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Human Genetics

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https://www.readbyqxmd.com/read/28940097/expanding-the-genetic-heterogeneity-of-intellectual-disability
#1
Shams Anazi, Sateesh Maddirevula, Vincenzo Salpietro, Yasmine T Asi, Saud Alsahli, Amal Alhashem, Hanan E Shamseldin, Fatema AlZahrani, Nisha Patel, Niema Ibrahim, Firdous M Abdulwahab, Mais Hashem, Nadia Alhashmi, Fathiya Al Murshedi, Adila Al Kindy, Ahmad Alshaer, Ahmed Rumayyan, Saeed Al Tala, Wesam Kurdi, Abdulaziz Alsaman, Ali Alasmari, Selina Banu, Tipu Sultan, Mohammed M Saleh, Hisham Alkuraya, Mustafa A Salih, Hesham Aldhalaan, Tawfeg Ben-Omran, Fatima Al Musafri, Rehab Ali, Jehan Suleiman, Brahim Tabarki, Ayman W El-Hattab, Caleb Bupp, Majid Alfadhel, Nada Al Tassan, Dorota Monies, Stefan T Arold, Mohamed Abouelhoda, Tammaryn Lashley, Henry Houlden, Eissa Faqeih, Fowzan S Alkuraya
Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families...
September 22, 2017: Human Genetics
https://www.readbyqxmd.com/read/28921393/genome-wide-compound-heterozygote-analysis-highlights-alleles-associated-with-adult-height-in-europeans
#2
Kaiyin Zhong, Gu Zhu, Xiaoxi Jing, A Emile J Hendriks, Sten L S Drop, M Arfan Ikram, Scott Gordon, Changqing Zeng, Andre G Uitterlinden, Nicholas G Martin, Fan Liu, Manfred Kayser
Adult height is the most widely genetically studied common trait in humans; however, the trait variance explainable by currently known height-associated single nucleotide polymorphisms (SNPs) identified from the previous genome-wide association studies (GWAS) is yet far from complete given the high heritability of this complex trait. To exam if compound heterozygotes (CH) may explain extra height variance, we conducted a genome-wide analysis to screen for CH in association with adult height in 10,631 Dutch Europeans enriched with extremely tall people, using our recently developed method implemented in the software package CollapsABEL...
September 18, 2017: Human Genetics
https://www.readbyqxmd.com/read/28913566/adar-rna-editing-in-human-disease-more-to-it-than-meets-the-i
#3
REVIEW
Angela Gallo, Dragana Vukic, David Michalík, Mary A O'Connell, Liam P Keegan
We review the structures and functions of ADARs and their involvements in human diseases. ADAR1 is widely expressed, particularly in the myeloid component of the blood system, and plays a prominent role in promiscuous editing of long dsRNA. Missense mutations that change ADAR1 residues and reduce RNA editing activity cause Aicardi-Goutières Syndrome, a childhood encephalitis and interferonopathy that mimics viral infection and resembles an extreme form of Systemic Lupus Erythmatosus (SLE). In Adar1 mouse mutant models aberrant interferon expression is prevented by eliminating interferon activation signaling from cytoplasmic dsRNA sensors, indicating that unedited cytoplasmic dsRNA drives the immune induction...
September 14, 2017: Human Genetics
https://www.readbyqxmd.com/read/28866814/from-mechanisms-to-therapy-rna-processing-s-impact-on-human-genetics
#4
EDITORIAL
Luiz O Penalva, Jeremy R Sanford
No abstract text is available yet for this article.
September 2, 2017: Human Genetics
https://www.readbyqxmd.com/read/28866801/recent-advances-in-assays-for-the-fragile-x-related-disorders
#5
REVIEW
Bruce E Hayward, Daman Kumari, Karen Usdin
The fragile X-related disorders are a group of three clinical conditions resulting from the instability of a CGG-repeat tract at the 5' end of the FMR1 transcript. Fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are disorders seen in carriers of FMR1 alleles with 55-200 repeats. Female carriers of these premutation (PM) alleles are also at risk of having a child who has an FMR1 allele with >200 repeats. Most of these full mutation (FM) alleles are epigenetically silenced resulting in a deficit of the FMR1 gene product, FMRP...
September 2, 2017: Human Genetics
https://www.readbyqxmd.com/read/28866788/enrichment-of-putatively-damaging-rare-variants-in-the-dyx2-locus-and-the-reading-related-genes-ccdc136-and-flnc
#6
Andrew K Adams, Shelley D Smith, Dongnhu T Truong, Erik G Willcutt, Richard K Olson, John C DeFries, Bruce F Pennington, Jeffrey R Gruen
Eleven loci with prior evidence for association with reading and language phenotypes were sequenced in 96 unrelated subjects with significant impairment in reading performance drawn from the Colorado Learning Disability Research Center collection. Out of 148 total individual missense variants identified, the chromosome 7 genes CCDC136 and FLNC contained 19. In addition, a region corresponding to the well-known DYX2 locus for RD contained 74 missense variants. Both allele sets were filtered for a minor allele frequency ≤0...
September 2, 2017: Human Genetics
https://www.readbyqxmd.com/read/28864994/a-genetic-variant-in-the-placenta-derived-mhc-class-i-chain-related-gene-a-increases-the-risk-of-preterm-birth-in-a-chinese-population
#7
Junjiao Song, Jing Li, Han Liu, Yuexin Gan, Yang Sun, Min Yu, Yongjun Zhang, Fei Luo, Ying Tian, Weiye Wang, Jun Zhang, Julian Little, Haidong Cheng, Dan Chen
Preterm birth (PTB) is a predominant contributor to neonatal mortality and morbidity worldwide. However, the pathophysiology of PTB is not well-understood. We tested the hypothesis that single-nucleotide polymorphisms (SNPs) in the placenta-derived MHC class I chain-related gene A (MICA) could disrupt placental development and hence result in PTB. Nineteen selected SNPs in MICA were genotyped in a case-control study of 127 premature infants and 634 term controls in a Chinese Han population. We found that significantly increased PTB risk was associated with homozygosity for the A variant of rs2256318 (adjusted odds ratio = 6...
September 1, 2017: Human Genetics
https://www.readbyqxmd.com/read/28864915/a-gene-based-test-of-association-through-an-orthogonal-decomposition-of-genotype-scores
#8
Zhongxue Chen, Kai Wang
The burden test and the sequence kernel association test (SKAT) are two popular methods for detecting association with rare variants. Treated as two different sources of association information, they are adaptively combined to form an optimal SKAT (SKAT-O) method for optimal power. We show that the burden test is part of rather than independent of the SKAT. We introduce a new test statistic that is the sum of the burden statistic and a statistic asymptotically independent of the burden statistic. The performance of this new test statistic is demonstrated through extensive simulation studies and applications to a Genetic Analysis Workshop 17 data set and the Ocular Hypertension Treatment Study data...
September 1, 2017: Human Genetics
https://www.readbyqxmd.com/read/28852871/smn-regulation-in-sma-and-in-response-to-stress-new-paradigms-and-therapeutic-possibilities
#9
REVIEW
Catherine E Dominguez, David Cunningham, Dawn S Chandler
Low levels of the survival of motor neuron (SMN) protein cause the neurodegenerative disease spinal muscular atrophy (SMA). SMA is a pediatric disease characterized by spinal motor neuron degeneration. SMA exhibits several levels of severity ranging from early antenatal fatality to only mild muscular weakness, and disease prognosis is related directly to the amount of functional SMN protein that a patient is able to express. Current therapies are being developed to increase the production of functional SMN protein; however, understanding the effect that natural stresses have on the production and function of SMN is of critical importance to ensuring that these therapies will have the greatest possible effect for patients...
August 29, 2017: Human Genetics
https://www.readbyqxmd.com/read/28836065/a-multi-stage-genome-wide-association-study-of-uterine-fibroids-in-african-americans
#10
Jacklyn N Hellwege, Janina M Jeff, Lauren A Wise, C Scott Gallagher, Melissa Wellons, Katherine E Hartmann, Sarah F Jones, Eric S Torstenson, Scott Dickinson, Edward A Ruiz-Narváez, Nadin Rohland, Alexander Allen, David Reich, Arti Tandon, Bogdan Pasaniuc, Nicholas Mancuso, Hae Kyung Im, David A Hinds, Julie R Palmer, Lynn Rosenberg, Joshua C Denny, Dan M Roden, Elizabeth A Stewart, Cynthia C Morton, Eimear E Kenny, Todd L Edwards, Digna R Velez Edwards
Uterine fibroids are benign tumors of the uterus affecting up to 77% of women by menopause. They are the leading indication for hysterectomy, and account for $34 billion annually in the United States. Race/ethnicity and age are the strongest known risk factors. African American (AA) women have higher prevalence, earlier onset, and larger and more numerous fibroids than European American women. We conducted a multi-stage genome-wide association study (GWAS) of fibroid risk among AA women followed by in silico genetically predicted gene expression profiling of top hits...
August 23, 2017: Human Genetics
https://www.readbyqxmd.com/read/28799012/mtdna-genomes-reveal-a-relaxation-of-selective-constraints-in-low-bmi-individuals-in-a-uyghur-population
#11
Hong-Xiang Zheng, Lei Li, Xiao-Yan Jiang, Shi Yan, Zhendong Qin, Xiaofeng Wang, Li Jin
Considerable attention has been focused on the effect of deleterious mutations caused by the recent relaxation of selective constraints on human health, including the prevalence of obesity, which might represent an adaptive response of energy-conserving metabolism under the conditions of modern society. Mitochondrial DNA (mtDNA) encoding 13 core subunits of oxidative phosphorylation plays an important role in metabolism. Therefore, we hypothesized that a relaxation of selection constraints on mtDNA and an increase in the proportion of deleterious mutations have played a role in obesity prevalence...
August 10, 2017: Human Genetics
https://www.readbyqxmd.com/read/28780673/investigating-the-genetic-relationship-between-alzheimer-s-disease-and-cancer-using-gwas-summary-statistics
#12
Yen-Chen Anne Feng, Kelly Cho, Sara Lindstrom, Peter Kraft, Jean Cormack, Liming Liang, Jane A Driver
Growing evidence from both epidemiology and basic science suggest an inverse association between Alzheimer's disease (AD) and cancer. We examined the genetic relationship between AD and various cancer types using GWAS summary statistics from the IGAP and GAME-ON consortia. Sample size ranged from 9931 to 54,162; SNPs were imputed to the 1000 Genomes European panel. Our results based on cross-trait LD Score regression showed a significant positive genetic correlation between AD and five cancers combined (colon, breast, prostate, ovarian, lung; r g = 0...
August 5, 2017: Human Genetics
https://www.readbyqxmd.com/read/28780672/defective-splicing-of-the-rb1-transcript-is-the-dominant-cause-of-retinoblastomas
#13
Kamil J Cygan, Rachel Soemedi, Christy L Rhine, Abraham Profeta, Eileen L Murphy, Michael F Murray, William G Fairbrother
Defective splicing is a common cause of genetic diseases. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations with most mapping to the critical GT or AG nucleotides within the 5' and 3' splice sites. However, splicing mutations are underreported and the fraction of splicing mutations that compose all disease alleles varies greatly across disease gene. For example, there is a great excess (46%; ~threefold) of hereditary disease alleles that map to splice sites in RB1 that cause retinoblastoma...
August 5, 2017: Human Genetics
https://www.readbyqxmd.com/read/28776093/identification-of-an-atypical-microdeletion-generating-the-rnf135-suz12-chimeric-gene-and-causing-a-position-effect-in-an-nf1-patient-with-overgrowth
#14
Luca Ferrari, Giulietta Scuvera, Arianna Tucci, Donatella Bianchessi, Francesco Rusconi, Francesca Menni, Elena Battaglioli, Donatella Milani, Paola Riva
Neurofibromatosis type I (NF1) microdeletion syndrome, which is present in 4-11% of NF1 patients, is associated with a severe phenotype as it is caused by the deletion of NF1 and other genes in the 17q11.2 region. The variable expressivity of the disease makes it challenging to establish genotype-phenotype correlations, which also affects prognosis and counselling. We here describe a 3-year-old NF1 patient with an atypical deletion and a complex phenotype. The patient showed overgrowth, café au lait spots, inguinal freckling, and neurological abnormalities...
August 3, 2017: Human Genetics
https://www.readbyqxmd.com/read/28762175/genetic-mutations-in-rna-binding-proteins-and-their-roles-in-als
#15
REVIEW
Katannya Kapeli, Fernando J Martinez, Gene W Yeo
Mutations in genes that encode RNA-binding proteins (RBPs) have emerged as critical determinants of neurological diseases, especially motor neuron disorders such as amyotrophic lateral sclerosis (ALS). RBPs are involved in all aspects of RNA processing, controlling the life cycle of RNAs from synthesis to degradation. Hallmark features of RBPs in neuron dysfunction include misregulation of RNA processing, mislocalization of RBPs to the cytoplasm, and abnormal aggregation of RBPs. Much progress has been made in understanding how ALS-associated mutations in RBPs drive pathogenesis...
July 31, 2017: Human Genetics
https://www.readbyqxmd.com/read/28664341/the-activity-of-the-serotonin-receptor-2c-is-regulated-by-alternative-splicing
#16
REVIEW
Stefan Stamm, Samuel B Gruber, Alexander G Rabchevsky, Ronald B Emeson
The central nervous system-specific serotonin receptor 2C (5HT2C) controls key physiological functions, such as food intake, anxiety, and motoneuron activity. Its deregulation is involved in depression, suicidal behavior, and spasticity, making it the target for antipsychotic drugs, appetite controlling substances, and possibly anti-spasm agents. Through alternative pre-mRNA splicing and RNA editing, the 5HT2C gene generates at least 33 mRNA isoforms encoding 25 proteins. The 5HT2C is a G-protein coupled receptor that signals through phospholipase C, influencing the expression of immediate/early genes like c-fos...
June 29, 2017: Human Genetics
https://www.readbyqxmd.com/read/28660352/erratum-to-haploinsufficiency-of-the-e3-ubiquitin-protein-ligase-gene-trip12-causes-intellectual-disability-with-or-without-autism-spectrum-disorders-speech-delay-and-dysmorphic-features
#17
Jing Zhang, Tomasz Gambin, Bo Yuan, Przemyslaw Szafranski, Jill A Rosenfeld, Mohammed Al Balwi, Abdulrahman Alswaid, Lihadh Al-Gazali, Aisha M Al Shamsi, Makanko Komara, Bassam R Ali, Elizabeth Roeder, Laura McAuley, Daniel S Roy, David K Manchester, Pilar Magoulas, Lauren E King, Vickie Hannig, Dominique Bonneau, Anne-Sophie Denommé-Pichon, Majida Charif, Thomas Besnard, Stéphane Bézieau, Benjamin Cogné, Joris Andrieux, Wenmiao Zhu, Weimin He, Francesco Vetrini, Patricia A Ward, Sau Wai Cheung, Weimin Bi, Christine M Eng, James R Lupski, Yaping Yang, Ankita Patel, Seema R Lalani, Fan Xia, Paweł Stankiewicz
No abstract text is available yet for this article.
August 2017: Human Genetics
https://www.readbyqxmd.com/read/28656458/a-genetic-risk-score-is-differentially-associated-with-migraine-with-and-without-aura
#18
Claudia Pisanu, Martin Preisig, Enrique Castelao, Jennifer Glaus, Giorgio Pistis, Alessio Squassina, Maria Del Zompo, Kathleen R Merikangas, Gérard Waeber, Peter Vollenweider, Jessica Mwinyi, Helgi B Schiöth
Although a number of migraine-associated single-nucleotide polymorphisms (SNP) with small effect size have been identified, little is known about the additive impact of these variants on migraine risk, frequency and severity. We investigated to what extent a genetic risk score (GRS) based on recently published, novel migraine-associated SNPs is associated with migraine prevalence, subtypes and severity in a large population-based sample. The sample comprised 446 subjects with migraine and 2511 controls from the CoLaus/PsyCoLaus study...
August 2017: Human Genetics
https://www.readbyqxmd.com/read/28653172/a-cis-eqtl-genetic-variant-of-the-cancer-testis-gene-ccdc116-is-associated-with-risk-of-multiple-cancers
#19
Na Qin, Cheng Wang, Qun Lu, Tongtong Huang, Meng Zhu, Lihua Wang, Fei Yu, Mingtao Huang, Yue Jiang, Juncheng Dai, Hongxia Ma, Guangfu Jin, Chen Wu, Dongxin Lin, Hongbing Shen, Zhibin Hu
Recent studies have found that cancer-testis (CT) genes, which are expressed predominantly in germ and cancer cells, may be candidate cancer drivers. Because of their crucial roles, genetic variants in these genes may contribute to the development of cancer. Here, we systematically evaluated associations of common variants in CT genes and their promoters for the risk of lung cancer in our initial GWAS (2331 cases and 3077 controls), followed by in silico replication using additional 10,512 lung cancer cases and 9562 controls...
August 2017: Human Genetics
https://www.readbyqxmd.com/read/28646452/dosage-effects-of-zp2-and-zp3-heterozygous-mutations-cause-human-infertility
#20
Wenqiang Liu, Kunming Li, Dandan Bai, Jiqing Yin, Yuanyuan Tang, Fengli Chi, Linfeng Zhang, Yu Wang, Jiaping Pan, Shanshan Liang, Yi Guo, Jingling Ruan, Xiaochen Kou, Yanhong Zhao, Hong Wang, Jiayu Chen, Xiaoming Teng, Shaorong Gao
The zona pellucida (ZP) is an extracellular matrix universally surrounding mammalian eggs, which is essential for oogenesis, fertilization, and pre-implantation embryo development. Here, we identified two novel heritable mutations of ZP2 and ZP3, both occurring in an infertile female patient with ZP-abnormal eggs. Mouse models with the same mutations were generated by CRISPR/Cas9 gene editing system, and oocytes obtained from female mice with either single heterozygous mutation showed approximately half of the normal ZP thickness compared to wild-type oocytes...
August 2017: Human Genetics
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