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American Journal of Human Genetics

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https://www.readbyqxmd.com/read/28823706/homozygous-mutations-in-tbc1d23-lead-to-a-non-degenerative-form-of-pontocerebellar-hypoplasia
#1
Isaac Marin-Valencia, Andreas Gerondopoulos, Maha S Zaki, Tawfeg Ben-Omran, Mariam Almureikhi, Ercan Demir, Alicia Guemez-Gamboa, Anne Gregor, Mahmoud Y Issa, Bart Appelhof, Susanne Roosing, Damir Musaev, Basak Rosti, Sara Wirth, Valentina Stanley, Frank Baas, Francis A Barr, Joseph G Gleeson
Pontocerebellar hypoplasia (PCH) represents a group of recessive developmental disorders characterized by impaired growth of the pons and cerebellum, which frequently follows a degenerative course. Currently, there are 10 partially overlapping clinical subtypes and 13 genes known mutated in PCH. Here, we report biallelic TBC1D23 mutations in six individuals from four unrelated families manifesting a non-degenerative form of PCH. In addition to reduced volume of pons and cerebellum, affected individuals had microcephaly, psychomotor delay, and ataxia...
August 16, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28823707/homozygous-truncating-variants-in-tbc1d23-cause-pontocerebellar-hypoplasia-and-alter-cortical-development
#2
Ekaterina L Ivanova, Frédéric Tran Mau-Them, Saima Riazuddin, Kimia Kahrizi, Vincent Laugel, Elise Schaefer, Anne de Saint Martin, Karen Runge, Zafar Iqbal, Marie-Aude Spitz, Mary Laura, Nathalie Drouot, Bénédicte Gérard, Jean-François Deleuze, Arjan P M de Brouwer, Attia Razzaq, Hélène Dollfus, Muhammad Zaman Assir, Patrick Nitchké, Maria-Victoria Hinckelmann, Hilger Ropers, Sheikh Riazuddin, Hossein Najmabadi, Hans van Bokhoven, Jamel Chelly
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly...
August 12, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28777935/de-novo-mutations-in-ywhag-cause-early-onset-epilepsy
#3
Ilaria Guella, Marna B McKenzie, Daniel M Evans, Sarah E Buerki, Eric B Toyota, Margot I Van Allen, Mohnish Suri, Frances Elmslie, Marleen E H Simon, Koen L I van Gassen, Delphine Héron, Boris Keren, Caroline Nava, Mary B Connolly, Michelle Demos, Matthew J Farrer
Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis...
August 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28777934/mutations-in-trappc12-manifest-in-progressive-childhood-encephalopathy-and-golgi-dysfunction
#4
Miroslav P Milev, Megan E Grout, Djenann Saint-Dic, Yong-Han Hank Cheng, Ian A Glass, Christopher J Hale, David S Hanna, Michael O Dorschner, Keshika Prematilake, Avraham Shaag, Orly Elpeleg, Michael Sacher, Dan Doherty, Simon Edvardson
Progressive childhood encephalopathy is an etiologically heterogeneous condition characterized by progressive central nervous system dysfunction in association with a broad range of morbidity and mortality. The causes of encephalopathy can be either non-genetic or genetic. Identifying the genetic causes and dissecting the underlying mechanisms are critical to understanding brain development and improving treatments. Here, we report that variants in TRAPPC12 result in progressive childhood encephalopathy. Three individuals from two unrelated families have either a homozygous deleterious variant (c...
August 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28777933/heterozygous-de-novo-ubtf-gain-of-function-variant-is-associated-with-neurodegeneration-in-childhood
#5
Simon Edvardson, Claudia M Nicolae, Pankaj B Agrawal, Cyril Mignot, Katelyn Payne, Asuri Narayan Prasad, Chitra Prasad, Laurie Sadler, Caroline Nava, Thomas E Mullen, Amber Begtrup, Berivan Baskin, Zöe Powis, Avraham Shaag, Boris Keren, George-Lucian Moldovan, Orly Elpeleg
Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2...
August 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28777932/long-noncoding-rnas-cupid1-and-cupid2-mediate-breast-cancer-risk-at-11q13-by-modulating-the-response-to-dna-damage
#6
Joshua A Betts, Mahdi Moradi Marjaneh, Fares Al-Ejeh, Yi Chieh Lim, Wei Shi, Haran Sivakumaran, Romain Tropée, Ann-Marie Patch, Michael B Clark, Nenad Bartonicek, Adrian P Wiegmans, Kristine M Hillman, Susanne Kaufmann, Amanda L Bain, Brian S Gloss, Joanna Crawford, Stephen Kazakoff, Shivangi Wani, Shu W Wen, Bryan Day, Andreas Möller, Nicole Cloonan, John Pearson, Melissa A Brown, Timothy R Mercer, Nicola Waddell, Kum Kum Khanna, Eloise Dray, Marcel E Dinger, Stacey L Edwards, Juliet D French
Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks...
August 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28777931/biallelic-mutations-in-mrps34-lead-to-instability-of-the-small-mitoribosomal-subunit-and-leigh-syndrome
#7
Nicole J Lake, Bryn D Webb, David A Stroud, Tara R Richman, Benedetta Ruzzenente, Alison G Compton, Hayley S Mountford, Juliette Pulman, Coralie Zangarelli, Marlene Rio, Nathalie Bodaert, Zahra Assouline, Mingma D Sherpa, Eric E Schadt, Sander M Houten, James Byrnes, Elizabeth M McCormick, Zarazuela Zolkipli-Cunningham, Katrina Haude, Zhancheng Zhang, Kyle Retterer, Renkui Bai, Sarah E Calvo, Vamsi K Mootha, John Christodoulou, Agnes Rötig, Aleksandra Filipovska, Ingrid Cristian, Marni J Falk, Metodi D Metodiev, David R Thorburn
The synthesis of all 13 mitochondrial DNA (mtDNA)-encoded protein subunits of the human oxidative phosphorylation (OXPHOS) system is carried out by mitochondrial ribosomes (mitoribosomes). Defects in the stability of mitoribosomal proteins or mitoribosome assembly impair mitochondrial protein translation, causing combined OXPHOS enzyme deficiency and clinical disease. Here we report four autosomal-recessive pathogenic mutations in the gene encoding the small mitoribosomal subunit protein, MRPS34, in six subjects from four unrelated families with Leigh syndrome and combined OXPHOS defects...
August 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28777930/from-peas-to-disease-modifier-genes-network-resilience-and-the-genetics-of-health
#8
REVIEW
Jesse D Riordan, Joseph H Nadeau
Phenotypes are rarely consistent across genetic backgrounds and environments, but instead vary in many ways depending on allelic variants, unlinked genes, epigenetic factors, and environmental exposures. In the extreme, individuals carrying the same causal DNA sequence variant but on different backgrounds can be classified as having distinct conditions. Similarly, some individuals that carry disease alleles are nevertheless healthy despite affected family members in the same environment. These genetic background effects often result from the action of so-called "modifier genes" that modulate the phenotypic manifestation of target genes in an epistatic manner...
August 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28777929/human-germline-genome-editing
#9
REVIEW
Kelly E Ormond, Douglas P Mortlock, Derek T Scholes, Yvonne Bombard, Lawrence C Brody, W Andrew Faucett, Nanibaa' A Garrison, Laura Hercher, Rosario Isasi, Anna Middleton, Kiran Musunuru, Daniel Shriner, Alice Virani, Caroline E Young
With CRISPR/Cas9 and other genome-editing technologies, successful somatic and germline genome editing are becoming feasible. To respond, an American Society of Human Genetics (ASHG) workgroup developed this position statement, which was approved by the ASHG Board in March 2017. The workgroup included representatives from the UK Association of Genetic Nurses and Counsellors, Canadian Association of Genetic Counsellors, International Genetic Epidemiology Society, and US National Society of Genetic Counselors...
August 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28757204/low-frequency-synonymous-coding-variation-in-cyp2r1-has-large-effects-on-vitamin-d-levels-and-risk-of-multiple-sclerosis
#10
Despoina Manousaki, Tom Dudding, Simon Haworth, Yi-Hsiang Hsu, Ching-Ti Liu, Carolina Medina-Gómez, Trudy Voortman, Nathalie van der Velde, Håkan Melhus, Cassianne Robinson-Cohen, Diana L Cousminer, Maria Nethander, Liesbeth Vandenput, Raymond Noordam, Vincenzo Forgetta, Celia M T Greenwood, Mary L Biggs, Bruce M Psaty, Jerome I Rotter, Babette S Zemel, Jonathan A Mitchell, Bruce Taylor, Mattias Lorentzon, Magnus Karlsson, Vincent V W Jaddoe, Henning Tiemeier, Natalia Campos-Obando, Oscar H Franco, Andre G Utterlinden, Linda Broer, Natasja M van Schoor, Annelies C Ham, M Arfan Ikram, David Karasik, Renée de Mutsert, Frits R Rosendaal, Martin den Heijer, Thomas J Wang, Lars Lind, Eric S Orwoll, Dennis O Mook-Kanamori, Karl Michaëlsson, Bryan Kestenbaum, Claes Ohlsson, Dan Mellström, Lisette C P G M de Groot, Struan F A Grant, Douglas P Kiel, M Carola Zillikens, Fernando Rivadeneira, Stephen Sawcer, Nicholas J Timpson, J Brent Richards
Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide...
August 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28757203/biallelic-mutations-in-lipt2-cause-a-mitochondrial-lipoylation-defect-associated-with-severe-neonatal-encephalopathy
#11
Florence Habarou, Yamina Hamel, Tobias B Haack, René G Feichtinger, Elise Lebigot, Iris Marquardt, Kanetee Busiah, Cécile Laroche, Marine Madrange, Coraline Grisel, Clément Pontoizeau, Monika Eisermann, Audrey Boutron, Dominique Chrétien, Bernadette Chadefaux-Vekemans, Robert Barouki, Christine Bole-Feysot, Patrick Nitschke, Nicolas Goudin, Nathalie Boddaert, Ivan Nemazanyy, Agnès Delahodde, Stefan Kölker, Richard J Rodenburg, G Christoph Korenke, Thomas Meitinger, Tim M Strom, Holger Prokisch, Agnes Rotig, Chris Ottolenghi, Johannes A Mayr, Pascale de Lonlay
Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (α-oxoglutarate dehydrogenase [α-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism...
August 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28757202/leveraging-multi-ethnic-evidence-for-risk-assessment-of-quantitative-traits-in-minority-populations
#12
Marc A Coram, Huaying Fang, Sophie I Candille, Themistocles L Assimes, Hua Tang
An essential component of precision medicine is the ability to predict an individual's risk of disease based on genetic and non-genetic factors. For complex traits and diseases, assessing the risk due to genetic factors is challenging because it requires knowledge of both the identity of variants that influence the trait and their corresponding allelic effects. Although the set of risk variants and their allelic effects may vary between populations, a large proportion of these variants were identified based on studies in populations of European descent...
August 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28757201/continuity-and-admixture-in-the-last-five-millennia-of-levantine-history-from-ancient-canaanite-and-present-day-lebanese-genome-sequences
#13
Marc Haber, Claude Doumet-Serhal, Christiana Scheib, Yali Xue, Petr Danecek, Massimo Mezzavilla, Sonia Youhanna, Rui Martiniano, Javier Prado-Martinez, Michał Szpak, Elizabeth Matisoo-Smith, Holger Schutkowski, Richard Mikulski, Pierre Zalloua, Toomas Kivisild, Chris Tyler-Smith
The Canaanites inhabited the Levant region during the Bronze Age and established a culture that became influential in the Near East and beyond. However, the Canaanites, unlike most other ancient Near Easterners of this period, left few surviving textual records and thus their origin and relationship to ancient and present-day populations remain unclear. In this study, we sequenced five whole genomes from ∼3,700-year-old individuals from the city of Sidon, a major Canaanite city-state on the Eastern Mediterranean coast...
August 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28735859/computational-prediction-of-position-effects-of-apparently-balanced-human-chromosomal-rearrangements
#14
Cinthya J Zepeda-Mendoza, Jonas Ibn-Salem, Tammy Kammin, David J Harris, Debra Rita, Karen W Gripp, Jennifer J MacKenzie, Andrea Gropman, Brett Graham, Ranad Shaheen, Fowzan S Alkuraya, Campbell K Brasington, Edward J Spence, Diane Masser-Frye, Lynne M Bird, Erica Spiegel, Rebecca L Sparkes, Zehra Ordulu, Michael E Talkowski, Miguel A Andrade-Navarro, Peter N Robinson, Cynthia C Morton
Interpretation of variants of uncertain significance, especially chromosomal rearrangements in non-coding regions of the human genome, remains one of the biggest challenges in modern molecular diagnosis. To improve our understanding and interpretation of such variants, we used high-resolution three-dimensional chromosomal structural data and transcriptional regulatory information to predict position effects and their association with pathogenic phenotypes in 17 subjects with apparently balanced chromosomal abnormalities...
August 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28712454/crispr-cas9-mediated-scanning-for-regulatory-elements-required-for-hprt1-expression-via-thousands-of-large-programmed-genomic-deletions
#15
Molly Gasperini, Gregory M Findlay, Aaron McKenna, Jennifer H Milbank, Choli Lee, Melissa D Zhang, Darren A Cusanovich, Jay Shendure
The extent to which non-coding mutations contribute to Mendelian disease is a major unknown in human genetics. Relatedly, the vast majority of candidate regulatory elements have yet to be functionally validated. Here, we describe a CRISPR-based system that uses pairs of guide RNAs (gRNAs) to program thousands of kilobase-scale deletions that deeply scan across a targeted region in a tiling fashion ("ScanDel"). We applied ScanDel to HPRT1, the housekeeping gene underlying Lesch-Nyhan syndrome, an X-linked recessive disorder...
August 3, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28686858/a-pentanucleotide-atttc-repeat-insertion-in-the-non-coding-region-of-dab1-mapping-to-sca37-causes-spinocerebellar-ataxia
#16
Ana I Seixas, Joana R Loureiro, Cristina Costa, Andrés Ordóñez-Ugalde, Hugo Marcelino, Cláudia L Oliveira, José L Loureiro, Ashutosh Dhingra, Eva Brandão, Vitor T Cruz, Angela Timóteo, Beatriz Quintáns, Guy A Rouleau, Patrizia Rizzu, Ángel Carracedo, José Bessa, Peter Heutink, Jorge Sequeiros, Maria J Sobrido, Paula Coutinho, Isabel Silveira
Advances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the non-coding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis...
July 6, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28686857/integrative-genetic-and-epigenetic-analysis-uncovers-regulatory-mechanisms-of-autoimmune-disease
#17
Parisa Shooshtari, Hailiang Huang, Chris Cotsapas
Genome-wide association studies in autoimmune and inflammatory diseases (AID) have uncovered hundreds of loci mediating risk. These associations are preferentially located in non-coding DNA regions and in particular in tissue-specific DNase I hypersensitivity sites (DHSs). While these analyses clearly demonstrate the overall enrichment of disease risk alleles on gene regulatory regions, they are not designed to identify individual regulatory regions mediating risk or the genes under their control, and thus uncover the specific molecular events driving disease risk...
July 6, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28686856/10-years-of-gwas-discovery-biology-function-and-translation
#18
REVIEW
Peter M Visscher, Naomi R Wray, Qian Zhang, Pamela Sklar, Mark I McCarthy, Matthew A Brown, Jian Yang
Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data...
July 6, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28686855/large-scale-identification-of-common-trait-and-disease-variants-affecting-gene-expression
#19
Mads Engel Hauberg, Wen Zhang, Claudia Giambartolomei, Oscar Franzén, David L Morris, Timothy J Vyse, Arno Ruusalepp, Pamela Sklar, Eric E Schadt, Johan L M Björkegren, Panos Roussos
No abstract text is available yet for this article.
July 6, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28686854/rest-final-exon-truncating-mutations-cause-hereditary-gingival-fibromatosis
#20
Yavuz Bayram, Janson J White, Nursel Elcioglu, Megan T Cho, Neda Zadeh, Asuman Gedikbasi, Sukru Palanduz, Sukru Ozturk, Kivanc Cefle, Ozgur Kasapcopur, Zeynep Coban Akdemir, Davut Pehlivan, Amber Begtrup, Claudia M B Carvalho, Ingrid Sophie Paine, Ali Mentes, Kivanc Bektas-Kayhan, Ender Karaca, Shalini N Jhangiani, Donna M Muzny, Richard A Gibbs, James R Lupski
Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern...
July 6, 2017: American Journal of Human Genetics
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