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American Journal of Human Genetics

Felix Marbach, Cecilie F Rustad, Angelika Riess, Dejan Đukić, Tzung-Chien Hsieh, Itamar Jobani, Trine Prescott, Andrea Bevot, Florian Erger, Gunnar Houge, Maria Redfors, Janine Altmueller, Tomasz Stokowy, Christian Gilissen, Christian Kubisch, Emanuela Scarano, Laura Mazzanti, Torunn Fiskerstrand, Peter M Krawitz, Davor Lessel, Christian Netzer
Over a relatively short period of time, the clinical geneticist's "toolbox" has been expanded by machine-learning algorithms for image analysis, which can be applied to the task of syndrome identification on the basis of facial photographs, but these technologies harbor potential beyond the recognition of established phenotypes. Here, we comprehensively characterized two individuals with a hitherto unknown genetic disorder caused by the same de novo mutation in LEMD2 (c.1436C>T;p.Ser479Phe), the gene which encodes the nuclear envelope protein LEM domain-containing protein 2 (LEMD2)...
March 20, 2019: American Journal of Human Genetics
Eduardo Calpena, Alexia Hervieu, Teresa Kaserer, Sigrid M A Swagemakers, Jacqueline A C Goos, Olajumoke Popoola, Maria Jesus Ortiz-Ruiz, Tina Barbaro-Dieber, Lucy Bownass, Eva H Brilstra, Elise Brimble, Nicola Foulds, Theresa A Grebe, Aster V E Harder, Melissa M Lees, Kristin G Monaghan, Ruth A Newbury-Ecob, Kai-Ren Ong, Deborah Osio, Francis Jeshira Reynoso Santos, Maura R Z Ruzhnikov, Aida Telegrafi, Ellen van Binsbergen, Marieke F van Dooren, Peter J van der Spek, Julian Blagg, Stephen R F Twigg, Irene M J Mathijssen, Paul A Clarke, Andrew O M Wilkie
The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Here, we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder...
March 13, 2019: American Journal of Human Genetics
Ranad Shaheen, Nan Jiang, Fatema Alzahrani, Nour Ewida, Tarfa Al-Sheddi, Eman Alobeid, Damir Musaev, Valentina Stanley, Mais Hashem, Niema Ibrahim, Firdous Abdulwahab, Abduljabbar Alshenqiti, Fatma Mujgan Sonmez, Nadia Saqati, Hamad Alzaidan, Mohammad M Al-Qattan, Futwan Al-Mohanna, Joseph G Gleeson, Fowzan S Alkuraya
Ciliopathies are clinical disorders of the primary cilium with widely recognized phenotypic and genetic heterogeneity. In two Arab consanguineous families, we mapped a ciliopathy phenotype that most closely matches Joubert syndrome (hypotonia, developmental delay, typical facies, oculomotor apraxia, polydactyly, and subtle posterior fossa abnormalities) to a single locus in which a founder homozygous truncating variant in FAM149B1 was identified by exome sequencing. We subsequently identified a third Arab consanguineous multiplex family in which the phenotype of Joubert syndrome/oral-facial-digital syndrome (OFD VI) was found to co-segregate with the same founder variant in FAM149B1...
March 12, 2019: American Journal of Human Genetics
Elisabetta Morini, Dadi Gao, Connor M Montgomery, Monica Salani, Chiara Mazzasette, Tobias A Krussig, Brooke Swain, Paula Dietrich, Jana Narasimhan, Vijayalakshmi Gabbeta, Amal Dakka, Jean Hedrick, Xin Zhao, Marla Weetall, Nikolai A Naryshkin, Gregory G Wojtkiewicz, Chien-Ping Ko, Michael E Talkowski, Ioannis Dragatsis, Susan A Slaugenhaupt
Familial dysautonomia (FD) is a recessive neurodegenerative disease caused by a splice mutation in Elongator complex protein 1 (ELP1, also known as IKBKAP); this mutation leads to variable skipping of exon 20 and to a drastic reduction of ELP1 in the nervous system. Clinically, many of the debilitating aspects of the disease are related to a progressive loss of proprioception; this loss leads to severe gait ataxia, spinal deformities, and respiratory insufficiency due to neuromuscular incoordination. There is currently no effective treatment for FD, and the disease is ultimately fatal...
March 12, 2019: American Journal of Human Genetics
Kevin C J Nixon, Justine Rousseau, Max H Stone, Mohammed Sarikahya, Sophie Ehresmann, Seiji Mizuno, Naomichi Matsumoto, Noriko Miyake, Diana Baralle, Shane McKee, Kosuke Izumi, Alyssa L Ritter, Solveig Heide, Delphine Héron, Christel Depienne, Hannah Titheradge, Jamie M Kramer, Philippe M Campeau
Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on five individuals with mutations in SMARCD1; the individuals present with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. Trio exome sequencing proved the mutations to be de novo in four of the five individuals. Mutations in other SWI/SNF components cause Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, or other syndromic and non-syndromic NDDs...
March 12, 2019: American Journal of Human Genetics
Margaux L A Hujoel, Steven Gazal, Farhad Hormozdiari, Bryce van de Geijn, Alkes L Price
Regulatory elements, e.g., enhancers and promoters, have been widely reported to be enriched for disease and complex trait heritability. We investigated how this enrichment varies with the age of the underlying genome sequence, the conservation of regulatory function across species, and the target gene of the regulatory element. We estimated heritability enrichment by applying stratified LD score regression to summary statistics from 41 independent diseases and complex traits (average N = 320K) and meta-analyzing results across traits...
March 11, 2019: American Journal of Human Genetics
Susan M Hiatt, Michelle L Thompson, Jeremy W Prokop, James M J Lawlor, David E Gray, E Martina Bebin, Tuula Rinne, Marlies Kempers, Rolph Pfundt, Bregje W van Bon, Cyril Mignot, Caroline Nava, Christel Depienne, Louisa Kalsner, Anita Rauch, Pascal Joset, Ruxandra Bachmann-Gagescu, Ingrid M Wentzensen, Kirsty McWalter, Gregory M Cooper
Developmental delay and intellectual disability (DD and ID) are heterogeneous phenotypes that arise in many rare monogenic disorders. Because of this rarity, developing cohorts with enough individuals to robustly identify disease-associated genes is challenging. Social-media platforms that facilitate data sharing among sequencing labs can help to address this challenge. Through one such tool, GeneMatcher, we identified nine DD- and/or ID-affected probands with a rare, heterozygous variant in the gene encoding the serine/threonine-protein kinase BRSK2...
March 6, 2019: American Journal of Human Genetics
Xuling Zhu, Ling Yin, Matt Theisen, Jenny Zhuo, Summar Siddiqui, Becca Levy, Vladimir Presnyak, Andrea Frassetto, Jaclyn Milton, Timothy Salerno, Kerry E Benenato, Joe Milano, Andy Lynn, Staci Sabnis, Kristine Burke, Gilles Besin, Christine M Lukacs, Lin T Guey, Patrick F Finn, Paolo G V Martini
Fabry disease is an X-linked lysosomal storage disease caused by loss of alpha galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of globotriaosylceramide and its analogs in all cells and tissues. Although enzyme replacement therapy (ERT) is considered standard of care, the long-term effects of ERT on renal and cardiac manifestations remain uncertain and thus novel therapies are desirable. We herein report preclinical studies evaluating systemic messenger RNA (mRNA) encoding human α-Gal A in wild-type (WT) mice, α-Gal A-deficient mice, and WT non-human primates (NHPs)...
February 28, 2019: American Journal of Human Genetics
Benjamin Cogné, Sophie Ehresmann, Eliane Beauregard-Lacroix, Justine Rousseau, Thomas Besnard, Thomas Garcia, Slavé Petrovski, Shiri Avni, Kirsty McWalter, Patrick R Blackburn, Stephan J Sanders, Kévin Uguen, Jacqueline Harris, Julie S Cohen, Moira Blyth, Anna Lehman, Jonathan Berg, Mindy H Li, Usha Kini, Shelagh Joss, Charlotte von der Lippe, Christopher T Gordon, Jennifer B Humberson, Laurie Robak, Daryl A Scott, Vernon R Sutton, Cara M Skraban, Jennifer J Johnston, Annapurna Poduri, Magnus Nordenskjöld, Vandana Shashi, Erica H Gerkes, Ernie M H F Bongers, Christian Gilissen, Yuri A Zarate, Malin Kvarnung, Kevin P Lally, Peggy A Kulch, Brina Daniels, Andres Hernandez-Garcia, Nicholas Stong, Julie McGaughran, Kyle Retterer, Kristian Tveten, Jennifer Sullivan, Madeleine R Geisheker, Asbjorg Stray-Pedersen, Jennifer M Tarpinian, Eric W Klee, Julie C Sapp, Jacob Zyskind, Øystein L Holla, Emma Bedoukian, Francesca Filippini, Anne Guimier, Arnaud Picard, Øyvind L Busk, Jaya Punetha, Rolph Pfundt, Anna Lindstrand, Ann Nordgren, Fayth Kalb, Megha Desai, Ashley Harmon Ebanks, Shalini N Jhangiani, Tammie Dewan, Zeynep H Coban Akdemir, Aida Telegrafi, Elaine H Zackai, Amber Begtrup, Xiaofei Song, Annick Toutain, Ingrid M Wentzensen, Sylvie Odent, Dominique Bonneau, Xénia Latypova, Wallid Deb, Sylvia Redon, Frédéric Bilan, Marine Legendre, Caitlin Troyer, Kerri Whitlock, Oana Caluseriu, Marine I Murphree, Pavel N Pichurin, Katherine Agre, Ralitza Gavrilova, Tuula Rinne, Meredith Park, Catherine Shain, Erin L Heinzen, Rui Xiao, Jeanne Amiel, Stanislas Lyonnet, Bertrand Isidor, Leslie G Biesecker, Dan Lowenstein, Jennifer E Posey, Anne-Sophie Denommé-Pichon, Claude Férec, Xiang-Jiao Yang, Jill A Rosenfeld, Brigitte Gilbert-Dussardier, Séverine Audebert-Bellanger, Richard Redon, Holly A F Stessman, Christoffer Nellaker, Yaping Yang, James R Lupski, David B Goldstein, Evan E Eichler, Francois Bolduc, Stéphane Bézieau, Sébastien Küry, Philippe M Campeau
Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals...
February 28, 2019: American Journal of Human Genetics
Elizabeth E Palmer, Seungbeom Hong, Fatema Al Zahrani, Mais O Hashem, Fajr A Aleisa, Heba M Jalal Ahmed, Tejaswi Kandula, Rebecca Macintosh, Andre E Minoche, Clare Puttick, Velimir Gayevskiy, Alexander P Drew, Mark J Cowley, Marcel Dinger, Jill A Rosenfeld, Rui Xiao, Megan T Cho, Suliat F Yakubu, Lindsay B Henderson, Maria J Guillen Sacoto, Amber Begtrup, Muddathir Hamad, Marwan Shinawi, Marisa V Andrews, Marilyn C Jones, Kristin Lindstrom, Ruth E Bristol, Saima Kayani, Molly Snyder, María Mercedes Villanueva, Angeles Schteinschnaider, Laurence Faivre, Christel Thauvin, Antonio Vitobello, Tony Roscioli, Edwin P Kirk, Ann Bye, Jasmeen Merzaban, Łukas Jaremko, Mariusz Jaremko, Rani K Sachdev, Fowzan S Alkuraya, Stefan T Arold
Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies...
February 27, 2019: American Journal of Human Genetics
Molly E Kuo, Arjan F Theil, Anneke Kievit, May Christine Malicdan, Wendy J Introne, Thomas Christian, Frans W Verheijen, Desiree E C Smith, Marisa I Mendes, Lidia Hussaarts-Odijk, Eric van der Meijden, Marjon van Slegtenhorst, Martina Wilke, Wim Vermeulen, Anja Raams, Catherine Groden, Shino Shimada, Rebecca Meyer-Schuman, Ya Ming Hou, William A Gahl, Anthony Antonellis, Gajja S Salomons, Grazia M S Mancini
Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging tRNA molecules with cognate amino acids. Consistent with the essential function and ubiquitous expression of ARSs, mutations in 32 of the 37 ARS-encoding loci cause severe, early-onset recessive phenotypes. Previous genetic and functional data suggest a loss-of-function mechanism; however, our understanding of the allelic and locus heterogeneity of ARS-related disease is incomplete. Cysteinyl-tRNA synthetase (CARS) encodes the enzyme that charges tRNACys with cysteine in the cytoplasm...
February 26, 2019: American Journal of Human Genetics
Emad Bahrami-Samani, Yi Xing
Gene expression is tightly regulated at the post-transcriptional level through splicing, transport, translation, and decay. RNA-binding proteins (RBPs) play key roles in post-transcriptional gene regulation, and genetic variants that alter RBP-RNA interactions can affect gene products and functions. We developed a computational method ASPRIN (Allele-Specific Protein-RNA Interaction) that uses a joint analysis of CLIP-seq (cross-linking and immunoprecipitation followed by high-throughput sequencing) and RNA-seq data to identify genetic variants that alter RBP-RNA interactions by directly observing the allelic preference of RBP from CLIP-seq experiments as compared to RNA-seq...
February 25, 2019: American Journal of Human Genetics
Kim M Keppler-Noreuil, Julie C Sapp, Marjorie J Lindhurst, Thomas N Darling, Jasmine Burton-Akright, Mohammadhadi Bagheri, Eva Dombi, Ashlyn Gruber, Paul F Jarosinski, Staci Martin, Neera Nathan, Scott M Paul, Ronald E Savage, Pamela L Wolters, Brian Schwartz, Brigitte C Widemann, Leslie G Biesecker
Proteus syndrome is a life-threatening segmental overgrowth syndrome caused by a mosaic gain-of-function AKT1 variant. There are no effective treatments for Proteus syndrome. Miransertib is an AKT1 inhibitor that, prior to this study, has been evaluated only in adult oncology trials. We designed a non-randomized, phase 0/1 pilot study of miransertib in adults and children with Proteus syndrome to identify an appropriate dosage starting point for a future efficacy trial using a pharmacodynamic endpoint. The primary endpoint was a 50% reduction in the tissue levels of AKT phosphorylation from biopsies in affected individuals...
February 22, 2019: American Journal of Human Genetics
Hernan D Gonorazky, Sergey Naumenko, Arun K Ramani, Viswateja Nelakuditi, Pouria Mashouri, Peiqui Wang, Dennis Kao, Krish Ohri, Senthuri Viththiyapaskaran, Mark A Tarnopolsky, Katherine D Mathews, Steven A Moore, Andres N Osorio, David Villanova, Dwi U Kemaladewi, Ronald D Cohn, Michael Brudno, James J Dowling
Gene-panel and whole-exome analyses are now standard methodologies for mutation detection in Mendelian disease. However, the diagnostic yield achieved is at best 50%, leaving the genetic basis for disease unsolved in many individuals. New approaches are thus needed to narrow the diagnostic gap. Whole-genome sequencing is one potential strategy, but it currently has variant-interpretation challenges, particularly for non-coding changes. In this study we focus on transcriptome analysis, specifically total RNA sequencing (RNA-seq), by using monogenetic neuromuscular disorders as proof of principle...
February 20, 2019: American Journal of Human Genetics
Lindsay C Burrage, John J Reynolds, Nissan Vida Baratang, Jennifer B Phillips, Jeremy Wegner, Ashley McFarquhar, Martin R Higgs, Audrey E Christiansen, Denise G Lanza, John R Seavitt, Mahim Jain, Xiaohui Li, David A Parry, Vandana Raman, David Chitayat, Ivan K Chinn, Alison A Bertuch, Lefkothea Karaviti, Alan E Schlesinger, Dawn Earl, Michael Bamshad, Ravi Savarirayan, Harsha Doddapaneni, Donna Muzny, Shalini N Jhangiani, Christine M Eng, Richard A Gibbs, Weimin Bi, Lisa Emrick, Jill A Rosenfeld, John Postlethwait, Monte Westerfield, Mary E Dickinson, Arthur L Beaudet, Emmanuelle Ranza, Celine Huber, Valérie Cormier-Daire, Wei Shen, Rong Mao, Jason D Heaney, Jordan S Orange, Débora Bertola, Guilherme L Yamamoto, Wagner A R Baratela, Merlin G Butler, Asim Ali, Mehdi Adeli, Daniel H Cohn, Deborah Krakow, Andrew P Jackson, Melissa Lees, Amaka C Offiah, Colleen M Carlston, John C Carey, Grant S Stewart, Carlos A Bacino, Philippe M Campeau, Brendan Lee
SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia...
February 11, 2019: American Journal of Human Genetics
Hae Ryung Chang, Sung Yoon Cho, Jae Hoon Lee, Eunkyung Lee, Jieun Seo, Hye Ran Lee, Denise P Cavalcanti, Outi Mäkitie, Helena Valta, Katta M Girisha, Chung Lee, Kausthubham Neethukrishna, Gandham S Bhavani, Anju Shukla, Sheela Nampoothiri, Shubha R Phadke, Mi Jung Park, Shiro Ikegawa, Zheng Wang, Martin R Higgs, Grant S Stewart, Eunyoung Jung, Myeong-Sok Lee, Jong Hoon Park, Eun A Lee, Hongtae Kim, Kyungjae Myung, Woosung Jeon, Kyoungyeul Lee, Dongsup Kim, Ok-Hwa Kim, Murim Choi, Han-Woong Lee, Yonghwan Kim, Tae-Joon Cho
SPONASTRIME dysplasia is a rare, recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole-exome sequencing (WES), we identified bi-allelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. TONSL is a multi-domain scaffold protein that interacts with DNA replication and repair factors and which plays critical roles in resistance to replication stress and the maintenance of genome integrity...
February 8, 2019: American Journal of Human Genetics
Kelsey E Grinde, Lisa A Brown, Alexander P Reiner, Timothy A Thornton, Sharon R Browning
Admixture mapping studies have become more common in recent years, due in part to technological advances and growing international efforts to increase the diversity of genetic studies. However, many open questions remain about appropriate implementation of admixture mapping studies, including how best to control for multiple testing, particularly in the presence of population structure. In this study, we develop a theoretical framework to characterize the correlation of local ancestry and admixture mapping test statistics in admixed populations with contributions from any number of ancestral populations and arbitrary population structure...
February 4, 2019: American Journal of Human Genetics
Tristan J Hayeck, Nicholas Stong, Charles J Wolock, Brett Copeland, Sitharthan Kamalakaran, David B Goldstein, Andrew S Allen
Different parts of a gene can be of differential importance to development and health. This regional heterogeneity is also apparent in the distribution of disease-associated mutations, which often cluster in particular regions of disease-associated genes. The ability to precisely estimate functionally important sub-regions of genes will be key in correctly deciphering relationships between genetic variation and disease. Previous methods have had some success using standing human variation to characterize this variability in importance by measuring sub-regional intolerance, i...
January 18, 2019: American Journal of Human Genetics
Ximena M Bustamante-Marin, Wei-Ning Yin, Patrick R Sears, Michael E Werner, Eva J Brotslaw, Brian J Mitchell, Corey M Jania, Kirby L Zeman, Troy D Rogers, Laura E Herring, Luc Refabért, Lucie Thomas, Serge Amselem, Estelle Escudier, Marie Legendre, Barbara R Grubb, Michael R Knowles, Maimoona A Zariwala, Lawrence E Ostrowski
Primary ciliary dyskinesia (PCD) is a genetic disorder in which impaired ciliary function leads to chronic airway disease. Exome sequencing of a PCD subject identified an apparent homozygous frameshift variant, c.887_890delTAAG (p.Val296Glyfs∗ 13), in exon 5; this frameshift introduces a stop codon in amino acid 308 of the growth arrest-specific protein 2-like 2 (GAS2L2). Further genetic screening of unrelated PCD subjects identified a second proband with a compound heterozygous variant carrying the identical frameshift variant and a large deletion (c...
January 18, 2019: American Journal of Human Genetics
Caroline F Wright, Ben West, Marcus Tuke, Samuel E Jones, Kashyap Patel, Thomas W Laver, Robin N Beaumont, Jessica Tyrrell, Andrew R Wood, Timothy M Frayling, Andrew T Hattersley, Michael N Weedon
More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray...
January 18, 2019: American Journal of Human Genetics
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