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American Journal of Human Genetics

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https://www.readbyqxmd.com/read/29656859/dual-molecular-effects-of-dominant-rora-mutations-cause-two-variants-of-syndromic-intellectual-disability-with-either-autism-or-cerebellar-ataxia
#1
Claire Guissart, Xenia Latypova, Paul Rollier, Tahir N Khan, Hannah Stamberger, Kirsty McWalter, Megan T Cho, Susanne Kjaergaard, Sarah Weckhuysen, Gaetan Lesca, Thomas Besnard, Katrin Õunap, Lynn Schema, Andreas G Chiocchetti, Marie McDonald, Julitta de Bellescize, Marie Vincent, Hilde Van Esch, Shannon Sattler, Irman Forghani, Isabelle Thiffault, Christine M Freitag, Deborah Sara Barbouth, Maxime Cadieux-Dion, Rebecca Willaert, Maria J Guillen Sacoto, Nicole P Safina, Christèle Dubourg, Lauren Grote, Wilfrid Carré, Carol Saunders, Sander Pajusalu, Emily Farrow, Anne Boland, Danielle Hays Karlowicz, Jean-François Deleuze, Monica H Wojcik, Rena Pressman, Bertrand Isidor, Annick Vogels, Wim Van Paesschen, Lihadh Al-Gazali, Aisha Mohamed Al Shamsi, Mireille Claustres, Aurora Pujol, Stephan J Sanders, François Rivier, Nicolas Leboucq, Benjamin Cogné, Souphatta Sasorith, Damien Sanlaville, Kyle Retterer, Sylvie Odent, Nicholas Katsanis, Stéphane Bézieau, Michel Koenig, Erica E Davis, Laurent Pasquier, Sébastien Küry
RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy...
April 10, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29656858/a-recurrent-de-novo-pacs2-heterozygous-missense-variant-causes-neonatal-onset-developmental-epileptic-encephalopathy-facial-dysmorphism-and-cerebellar-dysgenesis
#2
Heather E Olson, Nolwenn Jean-Marçais, Edward Yang, Delphine Heron, Katrina Tatton-Brown, Paul A van der Zwaag, Emilia K Bijlsma, Bryan L Krock, E Backer, Erik-Jan Kamsteeg, Margje Sinnema, Margot R F Reijnders, David Bearden, Amber Begtrup, Aida Telegrafi, Roelineke J Lunsing, Lydie Burglen, Gaetan Lesca, Megan T Cho, Lacey A Smith, Beth R Sheidley, Christelle Moufawad El Achkar, Phillip L Pearl, Annapurna Poduri, Cara M Skraban, Jennifer Tarpinian, Addie I Nesbitt, Dietje E Fransen van de Putte, Claudia A L Ruivenkamp, Patrick Rump, Nicolas Chatron, Isabelle Sabatier, Julitta De Bellescize, Laurent Guibaud, David A Sweetser, Jessica L Waxler, Klaas J Wierenga, Jean Donadieu, Vinodh Narayanan, Keri M Ramsey, Caroline Nava, Jean-Baptiste Rivière, Antonio Vitobello, Frédéric Tran Mau-Them, Christophe Philippe, Ange-Line Bruel, Yannis Duffourd, Laurel Thomas, Stefan H Lelieveld, Janneke Schuurs-Hoeijmakers, Han G Brunner, Boris Keren, Julien Thevenon, Laurence Faivre, Gary Thomas, Christel Thauvin-Robinet
Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals...
April 10, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29656860/truncating-variants-in-naa15-are-associated-with-variable-levels-of-intellectual-disability-autism-spectrum-disorder-and-congenital-anomalies
#3
Hanyin Cheng, Avinash V Dharmadhikari, Sylvia Varland, Ning Ma, Deepti Domingo, Robert Kleyner, Alan F Rope, Margaret Yoon, Asbjørg Stray-Pedersen, Jennifer E Posey, Sarah R Crews, Mohammad K Eldomery, Zeynep Coban Akdemir, Andrea M Lewis, Vernon R Sutton, Jill A Rosenfeld, Erin Conboy, Katherine Agre, Fan Xia, Magdalena Walkiewicz, Mauro Longoni, Frances A High, Marjon A van Slegtenhorst, Grazia M S Mancini, Candice R Finnila, Arie van Haeringen, Nicolette den Hollander, Claudia Ruivenkamp, Sakkubai Naidu, Sonal Mahida, Elizabeth E Palmer, Lucinda Murray, Derek Lim, Parul Jayakar, Michael J Parker, Stefania Giusto, Emanuela Stracuzzi, Corrado Romano, Jennifer S Beighley, Raphael A Bernier, Sébastien Küry, Mathilde Nizon, Mark A Corbett, Marie Shaw, Alison Gardner, Christopher Barnett, Ruth Armstrong, Karin S Kassahn, Anke Van Dijck, Geert Vandeweyer, Tjitske Kleefstra, Jolanda Schieving, Marjolijn J Jongmans, Bert B A de Vries, Rolph Pfundt, Bronwyn Kerr, Samantha K Rojas, Kym M Boycott, Richard Person, Rebecca Willaert, Evan E Eichler, R Frank Kooy, Yaping Yang, Joseph C Wu, James R Lupski, Thomas Arnesen, Gregory M Cooper, Wendy K Chung, Jozef Gecz, Holly A F Stessman, Linyan Meng, Gholson J Lyon
N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15...
April 9, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29606302/bi-allelic-alterations-in-aebp1-lead-to-defective-collagen-assembly-and-connective-tissue-structure-resulting-in-a-variant-of-ehlers-danlos-syndrome
#4
Patrick R Blackburn, Zhi Xu, Kathleen E Tumelty, Rose W Zhao, William J Monis, Kimberly G Harris, Jennifer M Gass, Margot A Cousin, Nicole J Boczek, Mario V Mitkov, Mark A Cappel, Clair A Francomano, Joseph E Parisi, Eric W Klee, Eissa Faqeih, Fowzan S Alkuraya, Matthew D Layne, Nazli B McDonnell, Paldeep S Atwal
AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1-/- mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS)...
March 29, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29606301/absence-of-cfap69-causes-male-infertility-due-to-multiple-morphological-abnormalities-of-the-flagella-in-human-and-mouse
#5
Frederick N Dong, Amir Amiri-Yekta, Guillaume Martinez, Antoine Saut, Julie Tek, Laurence Stouvenel, Patrick Lorès, Thomas Karaouzène, Nicolas Thierry-Mieg, Véronique Satre, Sophie Brouillet, Abbas Daneshipour, Seyedeh Hanieh Hosseini, Mélanie Bonhivers, Hamid Gourabi, Emmanuel Dulioust, Christophe Arnoult, Aminata Touré, Pierre F Ray, Haiqing Zhao, Charles Coutton
The multiple morphological abnormalities of the flagella (MMAF) phenotype is among the most severe forms of sperm defects responsible for male infertility. The phenotype is characterized by the presence in the ejaculate of immotile spermatozoa with severe flagellar abnormalities including flagella being short, coiled, absent, and of irregular caliber. Recent studies have demonstrated that MMAF is genetically heterogeneous, and genes thus far associated with MMAF account for only one-third of cases. Here we report the identification of homozygous truncating mutations (one stop-gain and one splicing variant) in CFAP69 of two unrelated individuals by whole-exome sequencing of a cohort of 78 infertile men with MMAF...
March 28, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29576218/mutations-in-pmpcb-encoding-the-catalytic-subunit-of-the-mitochondrial-presequence-protease-cause-neurodegeneration-in-early-childhood
#6
F-Nora Vögtle, Björn Brändl, Austin Larson, Manuela Pendziwiat, Marisa W Friederich, Susan M White, Alice Basinger, Cansu Kücükköse, Hiltrud Muhle, Johanna A Jähn, Oliver Keminer, Katherine L Helbig, Carolyn F Delto, Lisa Myketin, Dirk Mossmann, Nils Burger, Noriko Miyake, Audrey Burnett, Andreas van Baalen, Mark A Lovell, Naomichi Matsumoto, Maie Walsh, Hung-Chun Yu, Deepali N Shinde, Ulrich Stephani, Johan L K Van Hove, Franz-Josef Müller, Ingo Helbig
Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins...
March 21, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29606303/phewas-and-beyond-the-landscape-of-associations-with-medical-diagnoses-and-clinical-measures-across-38-662-individuals-from-geisinger
#7
Anurag Verma, Anastasia Lucas, Shefali S Verma, Yu Zhang, Navya Josyula, Anqa Khan, Dustin N Hartzel, Daniel R Lavage, Joseph Leader, Marylyn D Ritchie, Sarah A Pendergrass
Most phenome-wide association studies (PheWASs) to date have used a small to moderate number of SNPs for association with phenotypic data. We performed a large-scale single-cohort PheWAS, using electronic health record (EHR)-derived case-control status for 541 diagnoses using International Classification of Disease version 9 (ICD-9) codes and 25 median clinical laboratory measures. We calculated associations between these diagnoses and traits with ∼630,000 common frequency SNPs with minor allele frequency > 0...
March 19, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29606300/homozygous-mutations-in-wee2-cause-fertilization-failure-and-female-infertility
#8
Qing Sang, Bin Li, Yanping Kuang, Xueqian Wang, Zhihua Zhang, Biaobang Chen, Ling Wu, Qifeng Lyu, Yonglun Fu, Zheng Yan, Xiaoyan Mao, Yao Xu, Jian Mu, Qiaoli Li, Li Jin, Lin He, Lei Wang
Fertilization is a fundamental process of development and is a prerequisite for successful human reproduction. In mice, although several receptor proteins have been shown to play important roles in the process of fertilization, only three genes have been shown to cause fertilization failure and infertility when deleted in vivo. In clinical practice, some infertility case subjects suffer from recurrent failure of in vitro fertilization and intracytoplasmic sperm injection attempts due to fertilization failure, but the genetic basis of fertilization failure in humans remains largely unknown...
March 19, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29576217/bi-allelic-mutations-in-eprs-encoding-the-glutamyl-prolyl-aminoacyl-trna-synthetase-cause-a-hypomyelinating-leukodystrophy
#9
Marisa I Mendes, Mariana Gutierrez Salazar, Kether Guerrero, Isabelle Thiffault, Gajja S Salomons, Laurence Gauquelin, Luan T Tran, Diane Forget, Marie-Soleil Gauthier, Quinten Waisfisz, Desiree E C Smith, Cas Simons, Marjo S van der Knaap, Iris Marquardt, Aida Lemes, Hanna Mierzewska, Bernhard Weschke, Wolfgang Koehler, Benoit Coulombe, Nicole I Wolf, Geneviève Bernard
Hypomyelinating leukodystrophies are genetic disorders characterized by insufficient myelin deposition during development. They are diagnosed on the basis of both clinical and MRI features followed by genetic confirmation. Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase. EPRS is a bifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species...
March 15, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29551419/relationship-between-deleterious-variation-genomic-autozygosity-and-disease-risk-insights-from-the-1000-genomes-project
#10
Trevor J Pemberton, Zachary A Szpiech
Genomic regions of autozygosity (ROAs) represent segments of individual genomes that are homozygous for haplotypes inherited identical-by-descent (IBD) from a common ancestor. ROAs are nonuniformly distributed across the genome, and increased ROA levels are a reported risk factor for numerous complex diseases. Previously, we hypothesized that long ROAs are enriched for deleterious homozygotes as a result of young haplotypes with recent deleterious mutations-relatively untouched by purifying selection-being paired IBD as a consequence of recent parental relatedness, a pattern supported by ROA and whole-exome sequence data on 27 individuals...
March 10, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29526281/outcomes-of-counseling-after-education-about-carrier-results-a-randomized-controlled-trial
#11
Katie L Lewis, Kendall L Umstead, Jennifer J Johnston, Ilana M Miller, Lydia J Thompson, Kristen P Fishler, Leslie G Biesecker, Barbara B Biesecker
In-person education and counseling for all people receiving genetic results is the predominant model of disclosure but is challenged by the growing volume of low-impact results generated by sequencing. Evidence suggests that web-based tools may be as effective as in-person counseling at educating individuals about their low-impact results. However, the effects of counseling have not been assessed. To evaluate its utility, carrier results were returned to 459 post-reproductive participants from the ClinSeq cohort within a randomized controlled trial...
March 7, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29526279/whole-genome-sequence-based-haplotypes-reveal-single-origin-of-the-sickle-allele-during-the-holocene-wet-phase
#12
Daniel Shriner, Charles N Rotimi
Five classical designations of sickle haplotypes are made on the basis of the presence or absence of restriction sites and are named after the ethno-linguistic groups or geographic regions from which the individuals with sickle cell anemia originated. Each haplotype is thought to represent an independent occurrence of the sickle mutation rs334 (c.20A>T [p.Glu7Val] in HBB). We investigated the origins of the sickle mutation by using whole-genome-sequence data. We identified 156 carriers from the 1000 Genomes Project, the African Genome Variation Project, and Qatar...
March 7, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29526280/antisense-therapy-for-a-common-corneal-dystrophy-ameliorates-tcf4-repeat-expansion-mediated-toxicity
#13
Christina Zarouchlioti, Beatriz Sanchez-Pintado, Nathaniel J Hafford Tear, Pontus Klein, Petra Liskova, Kalyan Dulla, Ma'ayan Semo, Anthony A Vugler, Kirithika Muthusamy, Lubica Dudakova, Hannah J Levis, Pavlina Skalicka, Pirro Hysi, Michael E Cheetham, Stephen J Tuft, Peter Adamson, Alison J Hardcastle, Alice E Davidson
Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (≥50 copies) of a non-coding trinucleotide repeat in TCF4 confers >76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. The CEC model demonstrated that the repeat expansion leads to nuclear RNA foci, with the sequestration of splicing factor proteins (MBNL1 and MBNL2) to the foci and altered mRNA processing...
March 1, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29478780/inherited-dna-repair-defects-in-colorectal-cancer
#14
Saud H AlDubayan, Marios Giannakis, Nathanael D Moore, G Celine Han, Brendan Reardon, Tsuyoshi Hamada, Xinmeng Jasmine Mu, Reiko Nishihara, Zhirong Qian, Li Liu, Matthew B Yurgelun, Sapna Syngal, Levi A Garraway, Shuji Ogino, Charles S Fuchs, Eliezer M Van Allen
Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC, but their contribution to CRC risk is largely unknown. We evaluated the gene-level germline mutation enrichment of 40 DRGs in 680 unselected CRC individuals and 27,728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1,661 unselected CRC individuals and 1,456 individuals with early-onset CRC...
February 21, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29478781/biallelic-mutations-in-atp5f1d-which-encodes-a-subunit-of-atp-synthase-cause-a-metabolic-disorder
#15
Monika Oláhová, Wan Hee Yoon, Kyle Thompson, Sharayu Jangam, Liliana Fernandez, Jean M Davidson, Jennifer E Kyle, Megan E Grove, Dianna G Fisk, Jennefer N Kohler, Matthew Holmes, Annika M Dries, Yong Huang, Chunli Zhao, Kévin Contrepois, Zachary Zappala, Laure Frésard, Daryl Waggott, Erika M Zink, Young-Mo Kim, Heino M Heyman, Kelly G Stratton, Bobbie-Jo M Webb-Robertson, Michael Snyder, Jason D Merker, Stephen B Montgomery, Paul G Fisher, René G Feichtinger, Johannes A Mayr, Julie Hall, Ines A Barbosa, Michael A Simpson, Charu Deshpande, Katrina M Waters, David M Koeller, Thomas O Metz, Andrew A Morris, Susan Schelley, Tina Cowan, Marisa W Friederich, Robert McFarland, Johan L K Van Hove, Gregory M Enns, Shinya Yamamoto, Euan A Ashley, Michael F Wangler, Robert W Taylor, Hugo J Bellen, Jonathan A Bernstein, Matthew T Wheeler
ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c...
February 16, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29478779/loss-of-function-of-the-nuclear-receptor-nr2f2-encoding-coup-tf2-causes-testis-development-and-cardiac-defects-in-46-xx-children
#16
Anu Bashamboo, Caroline Eozenou, Anne Jorgensen, Joelle Bignon-Topalovic, Jean-Pierre Siffroi, Capucine Hyon, Attila Tar, Péter Nagy, Janos Sólyom, Zita Halász, Annnabel Paye-Jaouen, Sophie Lambert, David Rodriguez-Buritica, Rita Bertalan, Laetitia Martinerie, Ewa Rajpert-De Meyts, John C Achermann, Ken McElreavey
Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD)...
February 16, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29455859/heterozygous-mutations-in-oas1-cause-infantile-onset-pulmonary-alveolar-proteinosis-with-hypogammaglobulinemia
#17
Kazutoshi Cho, Masafumi Yamada, Kazunaga Agematsu, Hirokazu Kanegane, Noriko Miyake, Masahiro Ueki, Takuma Akimoto, Norimoto Kobayashi, Satoru Ikemoto, Mishie Tanino, Atsushi Fujita, Itaru Hayasaka, Satoshi Miyamoto, Mari Tanaka-Kubota, Koh Nakata, Masaaki Shiina, Kazuhiro Ogata, Hisanori Minakami, Naomichi Matsumoto, Tadashi Ariga
Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of a surfactant-like substance in alveolar spaces and hypoxemic respiratory failure. Genetic PAP (GPAP) is caused by mutations in genes encoding surfactant proteins or genes encoding a surfactant phospholipid transporter in alveolar type II epithelial cells. GPAP is also caused by mutations in genes whose products are implicated in surfactant catabolism in alveolar macrophages (AMs). We performed whole-exome sequence analysis in a family affected by infantile-onset PAP with hypogammaglobulinemia without causative mutations in genes associated with PAP: SFTPB, SFTPC, ABCA3, CSF2RA, CSF2RB, and GATA2...
February 12, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29429572/mutations-in-the-baf-complex-subunit-dpf2-are-associated-with-coffin-siris-syndrome
#18
Georgia Vasileiou, Silvia Vergarajauregui, Sabine Endele, Bernt Popp, Christian Büttner, Arif B Ekici, Marion Gerard, Nuria C Bramswig, Beate Albrecht, Jill Clayton-Smith, Jenny Morton, Susan Tomkins, Karen Low, Astrid Weber, Maren Wenzel, Janine Altmüller, Yun Li, Bernd Wollnik, George Hoganson, Maria-Renée Plona, Megan T Cho, Christian T Thiel, Hermann-Josef Lüdecke, Tim M Strom, Eduardo Calpena, Andrew O M Wilkie, Dagmar Wieczorek, Felix B Engel, André Reis
Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2)...
February 5, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29429573/loss-of-function-mutations-in-unc45a-cause-a-syndrome-associating-cholestasis-diarrhea-impaired-hearing-and-bone-fragility
#19
Clothilde Esteve, Ludmila Francescatto, Perciliz L Tan, Aurélie Bourchany, Cécile De Leusse, Evelyne Marinier, Arnaud Blanchard, Patrice Bourgeois, Céline Brochier-Armanet, Ange-Line Bruel, Arnauld Delarue, Yannis Duffourd, Emmanuelle Ecochard-Dugelay, Géraldine Hery, Frédéric Huet, Philippe Gauchez, Emmanuel Gonzales, Catherine Guettier-Bouttier, Mina Komuta, Caroline Lacoste, Raphaelle Maudinas, Karin Mazodier, Yves Rimet, Jean-Baptiste Rivière, Bertrand Roquelaure, Sabine Sigaudy, Xavier Stephenne, Christel Thauvin-Robinet, Julien Thevenon, Jacques Sarles, Nicolas Levy, Catherine Badens, Olivier Goulet, Jean-Pierre Hugot, Nicholas Katsanis, Laurence Faivre, Alexandre Fabre
Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function...
February 1, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29394991/biallelic-variants-in-cnpy3-encoding-an-endoplasmic-reticulum-chaperone-cause-early-onset-epileptic-encephalopathy
#20
Hiroki Mutoh, Mitsuhiro Kato, Tenpei Akita, Takuma Shibata, Hiroyuki Wakamoto, Hiroko Ikeda, Hiroki Kitaura, Kazushi Aoto, Mitsuko Nakashima, Tianying Wang, Chihiro Ohba, Satoko Miyatake, Noriko Miyake, Akiyoshi Kakita, Kensuke Miyake, Atsuo Fukuda, Naomichi Matsumoto, Hirotomo Saitsu
Early-onset epileptic encephalopathies, including West syndrome (WS), are a group of neurological disorders characterized by developmental impairments and intractable seizures from early infancy. We have now identified biallelic CNPY3 variants in three individuals with WS; these include compound-heterozygous missense and frameshift variants in a family with two affected siblings (individuals 1 and 2) and a homozygous splicing variant in a consanguineous family (individual 3). All three individuals showed hippocampal malrotation...
January 26, 2018: American Journal of Human Genetics
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