NK or T cells. It is an aggressive neoplasm with a very poor prognosis. Although extranodal NKTCL reportedly has a strong association with Epstein-Barr virus, the molecular pathogenesis of NKTCL has been unexplored. The recent technological advancements in next-generation sequencing (NGS) have made DNA sequencing cost- and time-effective, with more reliable results. Using the Ion Proton Comprehensive Cancer Panel, we sequenced 409 cancer-related genes to identify somatic mutations in five NKTCL tissue samples...
September 2016: Genomics & Informatics
Delphine Albrecht, Johanna Ceschin, Jim Dompierre, Florian Gueniot, Benoît Pinson, Bertrand Daignan-Fornier
Identifying synthetic lethal interactions has emerged as a promising new therapeutic approach aimed at targeting cancer cells directly. Here, we used the yeast Saccharomyces cerevisiae as a simple eukaryotic model to screen for mutations resulting in a synthetic lethality with 5-Amino-4-Imidazole CarboxAmide Ribonucleoside (AICAR) treatment. Indeed, AICAR has been reported to inhibit the proliferation of multiple cancer cell lines. Here, we found that loss of several histone-modifying enzymes, including Bre1 (histone H2B ubiquitination) and Set1 (histone H3 lysine 4 methylation), greatly enhanced AICAR inhibition on growth via combined-effects of both the drug and the mutations on G1 cyclins...
October 5, 2016: Genetics
M Phan, F Conte, K D Khandelwal, C W Ockeloen, T Bartzela, T Kleefstra, H van Bokhoven, M Rubini, H Zhou, C E L Carels
Tooth agenesis and orofacial clefts represent the most common developmental anomalies and their co-occurrence is often reported in patients as well in animal models. The aim of the present systematic review is to thoroughly investigate the current literature (PubMed, EMBASE) to identify the genes and genomic loci contributing to syndromic or non-syndromic co-occurrence of tooth agenesis and orofacial clefts, to gain insight into the molecular mechanisms underlying their dual involvement in the development of teeth and facial primordia...
December 2016: Human Genetics
Chaochen Wang, Ji-Eun Lee, Binbin Lai, Todd S Macfarlan, Shiliyang Xu, Lenan Zhuang, Chengyu Liu, Weiqun Peng, Kai Ge
Transcriptional enhancers control cell-type-specific gene expression. Primed enhancers are marked by histone H3 lysine 4 (H3K4) mono/di-methylation (H3K4me1/2). Active enhancers are further marked by H3K27 acetylation (H3K27ac). Mixed-lineage leukemia 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase with functional redundancy with MLL3 (KMT2C). However, its role in cell fate maintenance and transition is poorly understood. Here, we show in mouse embryonic stem cells (ESCs) that MLL4 associates with, but is surprisingly dispensable for the maintenance of, active enhancers of cell-identity genes...
October 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
Francisco Martínez, Alfonso Caro-Llopis, Mónica Roselló, Silvestre Oltra, Sonia Mayo, Sandra Monfort, Carmen Orellana
BACKGROUND: Intellectual disability is a very complex condition where more than 600 genes have been reported. Due to this extraordinary heterogeneity, a large proportion of patients remain without a specific diagnosis and genetic counselling. The need for new methodological strategies in order to detect a greater number of mutations in multiple genes is therefore crucial. METHODS: In this work, we screened a large panel of 1256 genes (646 pathogenic, 610 candidate) by next-generation sequencing to determine the molecular aetiology of syndromic intellectual disability...
September 12, 2016: Journal of Medical Genetics
Jun Lu, Guiling Mo, Yaojun Ling, Lijuan Ji
Kabuki syndrome (KS) is a rare genetic syndrome characterized by multiple congenital anomalies and varying degrees of mental retardation. Patients with KS often present with facial, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies and immunological defects. Mutation of the lysine methyltransferase 2D (KMT2D) gene (formerly known as MLL2) is the primary cause of KS. The present study reported the case of a 4‑year‑old Chinese girl who presented with atypical KS, including atypical facial features, unclear speech and suspected mental retardation...
October 2016: Molecular Medicine Reports
Ashleigh Long, Elena S Sinkovskaya, Andrew C Edmondson, Elaine Zackai, Samantha A Schrier Vergano
Kabuki syndrome (MIM 147920) is a well-described, multiple congenital anomaly syndrome characterized by growth and developmental delay, cardiac, renal, and vertebral anomalies, as well as persistent fetal finger pads and distinct facial features. Facies are characterized by long palpebral fissures with eversion of lateral third of the lower eyelid, resembling the "Kabuki make-up" theatre genre after which the syndrome is named. Kabuki syndrome is estimated to affect 1/32,000 births, with 55-80% of patients showing nonsense or frameshift mutations in the KMT2D (MLL2) gene, which encodes a histone transferase located on chromosome 12q...
August 29, 2016: American Journal of Medical Genetics. Part A
Patricia Johansson, Ludger Klein-Hitpass, Florian Grabellus, Georg Arnold, Wolfram Klapper, Roman Pförtner, Ulrich Dührsen, Anja Eckstein, Jan Dürig, Ralf Küppers
The pathogenesis of ocular adnexal marginal zone lymphomas of mucosa-associated lymphatic tissue-type (OAML) is still poorly understood. We analyzed 63 cases of such lymphomas for non-synonymous mutations in 24 candidate genes by amplicon sequencing. We validated frequent mutations in the NF-κB regulators MYD88, TNFAIP3 and TNIP1 in OAML, but also identified recurrent mutations in several additional components of the NF-κB pathway, including BCL10 and NFKBIA. Overall, 60% of cases had mutations in at least one component of NF-κB signaling, pointing to a central role of its genetic deregulation in OAML pathogenesis...
August 23, 2016: Oncotarget
G Bademci, F B Cengiz, J Foster Ii, D Duman, L Sennaroglu, O Diaz-Horta, T Atik, T Kirazli, L Olgun, H Alper, I Menendez, I Loclar, G Sennaroglu, S Tokgoz-Yilmaz, S Guo, Y Olgun, N Mahdieh, M Bonyadi, N Bozan, A Ayral, F Ozkinay, M Yildirim-Baylan, S H Blanton, M Tekin
The genetics of both syndromic (SHL) and non-syndromic hearing loss (NSHL) is characterized by a high degree of genetic heterogeneity. We analyzed whole exome sequencing data of 102 unrelated probands with apparently NSHL without a causative variant in known NSHL genes. We detected five causative variants in different SHL genes (SOX10, MITF, PTPN11, CHD7, and KMT2D) in five (4.9%) probands. Clinical re-evaluation of these probands shows that some of them have subtle syndromic findings, while none of them meets clinical criteria for the diagnosis of the associated syndrome (Waardenburg (SOX10 and MITF), Kallmann (CHD7 and SOX10), Noonan/LEOPARD (PTPN11), CHARGE (CHD7), or Kabuki (KMT2D)...
2016: Scientific Reports
Nina Bögershausen, Umut Altunoglu, Filippo Beleggia, Gökhan Yigit, Hülya Kayserili, Peter Nürnberg, Yun Li, Janine Altmüller, Bernd Wollnik
Kabuki syndrome (KS) is a rare developmental disorder characterized by multiple congenital malformations, postnatal growth retardation, intellectual disability, and recognizable facial features. It is mainly caused by mutations in either KMT2D or KDM6A. We describe a 14-year-old boy with KS presenting with an unusual combination of bilateral microphthalmia with orbital cystic venous lymphatic malformation and neonatal cholestasis with bile duct paucity, in addition to the typical clinical features of KS. We identified the novel KMT2D mutation c...
August 17, 2016: American Journal of Medical Genetics. Part A
Dina A Schott, Marinus J Blok, Willem J M Gerver, Koenraad Devriendt, Luc J I Zimmermann, Constance T R M Stumpel
Kabuki syndrome is a multiple congenital malformation syndrome with a spectrum of clinical features including short stature. Since there is no growth data on Kabuki syndrome patients with a proven KMT2D gene mutation, further research on growth and growth patterns is indicated. Data for this growth study on subjects with Kabuki syndrome were collected from referring clinicians. Subjects were eligible for inclusion in the study if the following criteria were met: a genetically confirmed diagnosis of Kabuki syndrome and no current treatment with growth hormones or other drugs that could influence growth...
August 17, 2016: American Journal of Medical Genetics. Part A
A Bouska, W Zhang, Q Gong, J Iqbal, A Scuto, J Vose, M Ludvigsen, K Fu, D D Weisenburger, T C Greiner, R D Gascoyne, A Rosenwald, G Ott, E Campo, L M Rimsza, J Delabie, E S Jaffe, R M Braziel, J M Connors, C-I Wu, L M Staudt, F D'Amore, T W McKeithan, W C Chan
Follicular lymphoma (FL) is typically an indolent disease, but 30-40% of FL cases transform into an aggressive lymphoma (tFL) with a poor prognosis. To identify the genetic changes that drive this transformation, we sequenced the exomes of 12 cases with paired FL and tFL biopsies and identified 45 recurrently mutated genes in the FL-tFL data set and 39 in the tFL cases. We selected 496 genes of potential importance in transformation and sequenced them in 23 additional tFL cases. Integration of the mutation data with copy-number abnormality (CNA) data provided complementary information...
July 8, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Valeria Spina, Hossein Khiabanian, Monica Messina, Sara Monti, Luciano Cascione, Alessio Bruscaggin, Elisa Spaccarotella, Antony B Holmes, Luca Arcaini, Marco Lucioni, Fabrizio Tabbò, Sakellarios Zairis, Fary Diop, Michaela Cerri, Sabina Chiaretti, Roberto Marasca, Maurilio Ponzoni, Silvia Deaglio, Antonio Ramponi, Enrico Tiacci, Laura Pasqualucci, Marco Paulli, Brunangelo Falini, Giorgio Inghirami, Francesco Bertoni, Robin Foà, Raul Rabadan, Gianluca Gaidano, Davide Rossi
Nodal marginal zone lymphoma (NMZL) is a rare, indolent B-cell tumor that is distinguished from splenic marginal zone lymphoma (SMZL) by the different pattern of dissemination. NMZL still lacks distinct markers and remains orphan of specific cancer gene lesions. By combining whole-exome sequencing, targeted sequencing of tumor-related genes, whole-transcriptome sequencing, and high-resolution single nucleotide polymorphism array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and we compare the molecular profile of NMZL with that of SMZL...
September 8, 2016: Blood
Abner Louissaint, Kristian T Schafernak, Julia T Geyer, Alexandra E Kovach, Mahmoud Ghandi, Dita Gratzinger, Christine G Roth, Christian N Paxton, Sunhee Kim, Chungdak Namgyal, Ryan Morin, Elizabeth A Morgan, Donna S Neuberg, Sarah T South, Marian H Harris, Robert P Hasserjian, Ephraim P Hochberg, Levi A Garraway, Nancy Lee Harris, David M Weinstock
Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy number analysis and exome and/or targeted sequencing of 26 PTNFLs (16 pediatric and 10 adult)...
August 25, 2016: Blood
Nina Bögershausen, Vincent Gatinois, Vera Riehmer, Hülya Kayserili, Jutta Becker, Michaela Thoenes, Pelin Özlem Simsek-Kiper, Mouna Barat-Houari, Nursel H Elcioglu, Dagmar Wieczorek, Sigrid Tinschert, Guillaume Sarrabay, Tim M Strom, Aurélie Fabre, Gareth Baynam, Elodie Sanchez, Gudrun Nürnberg, Umut Altunoglu, Yline Capri, Bertrand Isidor, Didier Lacombe, Carole Corsini, Valérie Cormier-Daire, Damien Sanlaville, Fabienne Giuliano, Kim-Hanh Le Quan Sang, Honorine Kayirangwa, Peter Nürnberg, Thomas Meitinger, Koray Boduroglu, Barbara Zoll, Stanislas Lyonnet, Andreas Tzschach, Alain Verloes, Nataliya Di Donato, Isabelle Touitou, Christian Netzer, Yun Li, David Geneviève, Gökhan Yigit, Bernd Wollnik
Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel...
September 2016: Human Mutation
Joshua B N Dawkins, Jun Wang, Eleni Maniati, James A Heward, Lola Koniali, Hemant M Kocher, Sarah A Martin, Claude Chelala, Frances R Balkwill, Jude Fitzgibbon, Richard P Grose
Genes encoding the histone H3 lysine 4 methyltransferases KMT2C and KMT2D are subject to deletion and mutation in pancreatic ductal adenocarcinoma (PDAC), where these lesions identify a group of patients with a more favorable prognosis. In this study, we demonstrate that low KMT2C and KMT2D expression in biopsies also defines better outcome groups, with median survivals of 15.9 versus 9.2 months (P = 0.029) and 19.9 versus 11.8 months (P = 0.001), respectively. Experiments with eight human pancreatic cell lines showed attenuated cell proliferation when these methyltransferases were depleted, suggesting that this improved outcome may reflect a cell-cycle block with diminished progression from G0-G1 RNA-seq analysis of PDAC cell lines following KMT2C or KMT2D knockdown identified 31 and 124 differentially expressed genes, respectively, with 19 genes in common...
August 15, 2016: Cancer Research
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