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American Journal of Human Genetics

Brian L Browning, Ying Zhou, Sharon R Browning
Genotype imputation is commonly performed in genome-wide association studies because it greatly increases the number of markers that can be tested for association with a trait. In general, one should perform genotype imputation using the largest reference panel that is available because the number of accurately imputed variants increases with reference panel size. However, one impediment to using larger reference panels is the increased computational cost of imputation. We present a new genotype imputation method, Beagle 5...
August 2, 2018: American Journal of Human Genetics
Marci L B Schwartz, Cara Zayac McCormick, Amanda L Lazzeri, D'Andra M Lindbuchler, Miranda L G Hallquist, Kandamurugu Manickam, Adam H Buchanan, Alanna Kulchak Rahm, Monica A Giovanni, Lauren Frisbie, Carroll N Flansburg, F Daniel Davis, Amy C Sturm, Christine Nicastro, Matthew S Lebo, Heather Mason-Suares, Lisa Marie Mahanta, David J Carey, Janet L Williams, Marc S Williams, David H Ledbetter, W Andrew Faucett, Michael F Murray
There is growing interest in communicating clinically relevant DNA sequence findings to research participants who join projects with a primary research goal other than the clinical return of such results. Since Geisinger's MyCode Community Health Initiative (MyCode) was launched in 2007, more than 200,000 participants have been broadly consented for discovery research. In 2013 the MyCode consent was amended to include a secondary analysis of research genomic sequences that allows for delivery of clinical results...
July 30, 2018: American Journal of Human Genetics
Janet H T Song, Craig B Lowe, David M Kingsley
Bipolar disorder (BD) and schizophrenia (SCZ) are highly heritable diseases that affect more than 3% of individuals worldwide. Genome-wide association studies have strongly and repeatedly linked risk for both of these neuropsychiatric diseases to a 100 kb interval in the third intron of the human calcium channel gene CACNA1C. However, the causative mutation is not yet known. We have identified a human-specific tandem repeat in this region that is composed of 30 bp units, often repeated hundreds of times. This large tandem repeat is unstable using standard polymerase chain reaction and bacterial cloning techniques, which may have resulted in its incorrect size in the human reference genome...
July 27, 2018: American Journal of Human Genetics
Shereen G Ghosh, Kerstin Becker, He Huang, Tracy D Salazar, Guoliang Chai, Vincenzo Salpietro, Lihadh Al-Gazali, Quinten Waisfisz, Haicui Wang, Keith K Vaux, Valentina Stanley, Andreea Manole, Ugur Akpulat, Marjan M Weiss, Stephanie Efthymiou, Michael G Hanna, Carlo Minetti, Pasquale Striano, Livia Pisciotta, Elisa De Grandis, Janine Altmüller, Peter Nürnberg, Holger Thiele, Uluc Yis, Tuncay Derya Okur, Ayse Ipek Polat, Nafise Amiri, Mohammad Doosti, Ehsan Ghayoor Karimani, Mehran B Toosi, Gabriel Haddad, Mert Karakaya, Brunhilde Wirth, Johanna M van Hagen, Nicole I Wolf, Reza Maroofian, Henry Houlden, Sebahattin Cirak, Joseph G Gleeson
ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families...
July 25, 2018: American Journal of Human Genetics
Jordan Kho, Xiaoyu Tian, Wing-Tak Wong, Terry Bertin, Ming-Ming Jiang, Shan Chen, Zixue Jin, Oleg A Shchelochkov, Lindsay C Burrage, Anilkumar K Reddy, Hong Jiang, Reem Abo-Zahrah, Shuangtao Ma, Ping Zhang, Karl-Dimiter Bissig, Jean J Kim, Sridevi Devaraj, George G Rodney, Ayelet Erez, Nathan S Bryan, Sandesh C S Nagamani, Brendan H Lee
Primary hypertension is a major risk factor for ischemic heart disease, stroke, and chronic kidney disease. Insights obtained from the study of rare Mendelian forms of hypertension have been invaluable in elucidating the mechanisms causing primary hypertension and development of antihypertensive therapies. Endothelial cells play a key role in the regulation of blood pressure; however, a Mendelian form of hypertension that is primarily due to endothelial dysfunction has not yet been described. Here, we show that the urea cycle disorder, argininosuccinate lyase deficiency (ASLD), can manifest as a Mendelian form of endothelial-dependent hypertension...
August 2, 2018: American Journal of Human Genetics
Levi S Teitz, Tatyana Pyntikova, Helen Skaletsky, David C Page
Amplicons-large, highly identical segmental duplications-are a prominent feature of mammalian Y chromosomes. Although they encode genes essential for fertility, these amplicons differ vastly between species, and little is known about the selective constraints acting on them. Here, we develop computational tools to detect amplicon copy number with unprecedented accuracy from high-throughput sequencing data. We find that one-sixth (16.9%) of 1,216 males from the 1000 Genomes Project have at least one deleted or duplicated amplicon...
August 2, 2018: American Journal of Human Genetics
D Gareth R Evans, Elke M van Veen, Helen J Byers, Andrew J Wallace, Jamie M Ellingford, Glenda Beaman, Javier Santoyo-Lopez, Timothy J Aitman, Diana M Eccles, Fiona I Lalloo, Miriam J Smith, William G Newman
Pathogenic variants in BRCA1 or BRCA2 are identified in ∼20% of families with multiple individuals affected by early-onset breast and/or ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1 or BRCA2 have not explained the missing heritability. Here, we report a dominantly inherited 5' UTR variant associated with epigenetic BRCA1 silencing due to promoter hypermethylation in two families affected by breast and ovarian cancer. BRCA1 promoter methylation of ten CpG dinucleotides in families who are affected by breast and/or ovarian cancer but do not have germline BRCA1 or BRCA2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing...
August 2, 2018: American Journal of Human Genetics
Laura Kasak, Margus Punab, Liina Nagirnaja, Marina Grigorova, Ave Minajeva, Alexandra M Lopes, Anna Maria Punab, Kenneth I Aston, Filipa Carvalho, Eve Laasik, Lee B Smith, Donald F Conrad, Maris Laan
Infertility affects around 7% of men worldwide. Idiopathic non-obstructive azoospermia (NOA) is defined as the absence of spermatozoa in the ejaculate due to failed spermatogenesis. There is a high probability that NOA is caused by rare genetic defects. In this study, whole-exome sequencing (WES) was applied to two Estonian brothers diagnosed with NOA and Sertoli cell-only syndrome (SCOS). Compound heterozygous loss-of-function (LoF) variants in FANCM (Fanconi anemia complementation group M) were detected as the most likely cause for their condition...
August 2, 2018: American Journal of Human Genetics
Christopher E Gillies, Rosemary Putler, Rajasree Menon, Edgar Otto, Kalyn Yasutake, Viji Nair, Paul Hoover, David Lieb, Shuqiang Li, Sean Eddy, Damian Fermin, Michelle T McNulty, Nir Hacohen, Krzysztof Kiryluk, Matthias Kretzler, Xiaoquan Wen, Matthew G Sampson
Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the condition. In nephrology, there is a paucity of eQTL studies of human kidney. Here, we used whole-genome sequencing (WGS) and microdissected glomerular (GLOM) and tubulointerstitial (TI) transcriptomes from 187 individuals with nephrotic syndrome (NS) to describe the eQTL landscape in these functionally distinct kidney structures...
August 2, 2018: American Journal of Human Genetics
Paul C Marcogliese, Vandana Shashi, Rebecca C Spillmann, Nicholas Stong, Jill A Rosenfeld, Mary Kay Koenig, Julián A Martínez-Agosto, Matthew Herzog, Agnes H Chen, Patricia I Dickson, Henry J Lin, Moin U Vera, Noriko Salamon, Damara Ortiz, Elena Infante, Wouter Steyaert, Bart Dermaut, Bruce Poppe, Hyung-Lok Chung, Zhongyuan Zuo, Pei-Tseng Lee, Oguz Kanca, Fan Xia, Yaping Yang, Edward C Smith, Joan Jasien, Sujay Kansagra, Gail Spiridigliozzi, Mays El-Dairi, Robert Lark, Kacie Riley, Dwight D Koeberl, Katie Golden-Grant, Shinya Yamamoto, Michael F Wangler, Ghayda Mirzaa, Dimitri Hemelsoet, Brendan Lee, Stanley F Nelson, David B Goldstein, Hugo J Bellen, Loren D M Pena
Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination...
August 2, 2018: American Journal of Human Genetics
Carol-Anne Martin, Kata Sarlós, Clare V Logan, Roshan Singh Thakur, David A Parry, Anna H Bizard, Andrea Leitch, Louise Cleal, Nadia Shaukat Ali, Mohammed A Al-Owain, William Allen, Janine Altmüller, Miriam Aza-Carmona, Bushra A Y Barakat, Jimena Barraza-García, Amber Begtrup, Massimo Bogliolo, Megan T Cho, Jaime Cruz-Rojo, Hassan Ali Mundi Dhahrabi, Nursel H Elcioglu, Gráinne S Gorman, Rebekah Jobling, Ian Kesterton, Yoshihito Kishita, Masakazu Kohda, Polona Le Quesne Stabej, Asam Jassim Malallah, Peter Nürnberg, Akira Ohtake, Yasushi Okazaki, Roser Pujol, Maria José Ramirez, Anya Revah-Politi, Masaru Shimura, Paul Stevens, Robert W Taylor, Lesley Turner, Hywel Williams, Carolyn Wilson, Gökhan Yigit, Laura Zahavich, Fowzan S Alkuraya, Jordi Surralles, Alejandro Iglesais, Kei Murayama, Bernd Wollnik, Mehul Dattani, Karen E Heath, Ian D Hickson, Andrew P Jackson
Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination...
August 2, 2018: American Journal of Human Genetics
Anne Gregor, Lynette G Sadleir, Reza Asadollahi, Silvia Azzarello-Burri, Agatino Battaglia, Lilian Bomme Ousager, Paranchai Boonsawat, Ange-Line Bruel, Rebecca Buchert, Eduardo Calpena, Benjamin Cogné, Bruno Dallapiccola, Felix Distelmaier, Frances Elmslie, Laurence Faivre, Tobias B Haack, Victoria Harrison, Alex Henderson, David Hunt, Bertrand Isidor, Pascal Joset, Satoko Kumada, Augusta M A Lachmeijer, Melissa Lees, Sally Ann Lynch, Francisco Martinez, Naomichi Matsumoto, Carey McDougall, Heather C Mefford, Noriko Miyake, Candace T Myers, Sébastien Moutton, Addie Nesbitt, Antonio Novelli, Carmen Orellana, Anita Rauch, Monica Rosello, Ken Saida, Avni B Santani, Ajoy Sarkar, Ingrid E Scheffer, Marwan Shinawi, Katharina Steindl, Joseph D Symonds, Elaine H Zackai, André Reis, Heinrich Sticht, Christiane Zweier
Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies...
August 2, 2018: American Journal of Human Genetics
Zeynep Coban-Akdemir, Janson J White, Xiaofei Song, Shalini N Jhangiani, Jawid M Fatih, Tomasz Gambin, Yavuz Bayram, Ivan K Chinn, Ender Karaca, Jaya Punetha, Cecilia Poli, Eric Boerwinkle, Chad A Shaw, Jordan S Orange, Richard A Gibbs, Tuuli Lappalainen, James R Lupski, Claudia M B Carvalho
Premature termination codon (PTC)-bearing transcripts are often degraded by nonsense-mediated decay (NMD) resulting in loss-of-function (LoF) alleles. However, not all PTCs result in LoF mutations, i.e., some such transcripts escape NMD and are translated to truncated peptide products that result in disease due to gain-of-function (GoF) effects. Since the location of the PTC is a major factor determining transcript fate, we hypothesized that depletion of protein-truncating variants (PTVs) within the gene region predicted to escape NMD in control databases could provide a rank for genic susceptibility for disease through GoF versus LoF...
August 2, 2018: American Journal of Human Genetics
Eveline Boudin, Tjeerd R de Jong, Tim C R Prickett, Bruno Lapauw, Kaatje Toye, Viviane Van Hoof, Ilse Luyckx, Aline Verstraeten, Hugo S A Heymans, Eelco Dulfer, Lut Van Laer, Ian R Berry, Angus Dobbie, Ed Blair, Bart Loeys, Eric A Espiner, Jan M Wit, Wim Van Hul, Peter Houpt, Geert R Mortier
The natriuretic peptide signaling pathway has been implicated in many cellular processes, including endochondral ossification and bone growth. More precisely, different mutations in the NPR-B receptor and the CNP ligand have been identified in individuals with either short or tall stature. In this study we show that the NPR-C receptor (encoded by NPR3) is also important for the regulation of linear bone growth. We report four individuals, originating from three different families, with a phenotype characterized by tall stature, long digits, and extra epiphyses in the hands and feet...
August 2, 2018: American Journal of Human Genetics
Fuxi Zhu, Chao Liu, Fengsong Wang, Xiaoyu Yang, Jingjing Zhang, Huan Wu, Zhiguo Zhang, Xiaojin He, Zhou Zhang, Ping Zhou, Zhaolian Wei, Yongliang Shang, Lina Wang, Ruidan Zhang, Ying-Chun Ouyang, Qing-Yuan Sun, Yunxia Cao, Wei Li
Acephalic spermatozoa syndrome is a severe teratozoospermia that leads to male infertility. Our previous work showed that biallelic SUN5 mutations are responsible for acephalic spermatozoa syndrome in about half of affected individuals, while pathogenic mechanisms in the other individuals remain to be elucidated. Here, we identified a homozygous nonsense mutation in the testis-specific gene PMFBP1 using whole-exome sequencing in a consanguineous family with two infertile brothers with acephalic spermatozoa syndrome...
August 2, 2018: American Journal of Human Genetics
Martin W Breuss, An Nguyen, Qiong Song, Thai Nguyen, Valentina Stanley, Kiely N James, Damir Musaev, Guoliang Chai, Sara A Wirth, Paula Anzenberg, Renee D George, Anide Johansen, Shaila Ali, Muhammad Zia-Ur-Rehman, Tipu Sultan, Maha S Zaki, Joseph G Gleeson
The dynamic shape of the endoplasmic reticulum (ER) is a reflection of its wide variety of critical cell biological functions. Consequently, perturbation of ER-shaping proteins can cause a range of human phenotypes. Here, we describe three affected children (from two consanguineous families) who carry homozygous loss-of-function mutations in LNPK (previously known as KIAA1715); this gene encodes lunapark, which is proposed to serve as a curvature-stabilizing protein within tubular three-way junctions of the ER...
August 2, 2018: American Journal of Human Genetics
Omer Weissbrod, Jonathan Flint, Saharon Rosset
Methods that estimate SNP-based heritability and genetic correlations from genome-wide association studies have proven to be powerful tools for investigating the genetic architecture of common diseases and exposing unexpected relationships between disorders. Many relevant studies employ a case-control design, yet most methods are primarily geared toward analyzing quantitative traits. Here we investigate the validity of three common methods for estimating SNP-based heritability and genetic correlation between diseases...
July 5, 2018: American Journal of Human Genetics
Barbara J Evans
No abstract text is available yet for this article.
July 5, 2018: American Journal of Human Genetics
Jennifer C Dreyfus, Mark E Sobel
No abstract text is available yet for this article.
July 5, 2018: American Journal of Human Genetics
Zhiwen Xu, Wing-Sze Lo, David B Beck, Luise A Schuch, Monika Oláhová, Robert Kopajtich, Yeeting E Chong, Charlotte L Alston, Elias Seidl, Liting Zhai, Ching-Fun Lau, Donna Timchak, Charles A LeDuc, Alain C Borczuk, Andrew F Teich, Jane Juusola, Christina Sofeso, Christoph Müller, Germaine Pierre, Tom Hilliard, Peter D Turnpenny, Matias Wagner, Matthias Kappler, Frank Brasch, John Paul Bouffard, Leslie A Nangle, Xiang-Lei Yang, Mingjie Zhang, Robert W Taylor, Holger Prokisch, Matthias Griese, Wendy K Chung, Paul Schimmel
The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities. Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases. Unlike dominantly inherited gain-of-function mutations, recessive loss-of-function mutations can potentially elucidate ex-translational activities. We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alpha2 beta2 phenylalanine-tRNA synthetase (FARS)...
July 5, 2018: American Journal of Human Genetics
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