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American Journal of Human Genetics

Sarah A McClymont, Paul W Hook, Alexandra I Soto, Xylena Reed, William D Law, Samuel J Kerans, Eric L Waite, Nicole J Briceno, Joey F Thole, Michael G Heckman, Nancy N Diehl, Zbigniew K Wszolek, Cedric D Moore, Heng Zhu, Jennifer A Akiyama, Diane E Dickel, Axel Visel, Len A Pennacchio, Owen A Ross, Michael A Beer, Andrew S McCallion
The progressive loss of midbrain (MB) dopaminergic (DA) neurons defines the motor features of Parkinson disease (PD), and modulation of risk by common variants in PD has been well established through genome-wide association studies (GWASs). We acquired open chromatin signatures of purified embryonic mouse MB DA neurons because we anticipated that a fraction of PD-associated genetic variation might mediate the variants' effects within this neuronal population. Correlation with >2,300 putative enhancers assayed in mice revealed enrichment for MB cis-regulatory elements (CREs), and these data were reinforced by transgenic analyses of six additional sequences in zebrafish and mice...
November 29, 2018: American Journal of Human Genetics
Clare V Logan, Jennie E Murray, David A Parry, Andrea Robertson, Roberto Bellelli, Žygimantė Tarnauskaitė, Rachel Challis, Louise Cleal, Valerie Borel, Adeline Fluteau, Javier Santoyo-Lopez, Tim Aitman, Inês Barroso, Donald Basel, Louise S Bicknell, Himanshu Goel, Hao Hu, Chad Huff, Michele Hutchison, Caroline Joyce, Rachel Knox, Amy E Lacroix, Sylvie Langlois, Shawn McCandless, Julie McCarrier, Kay A Metcalfe, Rose Morrissey, Nuala Murphy, Irène Netchine, Susan M O'Connell, Ann Haskins Olney, Nandina Paria, Jill A Rosenfeld, Mark Sherlock, Erin Syverson, Perrin C White, Carol Wise, Yao Yu, Margaret Zacharin, Indraneel Banerjee, Martin Reijns, Michael B Bober, Robert K Semple, Simon J Boulton, Jonathan J Rios, Andrew P Jackson
During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C...
November 23, 2018: American Journal of Human Genetics
Jacob C Ulirsch, Jeffrey M Verboon, Shideh Kazerounian, Michael H Guo, Daniel Yuan, Leif S Ludwig, Robert E Handsaker, Nour J Abdulhay, Claudia Fiorini, Giulio Genovese, Elaine T Lim, Aaron Cheng, Beryl B Cummings, Katherine R Chao, Alan H Beggs, Casie A Genetti, Colin A Sieff, Peter E Newburger, Edyta Niewiadomska, Michal Matysiak, Adrianna Vlachos, Jeffrey M Lipton, Eva Atsidaftos, Bertil Glader, Anupama Narla, Pierre-Emmanuel Gleizes, Marie-Françoise O'Donohue, Nathalie Montel-Lehry, David J Amor, Steven A McCarroll, Anne H O'Donnell-Luria, Namrata Gupta, Stacey B Gabriel, Daniel G MacArthur, Eric S Lander, Monkol Lek, Lydie Da Costa, David G Nathan, Andrei A Korostelev, Ron Do, Vijay G Sankaran, Hanna T Gazda
Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes...
November 21, 2018: American Journal of Human Genetics
Felix Brechtmann, Christian Mertes, Agnė Matusevičiūtė, Vicente A Yépez, Žiga Avsec, Maximilian Herzog, Daniel M Bader, Holger Prokisch, Julien Gagneur
RNA sequencing (RNA-seq) is gaining popularity as a complementary assay to genome sequencing for precisely identifying the molecular causes of rare disorders. A powerful approach is to identify aberrant gene expression levels as potential pathogenic events. However, existing methods for detecting aberrant read counts in RNA-seq data either lack assessments of statistical significance, so that establishing cutoffs is arbitrary, or rely on subjective manual corrections for confounders. Here, we describe OUTRIDER (Outlier in RNA-Seq Finder), an algorithm developed to address these issues...
November 21, 2018: American Journal of Human Genetics
Bobby G Ng, Jill A Rosenfeld, Lisa Emrick, Mahim Jain, Lindsay C Burrage, Brendan Lee, William J Craigen, David R Bearden, Brett H Graham, Hudson H Freeze
FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia...
November 21, 2018: American Journal of Human Genetics
Rick M Tankard, Mark F Bennett, Peter Degorski, Martin B Delatycki, Paul J Lockhart, Melanie Bahlo
Repeat expansions cause more than 30 inherited disorders, predominantly neurogenetic. These can present with overlapping clinical phenotypes, making molecular diagnosis challenging. Single-gene or small-panel PCR-based methods can help to identify the precise genetic cause, but they can be slow and costly and often yield no result. Researchers are increasingly performing genomic analysis via whole-exome and whole-genome sequencing (WES and WGS) to diagnose genetic disorders. However, until recently, analysis protocols could not identify repeat expansions in these datasets...
November 20, 2018: American Journal of Human Genetics
Mahmoud R Fassad, Amelia Shoemark, Marie Legendre, Robert A Hirst, France Koll, Pierrick le Borgne, Bruno Louis, Farheen Daudvohra, Mitali P Patel, Lucie Thomas, Mellisa Dixon, Thomas Burgoyne, Joseph Hayes, Andrew G Nicholson, Thomas Cullup, Lucy Jenkins, Siobhán B Carr, Paul Aurora, Michel Lemullois, Anne Aubusson-Fleury, Jean-François Papon, Christopher O'Callaghan, Serge Amselem, Claire Hogg, Estelle Escudier, Anne-Marie Tassin, Hannah M Mitchison
Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility...
November 20, 2018: American Journal of Human Genetics
Niki T Loges, Dinu Antony, Ales Maver, Matthew A Deardorff, Elif Yýlmaz Güleç, Alper Gezdirici, Tabea Nöthe-Menchen, Inga M Höben, Lena Jelten, Diana Frank, Claudius Werner, Johannes Tebbe, Kaman Wu, Elizabeth Goldmuntz, Goran Čuturilo, Bryan Krock, Alyssa Ritter, Rim Hjeij, Zeineb Bakey, Petra Pennekamp, Bernd Dworniczak, Han Brunner, Borut Peterlin, Cansaran Tanidir, Heike Olbrich, Heymut Omran, Miriam Schmidts
Dysfunction of motile monocilia, altering the leftward flow at the embryonic node essential for determination of left-right body asymmetry, is a major cause of laterality defects. Laterality defects are also often associated with reduced mucociliary clearance caused by defective multiple motile cilia of the airway and are responsible for destructive airway disease. Outer dynein arms (ODAs) are essential for ciliary beat generation, and human respiratory cilia contain different ODA heavy chains (HCs): the panaxonemally distributed γ-HC DNAH5, proximally located β-HC DNAH11 (defining ODA type 1), and the distally localized β-HC DNAH9 (defining ODA type 2)...
November 19, 2018: American Journal of Human Genetics
William B Dobyns, Kimberly A Aldinger, Gisele E Ishak, Ghayda M Mirzaa, Andrew E Timms, Megan E Grout, Marjolein H G Dremmen, Rachel Schot, Laura Vandervore, Marjon A van Slegtenhorst, Martina Wilke, Esmee Kasteleijn, Arthur S Lee, Brenda J Barry, Katherine R Chao, Krzysztof Szczałuba, Joyce Kobori, Andrea Hanson-Kahn, Jonathan A Bernstein, Lucinda Carr, Felice D'Arco, Kaori Miyana, Tetsuya Okazaki, Yoshiaki Saito, Masayuki Sasaki, Soma Das, Marsha M Wheeler, Michael J Bamshad, Deborah A Nickerson, Elizabeth C Engle, Frans W Verheijen, Dan Doherty, Grazia M S Mancini
To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals...
November 19, 2018: American Journal of Human Genetics
Linda Xu, Hanne Jensen, Jennifer J Johnston, Emilio Di Maria, Katja Kloth, Ileana Cristea, Julie C Sapp, Thomas N Darling, Laryssa A Huryn, Lisbeth Tranebjærg, Elisa Cinotti, Christian Kubisch, Eyvind Rødahl, Ove Bruland, Leslie G Biesecker, Gunnar Houge, Cecilie Bredrup
We have investigated a distinct disorder with progressive corneal neovascularization, keloid formation, chronic skin ulcers, wasting of subcutaneous tissue, flexion contractures of the fingers, and acro-osteolysis. In six affected individuals from four families, we found one of two recurrent variants in discoidin domain receptor tyrosine kinase 2 (DDR2): c.1829T>C (p.Leu610Pro) or c.2219A>G (p.Tyr740Cys). DDR2 encodes a collagen-responsive receptor tyrosine kinase that regulates connective-tissue formation...
November 8, 2018: American Journal of Human Genetics
Jennifer A Wambach, Daniel J Wegner, Nivedita Patni, Martin Kircher, Marcia C Willing, Dustin Baldridge, Chao Xing, Anil K Agarwal, Samantha A Schrier Vergano, Chirag Patel, Dorothy K Grange, Amy Kenney, Tasnim Najaf, Deborah A Nickerson, Michael J Bamshad, F Sessions Cole, Abhimanyu Garg
Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities...
November 5, 2018: American Journal of Human Genetics
Joshi Stephen, Sateesh Maddirevula, Sheela Nampoothiri, John D Burke, Matthew Herzog, Anju Shukla, Katharina Steindl, Ascia Eskin, Siddaramappa J Patil, Pascal Joset, Hane Lee, Lisa J Garrett, Tadafumi Yokoyama, Nicholas Balanda, Steven P Bodine, Nathanial J Tolman, Patricia M Zerfas, Allison Zheng, Georgia Ramantani, Katta M Girisha, Cecilia Rivas, Pujar V Suresh, Abdel Elkahloun, Hessa S Alsaif, Salma M Wakil, Laila Mahmoud, Rehab Ali, Michaela Prochazkova, Ashok B Kulkarni, Tawfeg Ben-Omran, Dilek Colak, H Douglas Morris, Anita Rauch, Julian A Martinez-Agosto, Stanley F Nelson, Fowzan S Alkuraya, William A Gahl, May Christine V Malicdan
Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals...
December 6, 2018: American Journal of Human Genetics
Ajai K Pathak, Anurag Kadian, Alena Kushniarevich, Francesco Montinaro, Mayukh Mondal, Linda Ongaro, Manvendra Singh, Pramod Kumar, Niraj Rai, Jüri Parik, Ene Metspalu, Siiri Rootsi, Luca Pagani, Toomas Kivisild, Mait Metspalu, Gyaneshwer Chaubey, Richard Villems
The Indus Valley has been the backdrop for several historic and prehistoric population movements between South Asia and West Eurasia. However, the genetic structure of present-day populations from Northwest India is poorly characterized. Here we report new genome-wide genotype data for 45 modern individuals from four Northwest Indian populations, including the Ror, whose long-term occupation of the region can be traced back to the early Vedic scriptures. Our results suggest that although the genetic architecture of most Northwest Indian populations fits well on the broader North-South Indian genetic cline, culturally distinct groups such as the Ror stand out by being genetically more akin to populations living west of India; such populations include prehistorical and early historical ancient individuals from the Swat Valley near the Indus Valley...
December 6, 2018: American Journal of Human Genetics
Dominic Nelson, Claudia Moreau, Marianne de Vriendt, Yixiao Zeng, Christoph Preuss, Hélène Vézina, Emmanuel Milot, Gregor Andelfinger, Damian Labuda, Simon Gravel
Learning the transmission history of alleles through a family or population plays an important role in evolutionary, demographic, and medical genetic studies. Most classical models of population genetics have attempted to do so under the assumption that the genealogy of a population is unavailable and that its idiosyncrasies can be described by a small number of parameters describing population size and mate choice dynamics. Large genetic samples have increased sensitivity to such modeling assumptions, and large-scale genealogical datasets become a useful tool to investigate realistic genealogies...
December 6, 2018: American Journal of Human Genetics
Xinyu Zhao, Anita Bhattacharyya
The analysis of animal models of neurological disease has been instrumental in furthering our understanding of neurodevelopment and brain diseases. However, animal models are limited in revealing some of the most fundamental aspects of development, genetics, pathology, and disease mechanisms that are unique to humans. These shortcomings are exaggerated in disorders that affect the brain, where the most significant differences between humans and animal models exist, and could underscore failures in targeted therapeutic interventions in affected individuals...
December 6, 2018: American Journal of Human Genetics
Peter D Turnpenny, Michael J Wright, Melissa Sloman, Richard Caswell, Anthony J van Essen, Erica Gerkes, Rolph Pfundt, Susan M White, Nava Shaul-Lotan, Lori Carpenter, G Bradley Schaefer, Alan Fryer, A Micheil Innes, Kirsten P Forbes, Wendy K Chung, Heather McLaughlin, Lindsay B Henderson, Amy E Roberts, Karen E Heath, Beatriz Paumard-Hernández, Blanca Gener, Katherine A Fawcett, Romana Gjergja-Juraški, Daniela T Pilz, Andrew E Fry
No abstract text is available yet for this article.
December 6, 2018: American Journal of Human Genetics
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
No abstract text is available yet for this article.
December 6, 2018: American Journal of Human Genetics
Arjan P M de Brouwer, Rami Abou Jamra, Nadine Körtel, Clara Soyris, Daniel L Polla, Modi Safra, Avia Zisso, Christopher A Powell, Pedro Rebelo-Guiomar, Nadja Dinges, Violeta Morin, Michael Stock, Mureed Hussain, Mohsin Shahzad, Saima Riazuddin, Zubair M Ahmed, Rolph Pfundt, Franziska Schwarz, Lonneke de Boer, André Reis, Detilina Grozeva, F Lucy Raymond, Sheikh Riazuddin, David A Koolen, Michal Minczuk, Jean-Yves Roignant, Hans van Bokhoven, Schraga Schwartz
We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs∗ 20), c.1348C>T (p.Arg450∗ ), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA...
December 6, 2018: American Journal of Human Genetics
Gemma L Carvill, Krysta L Engel, Aishwarya Ramamurthy, J Nicholas Cochran, Jolien Roovers, Hannah Stamberger, Nicholas Lim, Amy L Schneider, Georgie Hollingsworth, Dylan H Holder, Brigid M Regan, James Lawlor, Lieven Lagae, Berten Ceulemans, E Martina Bebin, John Nguyen, Gregory S Barsh, Sarah Weckhuysen, Miriam Meisler, Samuel F Berkovic, Peter De Jonghe, Ingrid E Scheffer, Richard M Myers, Gregory M Cooper, Heather C Mefford
Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs.1-3 This suggests that unknown genetic etiologies exist, potentially in the ∼98% of human genomes not covered by exome sequencing (ES). Here we describe seven likely pathogenic variants in regions outside of the annotated coding exons of the most frequently implicated epilepsy gene, SCN1A, encoding the alpha-1 sodium channel subunit...
December 6, 2018: American Journal of Human Genetics
Katharina Danhauser, Bader Alhaddad, Christine Makowski, Dorota Piekutowska-Abramczuk, Steffen Syrbe, Natalia Gomez-Ospina, Melanie A Manning, Anna Kostera-Pruszczyk, Claudia Krahn-Peper, Riccardo Berutti, Reka Kovács-Nagy, Mirjana Gusic, Elisabeth Graf, Lucia Laugwitz, Michaela Röblitz, Andreas Wroblewski, Hans Hartmann, Anibh M Das, Eva Bültmann, Fang Fang, Manting Xu, Ulrich A Schatz, Daniela Karall, Herta Zellner, Edda Haberlandt, René G Feichtinger, Johannes A Mayr, Thomas Meitinger, Holger Prokisch, Tim M Strom, Rafał Płoski, Georg F Hoffmann, Maciej Pronicki, Penelope E Bonnen, Susanne Morlot, Tobias B Haack
ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose from NAD+ to the target protein, and ADP-ribosylhydrolases, such as ADPRHL2, reverse the reaction. We used exome sequencing to identify five different bi-allelic pathogenic ADPRHL2 variants in 12 individuals from 8 families affected by a neurodegenerative disorder manifesting in childhood or adolescence with key clinical features including developmental delay or regression, seizures, ataxia, and axonal (sensori-)motor neuropathy...
November 1, 2018: American Journal of Human Genetics
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