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Cristina Caciolo, Paolo Alfieri, Giorgia Piccini, Maria Cristina Digilio, Francesca Romana Lepri, Marco Tartaglia, Deny Menghini, Stefano Vicari
BACKGROUND: Kabuki syndrome (KS) is a disorder characterized by multiple congenital anomalies affecting development and function of multiple systems. Over the years, researchers have attempted to characterize the neurobehavioral phenotype of KS in cohorts of patients enrolled on the basis of clinical assessment. The availability of molecular testing now allows for recruitment of patients with confirmed KS due to KMT2D and KDM6A. METHODS: The aims of the present study were to investigate the neuropsychological and behavioral profiles of individuals with molecularly confirmed diagnosis of KS, and determine the extent of heterogeneity occurring in these profiles between individuals with clinical diagnosis of KS with and without mutations in KMT2D...
March 13, 2018: Molecular Genetics & Genomic Medicine
Ping Hu, Fengchang Qiao, Yan Wang, Lulu Meng, Xiuqing Ji, Chunyu Luo, Tianhui Xu, Ran Zhou, Jingjing Zhang, Bin Yu, Leilei Wang, Ting Wang, Qiong Pan, Dingyuan Ma, Dong Liang, Zhengfeng Xu
OBJECTIVES: This study aimed to determine the diagnostic yield of targeted next-generation sequencing (NGS) in prenatal diagnosis of congenital heart defects (CHDs) and for investigating the possible genetic etiology of prenatal CHD cases. METHODS: Forty-four fetuses with CHDs and normal molecular karyotypes underwent targeted NGS in this study. Fetal genomic DNA was directly extracted from amniotic fluid cells in each prenatal case. A customized targeted NGS panel containing 77 CHD-associated genes was designed to detect variants in the coding regions and the splicing sites of these genes...
March 13, 2018: Ultrasound in Obstetrics & Gynecology
Anastasiya V Snezhkina, Elena N Lukyanova, Dmitry V Kalinin, Anatoly V Pokrovsky, Alexey A Dmitriev, Nadezhda V Koroban, Elena A Pudova, Maria S Fedorova, Nadezhda N Volchenko, Oleg A Stepanov, Ekaterina A Zhevelyuk, Sergey L Kharitonov, Anastasiya V Lipatova, Ivan S Abramov, Alexander V Golovyuk, Yegor E Yegorov, Khava S Vishnyakova, Alexey A Moskalev, George S Krasnov, Nataliya V Melnikova, Dmitry S Shcherbo, Marina V Kiseleva, Andrey D Kaprin, Boris Y Alekseev, Andrew R Zaretsky, Anna V Kudryavtseva
BACKGROUND: Carotid body tumor (CBT) is a form of head and neck paragangliomas (HNPGLs) arising at the bifurcation of carotid arteries. Paragangliomas are commonly associated with germline and somatic mutations involving at least one of more than thirty causative genes. However, the specific functionality of a number of these genes involved in the formation of paragangliomas has not yet been fully investigated. METHODS: Exome library preparation was carried out using Nextera® Rapid Capture Exome Kit (Illumina, USA)...
February 13, 2018: BMC Medical Genomics
Denis Soulières, Lisa Lictira, Ricard Mesía, Éva Remenár, Shau-Hsuan Li, Andrey Karpenko, Marie Chol, Ying A Wang, Nadia Solovieff, Laurence Bourdeau, Dalila Sellami, Sandrine Faivre
PURPOSE: The preplanned exploratory analysis of the BERIL-1 trial presented here aimed to identify biomarkers of response to the combination of buparlisib and paclitaxel. PATIENTS AND METHODS: BERIL-1 was a multicenter, randomized, double-blind, placebo-controlled phase 2 study. Patients with recurrent or metastatic SCCHN progressing on/after one previous platinum-based chemotherapy regimen in the recurrent or metastatic setting were treated with either buparlisib plus paclitaxel or placebo plus paclitaxel...
February 28, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Hideto Teranishi, Yuhki Koga, Kentaro Nakashima, Eiji Morihana, Kanako Ishii, Yasunari Sakai, Tomoaki Taguchi, Yoshinao Oda, Noriko Miyake, Naomichi Matsumoto, Shouichi Ohga
A 3-year-old Japanese girl treated for hypoplastic left heart syndrome and Dandy-Walker syndrome was diagnosed with Kabuki syndrome (KS) with a mutation of KMT2D; c.13285C>T:p.Q4429*. Concurrently, macrohematuria portended the diagnosis of Wilms tumor. Postoperative chemotherapy has achieved complete remission despite a prolonged and reduced regimen due to liver dysfunction and convulsions. Cancer predisposition has been suggested for KS due to oncogenic mutations in KMT2D or KDM6A. The first case of nephroblastoma exemplified the treatability of malignancies in KS patients, as shown in the 9 cases reviewed...
February 27, 2018: Journal of Pediatric Hematology/oncology
Doralina do Amaral Rabello, Vivian D'Afonseca da Silva Ferreira, Maria Gabriela Berzoti-Coelho, Sandra Mara Burin, Cíntia Leticia Magro, Maira da Costa Cacemiro, Belinda Pinto Simões, Felipe Saldanha-Araujo, Fabíola Attié de Castro, Fabio Pittella-Silva
Background: Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm whose pathogenesis is linked to the Philadelphia chromosome presence that generates the BCR - ABL 1 fusion oncogene. Tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM) dramatically improved the treatment efficiency and survival of CML patients by targeting BCR-ABL tyrosine kinase. The disease shows three distinct clinical-laboratory stages: chronic phase, accelerated phase and blast crisis...
2018: Cancer Cell International
Chengqi Xin, Chun Wang, Yachen Wang, Jingyuan Zhao, Liang Wang, Runjie Li, Jing Liu
BACKGROUND: Kabuki syndrome (KS) is a rare pediatric congenital disorder with multiple congenital anomalies and intellectual disabilities, which is inherited in an autosomal dominant manner. Mutations in KMT2D and KDM6A have been proven to be the primary cause in most cases of KS. CASE PRESENTATION: Here we report two Chinese boys with clinical features of KS referred to our hospital for clinical diagnosis. Next-generation sequencing was performed on MiSeq to analyze the genetic mutations in both patients...
February 27, 2018: BMC Medical Genetics
Tracy Lackraj, Rashmi Goswami, Robert Kridel
Follicular lymphoma (FL) is presented as a germinal centre B cell lymphoma that is characterized by an indolent clinical course, but remains - paradoxically - largely incurable to date. The last years have seen significant progress in our understanding of FL lymphomagenesis, which is a multi-step process beginning in the bone marrow with the hallmark t(14;18)(q32;q21) translocation. The pathobiology of FL is complex and combines broad somatic changes at the level of both the genome and the epigenome, the latter evidenced by highly recurrent mutations in chromatin-modifying genes such as KMT2D and CREBBP...
March 2018: Best Practice & Research. Clinical Haematology
Enrique Lin-Shiao, Yemin Lan, Mariel Coradin, Amy Anderson, Greg Donahue, Cory L Simpson, Payel Sen, Rizwan Saffie, Luca Busino, Benjamin A Garcia, Shelley L Berger, Brian C Capell
Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation, and differentiation, disruption of which may drive carcinogenesis. The epigenetic regulator KMT2D ( MLL4 ) is one of the most frequently mutated genes in all cancers, particularly epithelial cancers, yet its normal function in these tissues is unknown. Here, we identify a novel role for KMT2D in coordinating this fine balance, as depletion of KMT2D from undifferentiated epidermal keratinocytes results in reduced proliferation, premature spurious activation of terminal differentiation genes, and disorganized epidermal stratification...
January 15, 2018: Genes & Development
Kathryn B Manheimer, Felix Richter, Lisa J Edelmann, Sunita L D'Souza, Lisong Shi, Yufeng Shen, Jason Homsy, Marko T Boskovski, Angela C Tai, Joshua Gorham, Christopher Yasso, Elizabeth Goldmuntz, Martina Brueckner, Richard P Lifton, Wendy K Chung, Christine E Seidman, J G Seidman, Bruce D Gelb
Mosaicism due to somatic mutations can cause multiple diseases including cancer, developmental and overgrowth syndromes, neurodevelopmental disorders, autoinflammatory diseases, and atrial fibrillation. With the increased use of next generation sequencing technology, multiple tools have been developed to identify low-frequency variants, specifically from matched tumor-normal tissues in cancer studies. To investigate whether mosaic variants are implicated in congenital heart disease (CHD), we developed a pipeline using the cancer somatic variant caller MuTect to identify mosaic variants in whole-exome sequencing (WES) data from a cohort of parent/affected child trios (n = 715) and a cohort of healthy individuals (n = 416)...
February 7, 2018: Human Genetics
Kaixiang Cao, Clayton K Collings, Marc A Morgan, Stacy A Marshall, Emily J Rendleman, Patrick A Ozark, Edwin R Smith, Ali Shilatifard
Chromatin regulators control cellular differentiation by orchestrating dynamic developmental gene expression programs, and hence, malfunctions in the regulation of chromatin state contribute to both developmental disorders and disease state. Mll4 (Kmt2d), a member of the COMPASS (COMplex of Proteins ASsociated with Set1) protein family that implements histone H3 lysine 4 monomethylation (H3K4me1) at enhancers, is essential for embryonic development and functions as a pancancer tumor suppressor. We define the roles of Mll4/COMPASS and its catalytic activity in the maintenance and exit of ground-state pluripotency in murine embryonic stem cells (ESCs)...
January 2018: Science Advances
Damiano Fantini, Alexander P Glaser, Kalen J Rimar, Yiduo Wang, Matthew Schipma, Nobish Varghese, Alfred Rademaker, Amir Behdad, Aparna Yellapa, Yanni Yu, Christie Ching-Lin Sze, Lu Wang, Zibo Zhao, Susan E Crawford, Deqing Hu, Jonathan D Licht, Clayton K Collings, Elizabeth Bartom, Dan Theodorescu, Ali Shilatifard, Joshua J Meeks
The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) as it recapitulates the histology of human tumors in a background with intact immune system. However, it was unknown whether this carcinogen-induced model also mimicked human MIBC at the molecular and mutational level. In our study, we analyzed gene expression and mutational landscape of the BBN model by next-generation sequencing followed by a bioinformatic comparison to human MIBC using data from The Cancer Genome Atlas and other repositories...
January 25, 2018: Oncogene
Jana Paderova, Jana Drabova, Andrea Holubova, Marketa Vlckova, Marketa Havlovicova, Andrea Gregorova, Radka Pourova, Vera Romankova, Veronika Moslerova, Jan Geryk, Patricia Norambuena, Veronika Krulisova, Anna Krepelova, Milan Macek, Milan Macek
Kabuki syndrome is mainly caused by dominant de-novo pathogenic variants in the KMT2D and KDM6A genes. The clinical features of this syndrome are highly variable, making the diagnosis of Kabuki-like phenotypes difficult, even for experienced clinical geneticists. Herein we present molecular genetic findings of causal genetic variation using array comparative genome hybridization and a Mendeliome analysis, utilizing targeted exome analysis focusing on regions harboring rare disease-causing variants in Kabuki-like patients which remained KMT2D/KDM6A-negative...
January 4, 2018: European Journal of Medical Genetics
Meng-Meng Ji, Yao-Hui Huang, Jin-Yan Huang, Zhao-Fu Wang, Di Fu, Han Liu, Feng Liu, Christophe Leboeuf, Li Wang, Jing Ye, Yi-Ming Lu, Anne Janin, Shu Cheng, Wei-Li Zhao
Due to heterogeneous morphological and immunophenotypic features, approximately 50% of peripheral T-cell lymphomas are unclassifiable and categorized as peripheral T-cell lymphomas, not otherwise specified, presenting aggressive disease course and poor clinical outcome. Identification of actionable biomarkers is urgently needed to develop better therapeutic strategies. Epigenetic alterations play a crucial role in tumor progression. Histone modifications, particularly methylation and acetylation, are generally involved in chromatin state regulation...
January 5, 2018: Haematologica
Amanda Moccia, Anshika Srivastava, Jennifer M Skidmore, John A Bernat, Marsha Wheeler, Jessica X Chong, Deborah Nickerson, Michael Bamshad, Margaret A Hefner, Donna M Martin, Stephanie L Bielas
PurposeCHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7, encoding adenosine triphosphate-dependent chromodomain helicase DNA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5-30% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome...
January 4, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Yu-Chien Kao, Adepitan A Owosho, Yun-Shao Sung, Lei Zhang, Yumi Fujisawa, Jen-Chieh Lee, Leonard Wexler, Pedram Argani, David Swanson, Brendan C Dickson, Christopher D M Fletcher, Cristina R Antonescu
BCOR-CCNB3 sarcoma (BCS) is a recently defined genetic entity among undifferentiated round cell sarcomas, which was initially classified as and treated similarly to the Ewing sarcoma (ES) family of tumors. In contrast to ES, BCS shows consistent BCOR overexpression, and preliminary evidence suggests that these tumors share morphologic features with other tumors harboring BCOR genetic alterations, including BCOR internal tandem duplication (ITD) and BCOR-MAML3. To further investigate the pathologic features, clinical behavior, and their relationship to other round cell sarcomas, we collected 36 molecularly confirmed BCSs for a detailed histologic and immunohistochemical analysis...
October 25, 2017: American Journal of Surgical Pathology
Francesca Romana Lepri, Dario Cocciadiferro, Bartolomeo Augello, Paolo Alfieri, Valentina Pes, Alessandra Vancini, Cristina Caciolo, Gabriella Maria Squeo, Natascia Malerba, Iolanda Adipietro, Antonio Novelli, Stefano Sotgiu, Renzo Gherardi, Maria Cristina Digilio, Bruno Dallapiccola, Giuseppe Merla
Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in KMT2D/MLL2 and KDM6A/UTX, two interacting chromatin modifier responsible respectively for 56-75% and 5-8% of the cases. To date, three KS patients with mosaic KMT2D deletions in blood lymphocytes have been described. We report on three additional subjects displaying KMT2D gene mosaics including one in which a single nucleotide change results in a new frameshift mutation (p...
December 28, 2017: International Journal of Molecular Sciences
Luc Xerri, José Adélaïde, Cornel Popovici, Séverine Garnier, Arnaud Guille, Lenaïg Mescam-Mancini, Camille Laurent, Pierre Brousset, Carole Coze, Gérard Michel, Max Chaffanet, Reda Bouabdallah, Diane Coso, François Bertucci, Daniel Birnbaum
Langerhans cell histiocytosis (LCH) has a mostly favorable outcome, whereas Langerhans cell sarcoma (LCS) is an aggressive tumor. It is still unclear whether any specific molecular alterations could underlie the aggressive behavior of Langerhans cell proliferations. We used targeted next-generation sequencing and array-comparative genomic hybridization to profile 22 LCH samples from different patients together with 3 LCS samples corresponding to different relapses from the same patient. The third LCS relapse was a composite tumor including both B-cell chronic lymphocytic leukemia and LCS components...
February 2018: American Journal of Surgical Pathology
Michael R Green
Follicular lymphoma (FL) is an indolent malignancy of germinal center B (GCB)-cells. Although the overall survival of FL patients has recently improved with the introduction of novel therapies, there is significant heterogeneity in patient outcome and a need for rationally designed therapeutic strategies that target disease biology. Next generation sequencing studies have identified chromatin modifying gene (CMG) mutations as a hallmark of FL, highlighting epigenetic modifiers as an attractive therapeutic target in this disease...
November 20, 2017: Blood
Alexander H Li, Neil A Hanchard, Dieter Furthner, Susan Fernbach, Mahshid Azamian, Annarita Nicosia, Jill Rosenfeld, Donna Muzny, Lisa C A D'Alessandro, Shaine Morris, Shalini Jhangiani, Dhaval R Parekh, Wayne J Franklin, Mark Lewin, Jeffrey A Towbin, Daniel J Penny, Charles D Fraser, James F Martin, Christine Eng, James R Lupski, Richard A Gibbs, Eric Boerwinkle, John W Belmont
BACKGROUND: Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify likely damaging variants in putative candidate CVM genes. METHODS: Using a series of bioinformatics filters, we focused on genes harboring population-rare, putative loss-of-function (LOF), and predicted damaging variants in 1760 CVM candidate genes constructed a priori from the literature and model organism databases...
October 31, 2017: Genome Medicine
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