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Human Genomics

Hang Yang, Yanyun Ma, Mingyao Luo, Kun Zhao, Yinhui Zhang, Guoyan Zhu, Xiaogang Sun, Fanyan Luo, Lin Wang, Chang Shu, Zhou Zhou
BACKGROUND: Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene. Approximately 90% of classic MFS patients have a FBN1 mutation that can be identified by single-gene sequencing or gene-panel sequencing targeting FBN1. However, a small proportion of MFS patients carry a large genomic deletion in FBN1, which cannot be detected by routine sequencing. Here, we performed an MLPA (multiplex ligation-dependent probe amplification) test to detect large deletions and/or duplications in FBN1 and TGFBR2 in 115 unrelated Chinese patients with suspected MFS or early-onset aneurysm/dissection...
October 4, 2018: Human Genomics
Vasiliki Chondrou, Eleana F Stavrou, Georgios Markopoulos, Alexandra Kouraklis-Symeonidis, Vasilios Fotopoulos, Argiris Symeonidis, Efthymia Vlachaki, Panagiota Chalkia, George P Patrinos, Adamantia Papachatzopoulou, Argyro Sgourou
BACKGROUND: We aimed to clarify the emerging epigenetic landscape in a group of genes classified as "modifier genes" of the β-type globin genes (HBB cluster), known to operate in trans to accomplish the two natural developmental switches in globin expression, from embryonic to fetal during the first trimester of conception and from fetal to adult around the time of birth. The epigenetic alterations were determined in adult sickle cell anemia (SCA) homozygotes and SCA/β-thalassemia compound heterozygotes of Greek origin, who are under hydroxyurea (HU) treatment...
October 1, 2018: Human Genomics
Huilin Xie, Erge Zhang, Nanchao Hong, Qihua Fu, Fen Li, Sun Chen, Yu Yu, Kun Sun
BACKGROUND: Conotruncal heart defects (CTDs) are heterogeneous congenital heart malformations that result from outflow tract dysplasia; however, the genetic determinants underlying CTDs remain unclear. Increasing evidence demonstrates that dysfunctional TBX2 and TBX3 result in outflow tract malformations, implying that both of them are involved in CTD pathogenesis. We screened for TBX2 and TBX3 variants in a large cohort of CTD patients (n = 588) and population-matched healthy controls (n = 300) by target sequencing and genetically analyzed the expression and function of these variants...
September 17, 2018: Human Genomics
Yu Jin, Jingbo Wang, Maulana Bachtiar, Samuel S Chong, Caroline G L Lee
BACKGROUND: Genetic polymorphisms can contribute to phenotypic differences amongst individuals, including disease risk and drug response. Characterization of genetic polymorphisms that modulate gene expression and/or protein function may facilitate the identification of the causal variants. Here, we present the architecture of genetic polymorphisms in the human genome focusing on those predicted to be potentially functional/under natural selection and the pathways that they reside. RESULTS: In the human genome, polymorphisms that directly affect protein sequences and potentially affect function are the most constrained variants with the lowest single-nucleotide variant (SNV) density, least population differentiation and most significant enrichment of rare alleles...
September 15, 2018: Human Genomics
Wen Chen, Wenke Li, Yi Ma, Yujing Zhang, Bianmei Han, Xuewen Liu, Kun Zhao, Meixian Zhang, Jie Mi, Yuanyuan Fu, Zhou Zhou
BACKGROUND: Variants with known or possible pathogenicity located in genes that are unrelated to primary disease conditions are defined as secondary findings. Secondary findings are not the primary targets of whole exome and genome sequencing (WES/WGS) assay but can be of great practical value in early disease prevention and intervention. The driving force for this study was to investigate the impact of racial difference and disease background on secondary findings. Here, we analyzed secondary findings frequencies in 421 whole exome-sequenced Chinese children who are phenotypically normal or bear congenital heart diseases/juvenile obesity...
September 14, 2018: Human Genomics
Chandrakumar Sathishkumar, Paramasivam Prabu, Viswanathan Mohan, Muthuswamy Balasubramanyam
BACKGROUND: Studying epigenetics is expected to provide precious information on how environmental factors contribute to type 2 diabetes mellitus (T2DM) at the genomic level. With the progress of the whole-genome resequencing efforts, it is now known that 75-90% of the human genome was transcribed to generate a series of long non-coding RNAs (lncRNAs). While lncRNAs are gaining widespread attention as potential and robust biomarkers in the genesis as well as progression of several disease states, their clinical relevance and regulatory mechanisms are yet to be explored in the field of metabolic disorders including diabetes...
August 23, 2018: Human Genomics
Taobo Hu, Yogesh Kumar, Iram Shazia, Shen-Jia Duan, Yi Li, Lei Chen, Jin-Fei Chen, Rong Yin, Ava Kwong, Gilberto Ka-Kit Leung, Wai-Kin Mat, Zhenggang Wu, Xi Long, Cheuk-Hin Chan, Si Chen, Peggy Lee, Siu-Kin Ng, Timothy Y C Ho, Jianfeng Yang, Xiaofan Ding, Shui-Ying Tsang, Xuqing Zhou, Dan-Hua Zhang, En-Xiang Zhou, Lin Xu, Wai-Sang Poon, Hong-Yang Wang, Hong Xue
BACKGROUND: Massive occurrences of interstitial loss of heterozygosity (LOH) likely resulting from gene conversions were found by us in different cancers as a type of single-nucleotide variations (SNVs), comparable in abundance to the commonly investigated gain of heterozygosity (GOH) type of SNVs, raising the question of the relationships between these two opposing types of cancer mutations. METHODS: In the present study, SNVs in 12 tetra sample and 17 trio sample sets from four cancer types along with copy number variations (CNVs) were analyzed by AluScan sequencing, comparing tumor with white blood cells as well as tissues vicinal to the tumor...
August 22, 2018: Human Genomics
Travis J Struck, Brian K Mannakee, Ryan N Gutenkunst
The past decade has seen major investment in genome-wide association studies (GWAS). Among the many goals of GWAS, a major one is to identify and motivate research on novel genes involved in complex human disease. To assess whether this goal is being met, we quantified the effect of GWAS on the overall distribution of biomedical research publications and on the subsequent publication history of genes newly associated with complex disease. We found that the historical skew of publications toward genes involved in Mendelian disease has not changed since the advent of GWAS...
August 13, 2018: Human Genomics
Florencia C Cardoso, Susana Goncalves, Pablo G Mele, Natalia C Liria, Leonardo Sganga, Ignacio Diaz Perez, Ernesto J Podesta, Angela R Solano
BACKGROUND: Ovarian cancer is the leading cause of death worldwide among gynecologic malignancies. The recent approval of inhibitors of poly (ADP-ribose) polymerase (iPARP) in the treatment of ovarian cancer in the presence of a BRCA1/2 mutation has sparked the analysis of women with such diagnosis, which can further benefit from the detection of carriers in the family. Germline sequence and large rearrangements for BRCA1/2 were tested in 398 consecutive epithelial ovarian cancer (EOC) patients...
August 13, 2018: Human Genomics
Xiaowei Fan, Lifeng Ma, Zhiying Zhang, Yi Li, Meng Hao, Zhipeng Zhao, Yiduo Zhao, Fang Liu, Lijun Liu, Xingguang Luo, Peng Cai, Yansong Li, Longli Kang
BACKGROUND: High-altitude polycythemia (HAPC) is a chronic high-altitude disease that can lead to an increase in the production of red blood cells in the people who live in the plateau, a hypoxia environment, for a long time. The most frequent symptoms of HAPC include headache, dizziness, breathlessness, sleep disorders, and dilation of veins. Although chronic hypoxia is the main cause of HAPC, the fundamental pathophysiologic process and related molecular mechanisms responsible for its development remain largely unclear yet...
July 27, 2018: Human Genomics
Isabelle Cusin, Daniel Teixeira, Monique Zahn-Zabal, Valentine Rech de Laval, Anne Gleizes, Valeria Viassolo, Pierre O Chappuis, Pierre Hutter, Amos Bairoch, Pascale Gaudet
BACKGROUND: Germline pathogenic variants in the breast cancer type 1 susceptibility gene BRCA1 are associated with a 60% lifetime risk for breast and ovarian cancer. This overall risk estimate is for all BRCA1 variants; obviously, not all variants confer the same risk of developing a disease. In cancer patients, loss of BRCA1 function in tumor tissue has been associated with an increased sensitivity to platinum agents and to poly-(ADP-ribose) polymerase (PARP) inhibitors. For clinical management of both at-risk individuals and cancer patients, it would be important that each identified genetic variant be associated with clinical significance...
July 11, 2018: Human Genomics
Yabin Chen, Li Huang, Xiaodong Jiao, Sheikh Riazuddin, S Amer Riazuddin, J Fielding Hetmancik
BACKGROUND AND PURPOSE: Retinitis pigmentosa is an important cause of severe visual dysfunction. This study reports a novel splicing mutation in the lecithin retinol acyltransferase (LRAT) gene associated with early onset retinitis pigmentosa and characterizes the effects of this mutation on mRNA splicing and structure. METHODS: Genome-wide linkage analysis followed by dideoxy sequencing of the linked candidate gene LRAT was performed in a consanguineous Pakistani family with autosomal recessive retinitis pigmentosa...
July 4, 2018: Human Genomics
Jakub Piotr Fichna, Anna Macias, Marcin Piechota, Michał Korostyński, Anna Potulska-Chromik, Maria Jolanta Redowicz, Cezary Zekanowski
BACKGROUND: Limb girdle muscular dystrophies (LGMD) are a group of heterogeneous hereditary myopathies with similar clinical symptoms. Disease onset and progression are highly variable, with an elusive genetic background, and around 50% cases lacking molecular diagnosis. METHODS: Whole exome sequencing (WES) was performed in 73 patients with clinically diagnosed LGMD. A filtering strategy aimed at identification of variants related to the disease included integrative analysis of WES data and human phenotype ontology (HPO) terms, analysis of genes expressed in muscle, analysis of the disease-associated interactome and copy number variants analysis...
July 3, 2018: Human Genomics
Sankar Subramanian
Previous studies showed that the magnitude of selection pressure in constitutive exons is higher than that in alternatively spliced exons. The intensity of selection was also shown to be depended on the inclusion level of exons: the number of transcripts that include an exon. Here, we examined how the difference in selection pressure influences the patterns of clinical variants in human exons. Our analysis revealed a positive relationship between exon inclusion level and the abundance of pathogenic variants...
June 28, 2018: Human Genomics
Niv Sabath, Anna Vilborg, Joan A Steitz, Reut Shalgi
Naturally occurring stress-induced transcriptional readthrough is a recently discovered phenomenon, in which stress conditions lead to dramatic induction of long transcripts as a result of transcription termination failure. In 2015, we reported the induction of such downstream of gene (DoG) containing transcripts upon osmotic stress in human cells, while others observed similar transcripts in virus-infected and cancer cells. Using the rigorous methodology Cap-Seq, we demonstrated that DoGs result from transcriptional readthrough, not de novo initiation...
June 27, 2018: Human Genomics
Hui He, Zhiping Hu, Han Xiao, Fangfang Zhou, Binbin Yang
Epigenetics defines the persistent modifications of gene expression in a manner that does not involve the corresponding alterations in DNA sequences. It includes modifications of DNA nucleotides, nucleosomal remodeling, and post-translational modifications (PTMs). It is becoming evident that PTMs which act singly or in combination to form "histone codes" orchestrate the chromatin structure and dynamic functions. PTMs of histone tails have been demonstrated to influence numerous biological developments, as well as disease onset and progression...
June 22, 2018: Human Genomics
Kobi Perl, Ron Shamir, Karen B Avraham
BACKGROUND: Hearing loss is a major cause of disability worldwide, impairing communication, health, and quality of life. Emerging methods of gene therapy aim to address this morbidity, which can be employed to fix a genetic problem causing hair cell dysfunction and to promote the proliferation of supporting cells in the cochlea and their transdifferentiation into hair cells. In order to extend the applicability of gene therapy, the scientific community is focusing on discovery of additional deafness genes, identifying new genetic variants associated with hearing loss, and revealing new factors that can be manipulated in a coordinated manner to improve hair cell regeneration...
June 22, 2018: Human Genomics
Minjoo Kim, Minkyung Kim, Hye Jin Yoo, Jayoung Shon, Jong Ho Lee
BACKGROUND: Oxidative stress is associated with the increased risk of hypertension (HTN). This cross-sectional study is aimed to identify the association between the peroxisome proliferator-activated receptor-δ (PPARD) polymorphism and plasma malondialdehyde (MDA), an oxidative stress marker which is related to HTN development, and to determine whether PPARD gene is a candidate gene for HTN. RESULTS: One thousand seven hundred ninety-three individuals with normal blood pressure (BP) and HTN were included in this cross-sectional study...
June 18, 2018: Human Genomics
Sang-Nee Tan, Sai-Peng Sim, Alan Soo-Beng Khoo
BACKGROUND: The mechanism underlying chromosome rearrangement in nasopharyngeal carcinoma (NPC) remains elusive. It is known that most of the aetiological factors of NPC trigger oxidative stress. Oxidative stress is a potent apoptotic inducer. During apoptosis, chromatin cleavage and DNA fragmentation occur. However, cells may undergo DNA repair and survive apoptosis. Non-homologous end joining (NHEJ) pathway has been known as the primary DNA repair system in human cells. The NHEJ process may repair DNA ends without any homology, although region of microhomology (a few nucleotides) is usually utilised by this DNA repair system...
June 18, 2018: Human Genomics
Magnus Ingelman-Sundberg, Souren Mkrtchian, Yitian Zhou, Volker M Lauschke
BACKGROUND: Variability in genes implicated in drug pharmacokinetics or drug response can modulate treatment efficacy or predispose to adverse drug reactions. Besides common genetic polymorphisms, recent sequencing projects revealed a plethora of rare genetic variants in genes encoding proteins involved in drug metabolism, transport, and response. RESULTS: To understand the global importance of rare pharmacogenetic gene variants, we mapped the variability in 208 pharmacogenes by analyzing exome sequencing data from 60,706 unrelated individuals and estimated the importance of rare and common genetic variants using a computational prediction framework optimized for pharmacogenetic assessments...
May 25, 2018: Human Genomics
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