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American Journal of Human Genetics

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https://www.readbyqxmd.com/read/30290155/a-recurrent-de-novo-pacs2-heterozygous-missense-variant-causes-neonatal-onset-developmental-epileptic-encephalopathy-facial-dysmorphism-and-cerebellar-dysgenesis
#1
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
No abstract text is available yet for this article.
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30290154/mutations-in-kcnk4-that-affect-gating-cause-a-recognizable-neurodevelopmental-syndrome
#2
Christiane K Bauer, Paolo Calligari, Francesca Clementina Radio, Viviana Caputo, Maria Lisa Dentici, Nadia Falah, Frances High, Francesca Pantaleoni, Sabina Barresi, Andrea Ciolfi, Simone Pizzi, Alessandro Bruselles, Richard Person, Sarah Richards, Megan T Cho, Daniela J Claps Sepulveda, Stefano Pro, Roberta Battini, Giuseppe Zampino, Maria Cristina Digilio, Gianfranco Bocchinfuso, Bruno Dallapiccola, Lorenzo Stella, Marco Tartaglia
Aberrant activation or inhibition of potassium (K+ ) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30290153/activating-mutations-in-pak1-encoding-p21-activated-kinase-1-cause-a-neurodevelopmental-disorder
#3
Frederike L Harms, Katja Kloth, Annette Bley, Jonas Denecke, René Santer, Davor Lessel, Maja Hempel, Kerstin Kutsche
p21-activated kinases (PAKs) are serine/threonine protein kinases acting as effectors of CDC42 and RAC, which are members of the RHO family of small GTPases. PAK1's kinase activity is autoinhibited by homodimerization, whereas CDC42 or RAC1 binding causes PAK1 activation by dimer dissociation. Major functions of the PAKs include actin cytoskeleton reorganization, for example regulation of the cellular protruding activity during cell spreading. We report the de novo PAK1 mutations c.392A>G (p.Tyr131Cys) and c...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30290152/bi-allelic-loss-of-function-variants-in-dnmbp-cause-infantile-cataracts
#4
Muhammad Ansar, Hyung-Lok Chung, Rachel L Taylor, Aamir Nazir, Samina Imtiaz, Muhammad T Sarwar, Alkistis Manousopoulou, Periklis Makrythanasis, Sondas Saeed, Emilie Falconnet, Michel Guipponi, Constantin J Pournaras, Maqsood A Ansari, Emmanuelle Ranza, Federico A Santoni, Jawad Ahmed, Inayat Shah, Khitab Gul, Graeme Cm Black, Hugo J Bellen, Stylianos E Antonarakis
Infantile and childhood-onset cataracts form a heterogeneous group of disorders; among the many genetic causes, numerous pathogenic variants in additional genes associated with autosomal-recessive infantile cataracts remain to be discovered. We identified three consanguineous families affected by bilateral infantile cataracts. Using exome sequencing, we found homozygous loss-of-function variants in DNMBP: nonsense variant c.811C>T (p.Arg271∗ ) in large family F385 (nine affected individuals; LOD score = 5...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30290151/a-recurrent-de-novo-heterozygous-cog4-substitution-leads-to-saul-wilson-syndrome-disrupted-vesicular-trafficking-and-altered-proteoglycan-glycosylation
#5
Carlos R Ferreira, Zhi-Jie Xia, Aurélie Clément, David A Parry, Mariska Davids, Fulya Taylan, Prashant Sharma, Coleman T Turgeon, Bernardo Blanco-Sánchez, Bobby G Ng, Clare V Logan, Lynne A Wolfe, Benjamin D Solomon, Megan T Cho, Ganka Douglas, Daniel R Carvalho, Heiko Bratke, Marte Gjøl Haug, Jennifer B Phillips, Jeremy Wegner, Michael Tiemeyer, Kazuhiro Aoki, Ann Nordgren, Anna Hammarsjö, Angela L Duker, Luis Rohena, Hanne Buciek Hove, Jakob Ek, David Adams, Cynthia J Tifft, Tito Onyekweli, Tara Weixel, Ellen Macnamara, Kelly Radtke, Zöe Powis, Dawn Earl, Melissa Gabriel, Alvaro H Serrano Russi, Lauren Brick, Mariya Kozenko, Emma Tham, Kimiyo M Raymond, John A Phillips, George E Tiller, William G Wilson, Rizwan Hamid, May C V Malicdan, Gen Nishimura, Giedre Grigelioniene, Andrew Jackson, Monte Westerfield, Michael B Bober, William A Gahl, Hudson H Freeze
The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30290150/phenotype-specific-enrichment-of-mendelian-disorder-genes-near-gwas-regions-across-62-complex-traits
#6
Malika Kumar Freund, Kathryn S Burch, Huwenbo Shi, Nicholas Mancuso, Gleb Kichaev, Kristina M Garske, David Z Pan, Zong Miao, Karen L Mohlke, Markku Laakso, Päivi Pajukanta, Bogdan Pasaniuc, Valerie A Arboleda
Although recent studies provide evidence for a common genetic basis between complex traits and Mendelian disorders, a thorough quantification of their overlap in a phenotype-specific manner remains elusive. Here, we have quantified the overlap of genes identified through large-scale genome-wide association studies (GWASs) for 62 complex traits and diseases with genes containing mutations known to cause 20 broad categories of Mendelian disorders. We identified a significant enrichment of genes linked to phenotypically matched Mendelian disorders in GWAS gene sets; of the total 1,240 comparisons, a higher proportion of phenotypically matched or related pairs (n = 50 of 92 [54%]) than phenotypically unmatched pairs (n = 27 of 1,148 [2%]) demonstrated significant overlap, confirming a phenotype-specific enrichment pattern...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30269814/mutations-in-pigs-encoding-a-gpi-transamidase-cause-a-neurological-syndrome-ranging-from-fetal-akinesia-to-epileptic-encephalopathy
#7
Thi Tuyet Mai Nguyen, Yoshiko Murakami, Kristen M Wigby, Nissan V Baratang, Justine Rousseau, Anik St-Denis, Jill A Rosenfeld, Stephanie C Laniewski, Julie Jones, Alejandro D Iglesias, Marilyn C Jones, Diane Masser-Frye, Angela E Scheuerle, Denise L Perry, Ryan J Taft, Françoise Le Deist, Miles Thompson, Taroh Kinoshita, Philippe M Campeau
Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result of advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30269813/burden-testing-of-rare-variants-identified-through-exome-sequencing-via-publicly-available-control-data
#8
Michael H Guo, Lacey Plummer, Yee-Ming Chan, Joel N Hirschhorn, Margaret F Lippincott
The genetic causes of many Mendelian disorders remain undefined. Factors such as lack of large multiplex families, locus heterogeneity, and incomplete penetrance hamper these efforts for many disorders. Previous work suggests that gene-based burden testing-where the aggregate burden of rare, protein-altering variants in each gene is compared between case and control subjects-might overcome some of these limitations. The increasing availability of large-scale public sequencing databases such as Genome Aggregation Database (gnomAD) can enable burden testing using these databases as controls, obviating the need for additional control sequencing for each study...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30269812/arl3-mutations-cause-joubert-syndrome-by-disrupting-ciliary-protein-composition
#9
Sumaya Alkanderi, Elisa Molinari, Ranad Shaheen, Yasmin Elmaghloob, Louise A Stephen, Veronica Sammut, Simon A Ramsbottom, Shalabh Srivastava, George Cairns, Noel Edwards, Sarah J Rice, Nour Ewida, Amal Alhashem, Kathryn White, Colin G Miles, David H Steel, Fowzan S Alkuraya, Shehab Ismail, John A Sayer
Joubert syndrome (JBTS) is a genetically heterogeneous autosomal-recessive neurodevelopmental ciliopathy. We investigated further the underlying genetic etiology of Joubert syndrome by studying two unrelated families in whom JBTS was not associated with pathogenic variants in known JBTS-associated genes. Combined autozygosity mapping of both families highlighted a candidate locus on chromosome 10 (chr10: 101569997-109106128, UCSC Genome Browser hg 19), and exome sequencing revealed two missense variants in ARL3 within the candidate locus...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30245030/bi-allelic-mutations-in-ndufa6-establish-its-role-in-early-onset-isolated-mitochondrial-complex-i-deficiency
#10
Charlotte L Alston, Juliana Heidler, Marris G Dibley, Laura S Kremer, Lucie S Taylor, Carl Fratter, Courtney E French, Ruth I C Glasgow, René G Feichtinger, Isabelle Delon, Alistair T Pagnamenta, Helen Dolling, Hugh Lemonde, Neil Aiton, Alf Bjørnstad, Lisa Henneke, Jutta Gärtner, Holger Thiele, Katerina Tauchmannova, Gerardine Quaghebeur, Josef Houstek, Wolfgang Sperl, F Lucy Raymond, Holger Prokisch, Johannes A Mayr, Robert McFarland, Joanna Poulton, Michael T Ryan, Ilka Wittig, Marco Henneke, Robert W Taylor
Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30245029/genomic-landscape-and-mutational-signatures-of-deafness-associated-genes
#11
Hela Azaiez, Kevin T Booth, Sean S Ephraim, Bradley Crone, Elizabeth A Black-Ziegelbein, Robert J Marini, A Eliot Shearer, Christina M Sloan-Heggen, Diana Kolbe, Thomas Casavant, Michael J Schnieders, Carla Nishimura, Terry Braun, Richard J H Smith
The classification of genetic variants represents a major challenge in the post-genome era by virtue of their extraordinary number and the complexities associated with ascribing a clinical impact, especially for disorders exhibiting exceptional phenotypic, genetic, and allelic heterogeneity. To address this challenge for hearing loss, we have developed the Deafness Variation Database (DVD), a comprehensive, open-access resource that integrates all available genetic, genomic, and clinical data together with expert curation to generate a single classification for each variant in 152 genes implicated in syndromic and non-syndromic deafness...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30245028/an-ancient-fecundability-associated-polymorphism-creates-a-gata2-binding-site-in-a-distal-enhancer-of-hla-f
#12
Katelyn M Mika, Xilong Li, Francesco J DeMayo, Vincent J Lynch
Variation in female reproductive traits, such as fertility, fecundity, and fecundability, are heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits have been challenging. Here, we explore the functional significance and evolutionary history of a G/A polymorphism at SNP rs2523393, which is an eQTL for HLA-F and is significantly associated with fecundability (the probability of being pregnant within a single menstrual cycle). We replicated the association between the rs2523393 genotype and HLA-F expression by using GTEx data and demonstrate that HLA-F is upregulated in the endometrium during the window of implantation and by progesterone in decidual stromal cells...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30220433/clinpred-prediction-tool-to-identify-disease-relevant-nonsynonymous-single-nucleotide-variants
#13
Najmeh Alirezaie, Kristin D Kernohan, Taila Hartley, Jacek Majewski, Toby Dylan Hocking
Advances in high-throughput DNA sequencing have revolutionized the discovery of variants in the human genome; however, interpreting the phenotypic effects of those variants is still a challenge. While several computational approaches to predict variant impact are available, their accuracy is limited and further improvement is needed. Here, we introduce ClinPred, an efficient tool for identifying disease-relevant nonsynonymous variants. Our predictor incorporates two machine learning algorithms that use existing pathogenicity scores and, notably, benefits from inclusion of normal population allele frequency from the gnomAD database as an input feature...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30220432/genetic-association-of-albuminuria-with-cardiometabolic-disease-and-blood-pressure
#14
Mary E Haas, Krishna G Aragam, Connor A Emdin, Alexander G Bick, Gibran Hemani, George Davey Smith, Sekar Kathiresan
Excretion of albumin in urine, or albuminuria, is associated with the development of multiple cardiovascular and metabolic diseases. However, whether pathways leading to albuminuria are causal for cardiometabolic diseases is unclear. We addressed this question using a Mendelian randomization framework in the UK Biobank, a large population-based cohort. We first performed a genome-wide association study for albuminuria in 382,500 individuals and identified 32 new albuminuria loci. We constructed albuminuria genetic risk scores and tested for association with cardiometabolic diseases...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30219179/a-multiplex-homology-directed-dna-repair-assay-reveals-the-impact-of-more-than-1-000-brca1-missense-substitution-variants-on-protein-function
#15
Lea M Starita, Muhtadi M Islam, Tapahsama Banerjee, Aleksandra I Adamovich, Justin Gullingsrud, Stanley Fields, Jay Shendure, Jeffrey D Parvin
Loss-of-function pathogenic variants in BRCA1 confer a predisposition to breast and ovarian cancer. Genetic testing for sequence changes in BRCA1 frequently reveals a missense variant for which the impact on cancer risk and on the molecular function of BRCA1 is unknown. Functional BRCA1 is required for the homology-directed repair (HDR) of double-strand DNA breaks, a critical activity for maintaining genome integrity and tumor suppression. Here, we describe a multiplex HDR reporter assay for concurrently measuring the effects of hundreds of variants of BRCA1 for their role in DNA repair...
October 4, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30193139/retraction-notice-to-nested-inversion-polymorphisms-predispose-chromosome-22q11-2-to-meiotic-rearrangements
#16
Wolfram Demaerel, Matthew S Hestand, Elfi Vergaelen, Ann Swillen, Marcos López-Sánchez, Luis A Pérez-Jurado, Donna M McDonald-McGinn, Elaine Zackai, Beverly S Emanuel, Bernice E Morrow, Jeroen Breckpot, Koenraad Devriendt, Joris R Vermeesch
No abstract text is available yet for this article.
September 6, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30193138/irf2bpl-is-associated-with-neurological-phenotypes
#17
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, John M Graham, 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
No abstract text is available yet for this article.
September 6, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30193137/mutations-in-top3a-cause-a-bloom-syndrome-like-disorder
#18
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 Iglesias, Kei Murayama, Bernd Wollnik, Mehul Dattani, Karen E Heath, Ian D Hickson, Andrew P Jackson
No abstract text is available yet for this article.
September 6, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30193136/the-clinical-sequencing-evidence-generating-research-consortium-integrating-genomic-sequencing-in-diverse-and-medically-underserved-populations
#19
Laura M Amendola, Jonathan S Berg, Carol R Horowitz, Frank Angelo, Jeannette T Bensen, Barbara B Biesecker, Leslie G Biesecker, Gregory M Cooper, Kelly East, Kelly Filipski, Stephanie M Fullerton, Bruce D Gelb, Katrina A B Goddard, Benyam Hailu, Ragan Hart, Kristen Hassmiller-Lich, Galen Joseph, Eimear E Kenny, Barbara A Koenig, Sara Knight, Pui-Yan Kwok, Katie L Lewis, Amy L McGuire, Mary E Norton, Jeffrey Ou, Donald W Parsons, Bradford C Powell, Neil Risch, Mimsie Robinson, Christine Rini, Sarah Scollon, Anne M Slavotinek, David L Veenstra, Melissa P Wasserstein, Benjamin S Wilfond, Lucia A Hindorff, Sharon E Plon, Gail P Jarvik
The Clinical Sequencing Evidence-Generating Research (CSER) consortium, now in its second funding cycle, is investigating the effectiveness of integrating genomic (exome or genome) sequencing into the clinical care of diverse and medically underserved individuals in a variety of healthcare settings and disease states. The consortium comprises a coordinating center, six funded extramural clinical projects, and an ongoing National Human Genome Research Institute (NHGRI) intramural project. Collectively, these projects aim to enroll and sequence over 6,100 participants in four years...
September 6, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30173820/pubcasefinder-a-case-report-based-phenotype-driven-differential-diagnosis-system-for-rare-diseases
#20
Toyofumi Fujiwara, Yasunori Yamamoto, Jin-Dong Kim, Orion Buske, Toshihisa Takagi
Recently, to speed up the differential-diagnosis process based on symptoms and signs observed from an affected individual in the diagnosis of rare diseases, researchers have developed and implemented phenotype-driven differential-diagnosis systems. The performance of those systems relies on the quantity and quality of underlying databases of disease-phenotype associations (DPAs). Although such databases are often developed by manual curation, they inherently suffer from limited coverage. To address this problem, we propose a text-mining approach to increase the coverage of DPA databases and consequently improve the performance of differential-diagnosis systems...
September 6, 2018: American Journal of Human Genetics
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