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American Journal of Human Genetics

Bin Guan, James M Welch, Julie C Sapp, Hua Ling, Yulong Li, Jennifer J Johnston, Electron Kebebew, Leslie G Biesecker, William F Simonds, Stephen J Marx, Sunita K Agarwal
Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by parathyroid hormone excess and hypercalcemia and caused by hypersecreting parathyroid glands. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. The specific genetic or other cause(s) of FIHP are unknown. We performed exome sequencing on germline DNA of eight index-case individuals from eight unrelated kindreds with FIHP...
October 13, 2016: American Journal of Human Genetics
Luca Bello, Kevin M Flanigan, Robert B Weiss, Pietro Spitali, Annemieke Aartsma-Rus, Francesco Muntoni, Irina Zaharieva, Alessandra Ferlini, Eugenio Mercuri, Sylvie Tuffery-Giraud, Mireille Claustres, Volker Straub, Hanns Lochmüller, Andrea Barp, Sara Vianello, Elena Pegoraro, Jaya Punetha, Heather Gordish-Dressman, Mamta Giri, Craig M McDonald, Eric P Hoffman
The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor β [TGFβ]-binding protein 4) have been established as DMD modifiers...
October 12, 2016: American Journal of Human Genetics
Wenqing Fu, Sharon R Browning, Brian L Browning, Joshua M Akey
Identifying and characterizing genomic regions that are shared identical by descent (IBD) among individuals can yield insight into population history, facilitate the identification of adaptively evolving loci, and be an important tool in disease gene mapping. Although increasingly large collections of exome sequences have been generated, it is challenging to detect IBD segments in exomes, precluding many potentially informative downstream analyses. Here, we describe an approach, ExIBD, to robustly detect IBD segments in exome-sequencing data, rigorously evaluate its performance, and apply this method to high-coverage exomes from 6,515 European and African Americans...
October 6, 2016: American Journal of Human Genetics
Beryl Royer-Bertrand, Matteo Torsello, Donata Rimoldi, Ikram El Zaoui, Katarina Cisarova, Rosanna Pescini-Gobert, Franck Raynaud, Leonidas Zografos, Ann Schalenbourg, Daniel Speiser, Michael Nicolas, Laureen Vallat, Robert Klein, Serge Leyvraz, Giovanni Ciriello, Nicolò Riggi, Alexandre P Moulin, Carlo Rivolta
Uveal melanoma (UM) is a rare intraocular tumor that, similar to cutaneous melanoma, originates from melanocytes. To gain insights into its genetics, we performed whole-genome sequencing at very deep coverage of tumor-control pairs in 33 samples (24 primary and 9 metastases). Genome-wide, the number of coding mutations was rather low (only 17 variants per tumor on average; range 7-28), thus radically different from cutaneous melanoma, where hundreds of exonic DNA insults are usually detected. Furthermore, no UV light-induced mutational signature was identified...
October 6, 2016: American Journal of Human Genetics
Zehra Ordulu, Tammy Kammin, Harrison Brand, Vamsee Pillalamarri, Claire E Redin, Ryan L Collins, Ian Blumenthal, Carrie Hanscom, Shahrin Pereira, India Bradley, Barbara F Crandall, Pamela Gerrol, Mark A Hayden, Naveed Hussain, Bibi Kanengisser-Pines, Sibel Kantarci, Brynn Levy, Michael J Macera, Fabiola Quintero-Rivera, Erica Spiegel, Blair Stevens, Janet E Ulm, Dorothy Warburton, Louise E Wilkins-Haug, Naomi Yachelevich, James F Gusella, Michael E Talkowski, Cynthia C Morton
In this exciting era of "next-gen cytogenetics," integrating genomic sequencing into the prenatal diagnostic setting is possible within an actionable time frame and can provide precise delineation of balanced chromosomal rearrangements at the nucleotide level. Given the increased risk of congenital abnormalities in newborns with de novo balanced chromosomal rearrangements, comprehensive interpretation of breakpoints could substantially improve prediction of phenotypic outcomes and support perinatal medical care...
October 5, 2016: American Journal of Human Genetics
Sirui Zhou, Amirthagowri Ambalavanan, Daniel Rochefort, Pingxing Xie, Cynthia V Bourassa, Pascale Hince, Alexandre Dionne-Laporte, Dan Spiegelman, Ziv Gan-Or, Cathy Mirarchi, Vessela Zaharieva, Nicolas Dupré, Hatasu Kobayashi, Toshiaki Hitomi, Kouji Harada, Akio Koizumi, Lan Xiong, Patrick A Dion, Guy A Rouleau
Intracranial aneurysms (IAs) are the result of focal weakness in the artery wall and have a complex genetic makeup. To date, genome-wide association and sequencing studies have had limited success in identifying IA risk factors. Distinct populations, such as the French-Canadian (FC) population, have increased IA prevalence. In our study, we used exome sequencing to prioritize risk variants in a discovery cohort of six FC families affected by IA, and the analysis revealed an increased variation burden for ring finger protein 213 (RNF213)...
September 30, 2016: American Journal of Human Genetics
Gina L O'Grady, Heather A Best, Tamar E Sztal, Vanessa Schartner, Myriam Sanjuan-Vazquez, Sandra Donkervoort, Osorio Abath Neto, Roger Bryan Sutton, Biljana Ilkovski, Norma Beatriz Romero, Tanya Stojkovic, Jahannaz Dastgir, Leigh B Waddell, Anne Boland, Ying Hu, Caitlin Williams, Avnika A Ruparelia, Thierry Maisonobe, Anthony J Peduto, Stephen W Reddel, Monkol Lek, Taru Tukiainen, Beryl B Cummings, Himanshu Joshi, Juliette Nectoux, Susan Brammah, Jean-François Deleuze, Viola Oorschot Ing, Georg Ramm, Didem Ardicli, Kristen J Nowak, Beril Talim, Haluk Topaloglu, Nigel G Laing, Kathryn N North, Daniel G MacArthur, Sylvie Friant, Nigel F Clarke, Robert J Bryson-Richardson, Carsten G Bönnemann, Jocelyn Laporte, Sandra T Cooper
This study establishes PYROXD1 variants as a cause of early-onset myopathy and uses biospecimens and cell lines, yeast, and zebrafish models to elucidate the fundamental role of PYROXD1 in skeletal muscle. Exome sequencing identified recessive variants in PYROXD1 in nine probands from five families. Affected individuals presented in infancy or childhood with slowly progressive proximal and distal weakness, facial weakness, nasal speech, swallowing difficulties, and normal to moderately elevated creatine kinase...
September 28, 2016: American Journal of Human Genetics
Ines Kapferer-Seebacher, Melanie Pepin, Roland Werner, Timothy J Aitman, Ann Nordgren, Heribert Stoiber, Nicole Thielens, Christine Gaboriaud, Albert Amberger, Anna Schossig, Robert Gruber, Cecilia Giunta, Michael Bamshad, Erik Björck, Christina Chen, David Chitayat, Michael Dorschner, Marcus Schmitt-Egenolf, Christopher J Hale, David Hanna, Hans Christian Hennies, Irene Heiss-Kisielewsky, Anna Lindstrand, Pernilla Lundberg, Anna L Mitchell, Deborah A Nickerson, Eyal Reinstein, Marianne Rohrbach, Nikolaus Romani, Matthias Schmuth, Rachel Silver, Fulya Taylan, Anthony Vandersteen, Jana Vandrovcova, Ruwan Weerakkody, Margaret Yang, F Michael Pope, Peter H Byers, Johannes Zschocke
Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition...
September 27, 2016: American Journal of Human Genetics
Katelyn M Mika, Vincent J Lynch
Variation in female reproductive traits, such as fertility, fecundity, and fecundability, is heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits has been challenging. Here, we explore the functional significance and evolutionary history of a T/C polymorphism of SNP rs2071473, which we have previously shown is an eQTL for TAP2 and significantly associated with fecundability (time to pregnancy). We replicated the association between the rs2071473 genotype and TAP2 expression by using GTEx data and demonstrated that TAP2 is expressed by decidual stromal cells at the maternal-fetal interface...
September 24, 2016: American Journal of Human Genetics
Terry Hassold, Ernest B Hook, Patricia A Jacobs
No abstract text is available yet for this article.
October 6, 2016: American Journal of Human Genetics
Na Li, Lakshman Subrahmanyan, Emily Smith, Xiaoqing Yu, Samir Zaidi, Murim Choi, Shrikant Mane, Carol Nelson-Williams, Mohaddeseh Behjati, Mohammad Kazemi, Mohammad Hashemi, Mohsen Fathzadeh, Anand Narayanan, Likun Tian, Farhad Montazeri, Mitra Mani, Michael L Begleiter, Brian G Coon, Henry T Lynch, Eric N Olson, Hongyu Zhao, Jürgen Ruland, Richard P Lifton, Arya Mani
No abstract text is available yet for this article.
October 6, 2016: American Journal of Human Genetics
Kyle Thompson, Homa Majd, Christina Dallabona, Karit Reinson, Martin S King, Charlotte L Alston, Langping He, Tiziana Lodi, Simon A Jones, Aviva Fattal-Valevski, Nitay D Fraenkel, Ann Saada, Alon Haham, Pirjo Isohanni, Roshni Vara, Inês A Barbosa, Michael A Simpson, Charu Deshpande, Sanna Puusepp, Penelope E Bonnen, Richard J Rodenburg, Anu Suomalainen, Katrin Õunap, Orly Elpeleg, Ileana Ferrero, Robert McFarland, Edmund R S Kunji, Robert W Taylor
Mutations in SLC25A4 encoding the mitochondrial ADP/ATP carrier AAC1 are well-recognized causes of mitochondrial disease. Several heterozygous SLC25A4 mutations cause adult-onset autosomal-dominant progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions, whereas recessive SLC25A4 mutations cause childhood-onset mitochondrial myopathy and cardiomyopathy. Here, we describe the identification by whole-exome sequencing of seven probands harboring dominant, de novo SLC25A4 mutations...
October 6, 2016: American Journal of Human Genetics
Vandana Shashi, Loren D M Pena, Katherine Kim, Barbara Burton, Maja Hempel, Kelly Schoch, Magdalena Walkiewicz, Heather M McLaughlin, Megan Cho, Nicholas Stong, Scott E Hickey, Christine M Shuss, Michael S Freemark, Jane S Bellet, Martha Ann Keels, Melanie J Bonner, Maysantoine El-Dairi, Megan Butler, Peter G Kranz, Constance T R M Stumpel, Sylvia Klinkenberg, Karin Oberndorff, Malik Alawi, Rene Santer, Slavé Petrovski, Outi Kuismin, Satu Korpi-Heikkilä, Olli Pietilainen, Palotie Aarno, Mitja I Kurki, Alexander Hoischen, Anna C Need, David B Goldstein, Fanny Kortüm
The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder...
October 6, 2016: American Journal of Human Genetics
David A Parry, Claire E L Smith, Walid El-Sayed, James A Poulter, Roger C Shore, Clare V Logan, Chihiro Mogi, Koichi Sato, Fumikazu Okajima, Akihiro Harada, Hong Zhang, Mine Koruyucu, Figen Seymen, Jan C-C Hu, James P Simmer, Mushtaq Ahmed, Hussain Jafri, Colin A Johnson, Chris F Inglehearn, Alan J Mighell
Amelogenesis is the process of dental enamel formation, leading to the deposition of the hardest tissue in the human body. This process requires the intricate regulation of ion transport and controlled changes to the pH of the developing enamel matrix. The means by which the enamel organ regulates pH during amelogenesis is largely unknown. We identified rare homozygous variants in GPR68 in three families with amelogenesis imperfecta, a genetically and phenotypically heterogeneous group of inherited conditions associated with abnormal enamel formation...
October 6, 2016: American Journal of Human Genetics
Noriko Miyake, Ryoko Fukai, Chihiro Ohba, Takahiro Chihara, Masayuki Miura, Hiroshi Shimizu, Akiyoshi Kakita, Eri Imagawa, Masaaki Shiina, Kazuhiro Ogata, Jiu Okuno-Yuguchi, Noboru Fueki, Yoshifumi Ogiso, Hiroshi Suzumura, Yoshiyuki Watabe, George Imataka, Huey Yin Leong, Aviva Fattal-Valevski, Uri Kramer, Satoko Miyatake, Mitsuhiro Kato, Nobuhiko Okamoto, Yoshinori Sato, Satomi Mitsuhashi, Ichizo Nishino, Naofumi Kaneko, Akira Nishiyama, Tomohiko Tamura, Takeshi Mizuguchi, Mitsuko Nakashima, Fumiaki Tanaka, Hirotomo Saitsu, Naomichi Matsumoto
We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells...
October 6, 2016: American Journal of Human Genetics
Nilah M Ioannidis, Joseph H Rothstein, Vikas Pejaver, Sumit Middha, Shannon K McDonnell, Saurabh Baheti, Anthony Musolf, Qing Li, Emily Holzinger, Danielle Karyadi, Lisa A Cannon-Albright, Craig C Teerlink, Janet L Stanford, William B Isaacs, Jianfeng Xu, Kathleen A Cooney, Ethan M Lange, Johanna Schleutker, John D Carpten, Isaac J Powell, Olivier Cussenot, Geraldine Cancel-Tassin, Graham G Giles, Robert J MacInnis, Christiane Maier, Chih-Lin Hsieh, Fredrik Wiklund, William J Catalona, William D Foulkes, Diptasri Mandal, Rosalind A Eeles, Zsofia Kote-Jarai, Carlos D Bustamante, Daniel J Schaid, Trevor Hastie, Elaine A Ostrander, Joan E Bailey-Wilson, Predrag Radivojac, Stephen N Thibodeau, Alice S Whittemore, Weiva Sieh
The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons...
October 6, 2016: American Journal of Human Genetics
Paul L Auer, Alex P Reiner, Gao Wang, Hyun Min Kang, Goncalo R Abecasis, David Altshuler, Michael J Bamshad, Deborah A Nickerson, Russell P Tracy, Stephen S Rich, Suzanne M Leal
Massively parallel whole-genome sequencing (WGS) data have ushered in a new era in human genetics. These data are now being used to understand the role of rare variants in complex traits and to advance the goals of precision medicine. The technological and computing advances that have enabled us to generate WGS data on thousands of individuals have also outpaced our ability to perform analyses in scientifically and statistically rigorous and thoughtful ways. The past several years have witnessed the application of whole-exome sequencing (WES) to complex traits and diseases...
October 6, 2016: American Journal of Human Genetics
Jae Hoon Sul, Brian E Cade, Michael H Cho, Dandi Qiao, Edwin K Silverman, Susan Redline, Shamil Sunyaev
Recently, multiple studies have performed whole-exome or whole-genome sequencing to identify groups of rare variants associated with complex traits and diseases. They have primarily utilized case-control study designs that often require thousands of individuals to reach acceptable statistical power. Family-based studies can be more powerful because a rare variant can be enriched in an extended pedigree and segregate with the phenotype. Although many methods have been proposed for using family data to discover rare variants involved in a disease, a majority of them focus on a specific pedigree structure and are designed to analyze either binary or continuously measured outcomes...
October 6, 2016: American Journal of Human Genetics
Elisabetta Flex, Marcello Niceta, Serena Cecchetti, Isabelle Thiffault, Margaret G Au, Alessandro Capuano, Emanuela Piermarini, Anna A Ivanova, Joshua W Francis, Giovanni Chillemi, Balasubramanian Chandramouli, Giovanna Carpentieri, Charlotte A Haaxma, Andrea Ciolfi, Simone Pizzi, Ganka V Douglas, Kara Levine, Antonella Sferra, Maria Lisa Dentici, Rolph R Pfundt, Jean-Baptiste Le Pichon, Emily Farrow, Frank Baas, Fiorella Piemonte, Bruno Dallapiccola, John M Graham, Carol J Saunders, Enrico Bertini, Richard A Kahn, David A Koolen, Marco Tartaglia
Microtubules are dynamic cytoskeletal elements coordinating and supporting a variety of neuronal processes, including cell division, migration, polarity, intracellular trafficking, and signal transduction. Mutations in genes encoding tubulins and microtubule-associated proteins are known to cause neurodevelopmental and neurodegenerative disorders. Growing evidence suggests that altered microtubule dynamics may also underlie or contribute to neurodevelopmental disorders and neurodegeneration. We report that biallelic mutations in TBCD, encoding one of the five co-chaperones required for assembly and disassembly of the αβ-tubulin heterodimer, the structural unit of microtubules, cause a disease with neurodevelopmental and neurodegenerative features characterized by early-onset cortical atrophy, secondary hypomyelination, microcephaly, thin corpus callosum, developmental delay, intellectual disability, seizures, optic atrophy, and spastic quadriplegia...
October 6, 2016: American Journal of Human Genetics
Antonella Sferra, Gilbert Baillat, Teresa Rizza, Sabina Barresi, Elisabetta Flex, Giorgio Tasca, Adele D'Amico, Emanuele Bellacchio, Andrea Ciolfi, Viviana Caputo, Serena Cecchetti, Annalaura Torella, Ginevra Zanni, Daria Diodato, Emanuela Piermarini, Marcello Niceta, Antonietta Coppola, Enrico Tedeschi, Diego Martinelli, Carlo Dionisi-Vici, Vincenzo Nigro, Bruno Dallapiccola, Claudia Compagnucci, Marco Tartaglia, Georg Haase, Enrico Bertini
Tubulinopathies constitute a family of neurodevelopmental/neurodegenerative disorders caused by mutations in several genes encoding tubulin isoforms. Loss-of-function mutations in TBCE, encoding one of the five tubulin-specific chaperones involved in tubulin folding and polymerization, cause two rare neurodevelopmental syndromes, hypoparathyroidism-retardation-dysmorphism and Kenny-Caffey syndrome. Although a missense mutation in Tbce has been associated with progressive distal motor neuronopathy in the pmn/pmn mice, no similar degenerative phenotype has been recognized in humans...
October 6, 2016: American Journal of Human Genetics
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