Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate
We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 24, 2018 Category: Genetics & Stem Cells Authors: Liza L. Cox, Timothy C. Cox, Lina M. Moreno Uribe, Ying Zhu, Chika T. Richter, Nichole Nidey, Jennifer M. Standley, Mei Deng, Elizabeth Blue, Jessica X. Chong, Yueqin Yang, Russ P. Carstens, Deepti Anand, Salil A. Lachke, Joshua D. Smith, Michael O. Dorsc Tags: Article Source Type: research

Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome
The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 24, 2018 Category: Genetics & Stem Cells Authors: M. Cecilia Poli, Fr édéric Ebstein, Sarah K. Nicholas, Marietta M. de Guzman, Lisa R. Forbes, Ivan K. Chinn, Emily M. Mace, Tiphanie P. Vogel, Alexandre F. Carisey, Felipe Benavides, Zeynep H. Coban-Akdemir, Richard A. Gibbs, Shalini N. Jhangiani, Donna Tags: Article Source Type: research

Landscape of Conditional eQTL in Dorsolateral Prefrontal Cortex and Co-localization with Schizophrenia GWAS
Causal genes and variants within genome-wide association study (GWAS) loci can be identified by integrating GWAS statistics with expression quantitative trait loci (eQTL) and determining which variants underlie both GWAS and eQTL signals. Most analyses, however, consider only the marginal eQTL signal, rather than dissect this signal into multiple conditionally independent signals for each gene. Here we show that analyzing conditional eQTL signatures, which could be important under specific cellular or temporal contexts, leads to improved fine mapping of GWAS associations. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 24, 2018 Category: Genetics & Stem Cells Authors: Amanda Dobbyn, Laura M. Huckins, James Boocock, Laura G. Sloofman, Benjamin S. Glicksberg, Claudia Giambartolomei, Gabriel E. Hoffman, Thanneer M. Perumal, Kiran Girdhar, Yan Jiang, Towfique Raj, Douglas M. Ruderfer, Robin S. Kramer, Dalila Pinto, the Com Tags: Article Source Type: research

Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-wide Study: Results from The Michigan Genomics Initiative
The objective of this study was to evaluate whether polygenic risk scores (PRS) for common cancers are associated with multiple phenotypes in a phenome-wide association study (PheWAS) conducted in 28,260 unrelated, genotyped patients of recent European ancestry who consented to participate in the Michigan Genomics Initiative, a longitudinal biorepository effort within Michigan Medicine. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 17, 2018 Category: Genetics & Stem Cells Authors: Lars G. Fritsche, Stephen B. Gruber, Zhenke Wu, Ellen M. Schmidt, Matthew Zawistowski, Stephanie E. Moser, Victoria M. Blanc, Chad M. Brummett, Sachin Kheterpal, Gon çalo R. Abecasis, Bhramar Mukherjee Tags: Article Source Type: research

Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy
Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by a...
Source: The American Journal of Human Genetics - May 10, 2018 Category: Genetics & Stem Cells Authors: Arcangela Iuso, Marit Wiersma, Hans-Joachim Sch üller, Ben Pode-Shakked, Dina Marek-Yagel, Mathias Grigat, Thomas Schwarzmayr, Riccardo Berutti, Bader Alhaddad, Bart Kanon, Nicola A. Grzeschik, Jürgen G. Okun, Zeev Perles, Yishay Salem, Ortal Barel, Ami Tags: Article Source Type: research

Estimation of Genetic Correlation via Linkage Disequilibrium Score Regression and Genomic Restricted Maximum Likelihood
Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be  estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors ) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 10, 2018 Category: Genetics & Stem Cells Authors: Guiyan Ni, Gerhard Moser, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Naomi R. Wray, S. Hong Lee Tags: Report Source Type: research

Mutations in PPCS, Encoding Phosphopantothenoylcystein Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy
Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcystein synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcystein. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by acc...
Source: The American Journal of Human Genetics - May 10, 2018 Category: Genetics & Stem Cells Authors: Arcangela Iuso, Marit Wiersma, Hans-Joachim Sch üller, Ben Pode-Shakked, Dina Marek-Yagel, Mathias Grigat, Thomas Schwarzmayr, Riccardo Berutti, Bader Alhaddad, Bart Kanon, Nicola A. Grzeschik, Jürgen G. Okun, Zeev Perles, Yishay Salem, Ortal Barel, Ami Tags: Article Source Type: research

A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole-Genome-Sequencing Studies
Analysis of de novo mutations (DNMs) from sequencing data of nuclear families has identified risk genes for many complex diseases, including multiple neurodevelopmental and psychiatric disorders. Most of these efforts have focused on mutations in protein-coding sequences. Evidence from genome-wide association studies (GWASs) strongly suggests that variants important to human diseases often lie in non-coding regions. Extending DNM-based approaches to non-coding sequences is challenging, however, because the functional significance of non-coding mutations is difficult to predict. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 10, 2018 Category: Genetics & Stem Cells Authors: Yuwen Liu, Yanyu Liang, A. Ercument Cicek, Zhongshan Li, Jinchen Li, Rebecca A. Muhle, Martina Krenzer, Yue Mei, Yan Wang, Nicholas Knoblauch, Jean Morrison, Siming Zhao, Yi Jiang, Evan Geller, Iuliana Ionita-Laza, Jinyu Wu, Kun Xia, James P. Noonan, Zhon Tags: Article Source Type: research

Preconception Carrier Screening by Genome Sequencing: Results from the Clinical Laboratory
We report here on the clinical laboratory results from this expanded carrier screening program. Variants were filtered and classified using the latest American College of Medical Genetics and Genomics (ACMG) guideline; only pathogenic and likely pathogenic variants were confirmed by orthologous methods before being reported. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 10, 2018 Category: Genetics & Stem Cells Authors: Sumit Punj, Yassmine Akkari, Jennifer Huang, Fei Yang, Allison Creason, Christine Pak, Amiee Potter, Michael O. Dorschner, Deborah A. Nickerson, Peggy D. Robertson, Gail P. Jarvik, Laura M. Amendola, Jennifer Schleit, Dana Kostiner Simpson, Alan F. Rope, Tags: Article Source Type: research

Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy
The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3, EXOSC8, and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in  vitro in affected individuals’ fibroblasts and skeletal muscle and in vivo in zebrafish. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 3, 2018 Category: Genetics & Stem Cells Authors: David T. Burns, Sandra Donkervoort, Juliane S. M üller, Ellen Knierim, Diana Bharucha-Goebel, Eissa Ali Faqeih, Stephanie K. Bell, Abdullah Y. AlFaifi, Dorota Monies, Francisca Millan, Kyle Retterer, Sarah Dyack, Sara MacKay, Susanne Morales-Gonzalez, Mi Tags: Article Source Type: research

Profiling and Leveraging Relatedness in a Precision Medicine Cohort of 92,455 Exomes
Large-scale human genetics studies are ascertaining increasing proportions of populations as they continue growing in both number and scale. As a result, the amount of cryptic relatedness within these study cohorts is growing rapidly and has significant implications on downstream analyses. We demonstrate this growth empirically among the first 92,455 exomes from the DiscovEHR cohort and, via a custom simulation framework we developed called SimProgeny, show that these measures are in line with expectations given the underlying population and ascertainment approach. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 3, 2018 Category: Genetics & Stem Cells Authors: Jeffrey Staples, Evan K. Maxwell, Nehal Gosalia, Claudia Gonzaga-Jauregui, Christopher Snyder, Alicia Hawes, John Penn, Ricardo Ulloa, Xiaodong Bai, Alexander E. Lopez, Cristopher V. Van Hout, Colm O ’Dushlaine, Tanya M. Teslovich, Shane E. McCarthy, Su Tags: Article Source Type: research

A Comprehensive cis-eQTL Analysis Revealed Target Genes in Breast Cancer Susceptibility Loci Identified in Genome-wide Association Studies
Genome-wide association studies (GWASs) have identified more than 150 common genetic loci for breast cancer risk. However, the target genes and underlying mechanisms remain largely unknown. We conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using normal or tumor breast transcriptome data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), and the Genotype-Tissue Expression (GTEx) project. We identified a total of 101 genes for 51 lead variants after combing the results of a meta-analysis of METABRIC and TCGA, and the results from GTEx at a...
Source: The American Journal of Human Genetics - May 3, 2018 Category: Genetics & Stem Cells Authors: Xingyi Guo, Weiqiang Lin, Jiandong Bao, Qiuyin Cai, Xiao Pan, Mengqiu Bai, Yuan Yuan, Jiajun Shi, Yaqiong Sun, Mi-Ryung Han, Jing Wang, Qi Liu, Wanqing Wen, Bingshan Li, Jirong Long, Jianghua Chen, Wei Zheng Tags: Article Source Type: research

A Mixed-Effects Model for Powerful Association Tests in Integrative Functional Genomics
Genome-wide association studies (GWASs) have successfully identified thousands of genetic variants for many complex diseases; however, these variants explain only a small fraction of the heritability. Recently, genetic association studies that leverage external transcriptome data have received much attention and shown promise for discovering novel variants. One such approach, PrediXcan, is to use predicted gene expression through genetic regulation. However, there are limitations in this approach. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 3, 2018 Category: Genetics & Stem Cells Authors: Yu-Ru Su, Chongzhi Di, Stephanie Bien, Licai Huang, Xinyuan Dong, Goncalo Abecasis, Sonja Berndt, Stephane Bezieau, Hermann Brenner, Bette Caan, Graham Casey, Jenny Chang-Claude, Stephen Chanock, Sai Chen, Charles Connolly, Keith Curtis, Jane Figueiredo, Tags: Article Source Type: research

C11orf70 Mutations Disrupting the Intraflagellar Transport-Dependent Assembly of Multiple Axonemal Dyneins Cause Primary Ciliary Dyskinesia
Primary ciliary dyskinesia (PCD) is a genetically and phenotypically heterogeneous disorder characterized by destructive respiratory disease and laterality abnormalities due to randomized left-right body asymmetry. PCD is mostly caused by mutations affecting the core axoneme structure of motile cilia that is essential for movement. Genes that cause PCD when mutated include a group that encode proteins essential for the assembly of the ciliary dynein motors and the active transport process that delivers them from their cytoplasmic assembly site into the axoneme. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 3, 2018 Category: Genetics & Stem Cells Authors: Mahmoud R. Fassad, Amelia Shoemark, Pierrick le Borgne, France Koll, Mitali Patel, Mellisa Dixon, Jane Hayward, Charlotte Richardson, Emily Frost, Lucy Jenkins, Thomas Cullup, Eddie M.K. Chung, Michel Lemullois, Anne Aubusson-Fleury, Claire Hogg, David R. Tags: Article Source Type: research

Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms
Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis as a result of defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open-reading frame C11orf70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high-resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11orf70 cause immotility of respiratory cilia and sperm flagella, respectively, as a result of the loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicat...
Source: The American Journal of Human Genetics - May 3, 2018 Category: Genetics & Stem Cells Authors: Inga M. H öben, Rim Hjeij, Heike Olbrich, Gerard W. Dougherty, Tabea Nöthe-Menchen, Isabella Aprea, Diana Frank, Petra Pennekamp, Bernd Dworniczak, Julia Wallmeier, Johanna Raidt, Kim G. Nielsen, Maria C. Philipsen, Francesca Santamaria, Laura Venditto, Tags: Report Source Type: research

FUN-LDA: A Latent Dirichlet Allocation Model for Predicting Tissue-Specific Functional Effects of Noncoding Variation: Methods and Applications
We describe a method based on a latent Dirichlet  allocation model for predicting functional effects of noncoding genetic variants in a cell-type- and/or tissue-specific way (FUN-LDA). Using this unsupervised approach, we predict tissue-specific functional effects for every position in the human genome in 127 different tissues and cell types. We demonstrate the usefulness of our predictions by using several validation experiments. Using eQTL data from several sources, including the GTEx project, Geuvadis project, and TwinsUK cohort, we show that eQTLs in specific tissues tend to be most enriched among the predicted fu...
Source: The American Journal of Human Genetics - May 3, 2018 Category: Genetics & Stem Cells Authors: Daniel Backenroth, Zihuai He, Krzysztof Kiryluk, Valentina Boeva, Lynn Pethukova, Ekta Khurana, Angela Christiano, Joseph D. Buxbaum, Iuliana Ionita-Laza Tags: Article Source Type: research

The Post-GWAS Era: From Association to Function
During the past 12 years, genome-wide association studies (GWASs) have uncovered thousands of genetic variants that influence risk for complex human traits and diseases. Yet functional studies aimed at delineating the causal genetic variants and biological mechanisms underlying the observed statistical associations with disease risk have lagged. In this review, we highlight key advances in the field of functional genomics that may facilitate the derivation of biological meaning post-GWAS. We highlight the evidence suggesting that causal variants underlying disease risk often function through regulatory effects on the expre...
Source: The American Journal of Human Genetics - May 3, 2018 Category: Genetics & Stem Cells Authors: Michael D. Gallagher, Alice S. Chen-Plotkin Tags: Review Source Type: research

This Month in The Journal
Large-scale sequencing projects have provided great insights into human genetic diversity, disease susceptibility, and demographic history. To a large extent, however, such studies have focused on individuals of European descent. Recent efforts, including the H3Africa Initiative, aim to expand genomic studies of African populations with a view toward improving health outcomes as well as  our overall understanding of human genetic diversity. In this issue, Retshabile et al. report their findings of a whole-exome sequencing project focused on residents of the southern African nation of Botswana. (Source: The Americ...
Source: The American Journal of Human Genetics - May 3, 2018 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

An Osteoporosis Risk SNP at 1p36.12 Acts as an Allele-Specific Enhancer to Modulate LINC00339 Expression via Long-Range Loop Formation
Genome-wide association studies (GWASs) have reproducibly associated variants within intergenic regions of 1p36.12 locus with osteoporosis, but the functional roles underlying these noncoding variants are unknown. Through an integrative functional genomic and epigenomic analyses, we prioritized rs6426749 as a potential causal SNP for osteoporosis at 1p36.12. Dual-luciferase assay and CRISPR/Cas9 experiments demonstrate that rs6426749 acts as a distal allele-specific enhancer regulating expression of a lncRNA (LINC00339) ( ∼360 kb) via long-range chromatin loop formation and that this loop is mediated by CTCF occupied n...
Source: The American Journal of Human Genetics - April 26, 2018 Category: Genetics & Stem Cells Authors: Xiao-Feng Chen, Dong-Li Zhu, Man Yang, Wei-Xin Hu, Yuan-Yuan Duan, Bing-Jie Lu, Yu Rong, Shan-Shan Dong, Ruo-Han Hao, Jia-Bin Chen, Yi-Xiao Chen, Shi Yao, Hlaing Nwe Thynn, Yan Guo, Tie-Lin Yang Tags: Article Source Type: research

Haplotype Sharing Provides Insights into Fine-Scale Population History and Disease in Finland
Finland provides unique opportunities to investigate population and medical genomics because of its adoption of unified national electronic health records, detailed historical and birth records, and serial population bottlenecks. We assembled a comprehensive view of recent population history ( ≤100 generations), the timespan during which most rare-disease-causing alleles arose, by comparing pairwise haplotype sharing from 43,254 Finns to that of 16,060 Swedes, Estonians, Russians, and Hungarians from geographically and linguistically adjacent countries with different population histori es. (Source: The American Jou...
Source: The American Journal of Human Genetics - April 26, 2018 Category: Genetics & Stem Cells Authors: Alicia R. Martin, Konrad J. Karczewski, Sini Kerminen, Mitja I. Kurki, Antti-Pekka Sarin, Mykyta Artomov, Johan G. Eriksson, T õnu Esko, Giulio Genovese, Aki S. Havulinna, Jaakko Kaprio, Alexandra Konradi, László Korányi, Anna Kostareva, Minna Männik Tags: Article Source Type: research

Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese
Genome-wide association studies (GWASs) and genome-wide linkage studies (GWLSs) have identified numerous risk genes affecting the susceptibility to leprosy. However, most of the reported GWAS hits are noncoding variants and account for only part of the estimated heritability for this disease. In order to identify additional risk genes and map the potentially functional variants within the GWAS loci, we performed a three-stage study combining whole-exome sequencing (WES; discovery stage), targeted next-generation sequencing (NGS; screening stage), and refined validation of risk missense variants in 1,433 individuals with le...
Source: The American Journal of Human Genetics - April 26, 2018 Category: Genetics & Stem Cells Authors: Dong Wang, Yu Fan, Mahadev Malhi, Rui Bi, Yong Wu, Min Xu, Xiu-Feng Yu, Heng Long, Yu-Ye Li, Deng-Feng Zhang, Yong-Gang Yao Tags: Article Source Type: research

Patterns of Genetic Coding Variation in a Native American Population before and after European Contact
In this study, we analyze the whole-exome sequences of modern and ancient individuals from a Northwest Coast First Nation, with a demographic history similar to other indigenous populations from the Americas. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 26, 2018 Category: Genetics & Stem Cells Authors: John Lindo, Mary Rogers, Elizabeth K. Mallott, Barbara Petzelt, Joycelynn Mitchell, David Archer, Jerome S. Cybulski, Ripan S. Malhi, Michael DeGiorgio Tags: Article Source Type: research

The Effect of ACTN3 Gene Doping on Skeletal Muscle Performance
Loss of expression of ACTN3, due to homozygosity of the common null polymorphism (p.Arg577X), is underrepresented in elite sprint/power athletes and has been associated with reduced muscle mass and strength in humans and mice. To investigate ACTN3 gene dosage in performance and whether expression could enhance muscle force, we performed meta-analysis and expression studies. Our general meta-analysis using a Bayesian random effects model in elite sprint/power athlete cohorts demonstrated a consistent homozygous-group effect across studies (per allele OR = 1.4, 95% CI 1.3 –1.6) but substantial heterogeneity in heterozy...
Source: The American Journal of Human Genetics - April 26, 2018 Category: Genetics & Stem Cells Authors: Fleur C. Garton, Peter J. Houweling, Damjan Vukcevic, Lyra R. Meehan, Fiona X.Z. Lee, Monkol Lek, Kelly N. Roeszler, Marshall W. Hogarth, Chrystal F. Tiong, Diana Zannino, Nan Yang, Stephen Leslie, Paul Gregorevic, Stewart I. Head, Jane T. Seto, Kathryn N Tags: Article Source Type: research

Whole-Exome Sequencing Reveals Uncaptured Variation and Distinct Ancestry in the Southern African Population of Botswana
Large-scale, population-based genomic studies have provided a context for modern medical genetics. Among such studies, however, African populations have remained relatively underrepresented. The breadth of genetic diversity across the African continent argues for an exploration of local genomic context to facilitate burgeoning disease mapping studies in Africa. We sought to characterize genetic variation and to assess population substructure within a cohort of HIV-positive children from Botswana —a Southern African country that is regionally underrepresented in genomic databases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 26, 2018 Category: Genetics & Stem Cells Authors: Gaone Retshabile, Busisiwe C. Mlotshwa, Lesedi Williams, Savannah Mwesigwa, Gerald Mboowa, Zhuoyi Huang, Navin Rustagi, Shanker Swaminathan, Eric Katagirya, Samuel Kyobe, Misaki Wayengera, Grace P. Kisitu, David P. Kateete, Eddie M. Wampande, Koketso Mapl Tags: Article Source Type: research

Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease
Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 miss ense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshi...
Source: The American Journal of Human Genetics - April 26, 2018 Category: Genetics & Stem Cells Authors: Emilie Cornec-Le Gall, Rory J. Olson, Whitney Besse, Christina M. Heyer, Vladimir G. Gainullin, Jessica M. Smith, Marie-Pierre Audr ézet, Katharina Hopp, Binu Porath, Beili Shi, Saurabh Baheti, Sarah R. Senum, Jennifer Arroyo, Charles D. Madsen, Claude F Tags: Article Source Type: research

Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms
In this study, trio whole-exome sequencing of a prospectively identified nephronophthisis (NPHP) proband and her parents identified compound-heterozygous variants in IFT140, a gene previously associated with NPHP-related ciliopathies. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 26, 2018 Category: Genetics & Stem Cells Authors: Thomas A. Forbes, Sara E. Howden, Kynan Lawlor, Belinda Phipson, Jovana Maksimovic, Lorna Hale, Sean Wilson, Catherine Quinlan, Gladys Ho, Katherine Holman, Bruce Bennetts, Joanna Crawford, Peter Trnka, Alicia Oshlack, Chirag Patel, Andrew Mallett, Cas Si Tags: Article Source Type: research

A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships
Phosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in  vivo. Using a massively parallel approach that leverages an artificial humanized yeast model, we derived high-confidence estimates of functional impact for 7,244 single ami...
Source: The American Journal of Human Genetics - April 26, 2018 Category: Genetics & Stem Cells Authors: Taylor L. Mighell, Sara Evans-Dutson, Brian J. O ’Roak Tags: Article Source Type: research

Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia
ROR α, 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. Howeve r, 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, on e canonical splice ...
Source: The American Journal of Human Genetics - April 12, 2018 Category: Genetics & Stem Cells Authors: 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 Tags: Article Source Type: research

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies
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 ...
Source: The American Journal of Human Genetics - April 12, 2018 Category: Genetics & Stem Cells Authors: Hanyin Cheng, Avinash V. Dharmadhikari, Sylvia Varland, Ning Ma, Deepti Domingo, Robert Kleyner, Alan F. Rope, Margaret Yoon, Asbj ørg Stray-Pedersen, Jennifer E. Posey, Sarah R. Crews, Mohammad K. Eldomery, Zeynep Coban Akdemir, Andrea M. Lewis, Vernon Tags: Report Source Type: research

A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis
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. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 12, 2018 Category: Genetics & Stem Cells Authors: Heather E. Olson, Nolwenn Jean-Mar çais, 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 Tags: Report Source Type: research

Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia
ROR α, 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. Howeve r, 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, on e canonical splice ...
Source: The American Journal of Human Genetics - April 12, 2018 Category: Genetics & Stem Cells Authors: 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 Tags: Article Source Type: research

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies
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 ...
Source: The American Journal of Human Genetics - April 12, 2018 Category: Genetics & Stem Cells Authors: Hanyin Cheng, Avinash V. Dharmadhikari, Sylvia Varland, Ning Ma, Deepti Domingo, Robert Kleyner, Alan F. Rope, Margaret Yoon, Asbj ørg Stray-Pedersen, Jennifer E. Posey, Sarah R. Crews, Mohammad K. Eldomery, Zeynep Coban Akdemir, Andrea M. Lewis, Vernon Tags: Report Source Type: research

A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis
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. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 12, 2018 Category: Genetics & Stem Cells Authors: Heather E. Olson, Nolwenn Jean-Mar çais, 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 Tags: Report Source Type: research

L-GATOR: Genetic Association Testing for a Longitudinally Measured Quantitative Trait in Samples with Related Individuals
In complex-trait mapping, when each subject has multiple measurements of a quantitative trait over time, power for detecting genetic association can be gained by the inclusion of all measurements and not just single time points or averages in the analysis. To increase power and control type 1 error, one should account for dependence among observations for a single individual as well as dependence between observations of related individuals if they are present in the sample. We propose L-GATOR, a retrospective, mixed-effects method for association mapping of longitudinally measured traits in samples with related individuals...
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Xiaowei Wu, Mary Sara McPeek Tags: Article Source Type: research

Identification of Misclassified ClinVar Variants via Disease Population Prevalence
There is a significant interest in the standardized classification of human genetic variants. We used whole-genome sequence data from 10,495 unrelated individuals to contrast population frequency of pathogenic variants to the expected population prevalence of the disease. Analyses included the ACMG-recommended 59 gene-condition sets for incidental findings and 463 genes associated with 265 OrphaNet conditions. A total of 25,505 variants were used to identify patterns of inflation (i.e., excess genetic risk and misclassification). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Naisha Shah, Ying-Chen Claire Hou, Hung-Chun Yu, Rachana Sainger, C. Thomas Caskey, J. Craig Venter, Amalio Telenti Tags: Article Source Type: research

A Common Type 2 Diabetes Risk Variant Potentiates Activity of an Evolutionarily Conserved Islet Stretch Enhancer and Increases C2CD4A and C2CD4B Expression
Genome-wide association studies (GWASs) and functional genomics approaches implicate enhancer disruption in islet dysfunction and type 2 diabetes (T2D) risk. We applied genetic fine-mapping and functional (epi)genomic approaches to a T2D- and proinsulin-associated 15q22.2 locus to identify a most likely causal variant, determine its direction of effect, and elucidate plausible target genes. Fine-mapping and conditional analyses of proinsulin levels of 8,635 non-diabetic individuals from the METSIM study support a single association signal represented by a cluster of 16 strongly associated (p 0.8) with the GWAS index SNP rs...
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Ina Kycia, Brooke N. Wolford, Jeroen R. Huyghe, Christian Fuchsberger, Swarooparani Vadlamudi, Romy Kursawe, Ryan P. Welch, Ricardo d ’Oliveira Albanus, Asli Uyar, Shubham Khetan, Nathan Lawlor, Mohan Bolisetty, Anubhuti Mathur, Johanna Kuusisto, Markku Tags: Article Source Type: research

LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections
The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs ∗25 and p.Glu750∗) in LTBP3 were identified in affected members of one family. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Dong-chuan Guo, Ellen S. Regalado, Amelie Pinard, Jiyuan Chen, Kwanghyuk Lee, Christina Rigelsky, Lior Zilberberg, Ellen M. Hostetler, Micheala Aldred, Stephanie E. Wallace, Siddharth K. Prakash, University of Washington Center for Mendelian Genomics, Suz Tags: Report Source Type: research

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome
(The American Journal of Human Genetics 101, 239 –254; August 3, 2017) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Nicole J. Lake, Bryn D. Webb, David A. Stroud, Tara R. Richman, Benedetta Ruzzenente, Alison G. Compton, Hayley S. Mountford, Juliette Pulman, Coralie Zangarelli, Marlene Rio, Nathalie Boddaert, Zahra Assouline, Mingma D. Sherpa, Eric E. Schadt, Sander M. Tags: Correction Source Type: research

This Month in The Journal
Fuchs endothelial corneal dystrophy (FECD) is a common ocular disease caused by the expansion of a trinucleotide repeat in TCF4; greater than 50 copies of the non-coding repeat lead to increased disease risk. Like that of other repeat-expansion disorders, the pathogenicity is attributed to RNA aggregates, the sequestering of RNA splicing factors, and depletion of the encoded protein. These attributes suggest that therapies that use antisense oligonucleotides (ASOs) to target the TCF4 repeat could be effective. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa
(The American Journal of Human Genetics 99; 236 –245, July 7, 2016) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Andrea Angius, Paolo Uva, Insa Buers, Manuela Oppo, Alessandro Puddu, Stefano Onano, Ivana Persico, Angela Loi, Loredana Marcia, Wolfgang H öhne, Gianmauro Cuccuru, Giorgio Fotia, Manila Deiana, Mara Marongiu, Hatice Tuba Atalay, Sibel Inan, Osama El Ass Tags: Correction Source Type: research

L-GATOR: Genetic Association Testing for a Longitudinally Measured Quantitative Trait in Samples with Related Individuals
In complex-trait mapping, when each subject has multiple measurements of a quantitative trait over time, power for detecting genetic association can be gained by the inclusion of all measurements and not just single time points or averages in the analysis. To increase power and control type 1 error, one should account for dependence among observations for a single individual as well as dependence between observations of related individuals if they are present in the sample. We propose L-GATOR, a retrospective, mixed-effects method for association mapping of longitudinally measured traits in samples with related individuals...
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Xiaowei Wu, Mary Sara McPeek Tags: Article Source Type: research

Identification of Misclassified ClinVar Variants via Disease Population Prevalence
There is a significant interest in the standardized classification of human genetic variants. We used whole-genome sequence data from 10,495 unrelated individuals to contrast population frequency of pathogenic variants to the expected population prevalence of the disease. Analyses included the ACMG-recommended 59 gene-condition sets for incidental findings and 463 genes associated with 265 OrphaNet conditions. A total of 25,505 variants were used to identify patterns of inflation (i.e., excess genetic risk and misclassification). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Naisha Shah, Ying-Chen Claire Hou, Hung-Chun Yu, Rachana Sainger, C. Thomas Caskey, J. Craig Venter, Amalio Telenti Tags: Article Source Type: research

A Common Type 2 Diabetes Risk Variant Potentiates Activity of an Evolutionarily Conserved Islet Stretch Enhancer and Increases C2CD4A and C2CD4B Expression
Genome-wide association studies (GWASs) and functional genomics approaches implicate enhancer disruption in islet dysfunction and type 2 diabetes (T2D) risk. We applied genetic fine-mapping and functional (epi)genomic approaches to a T2D- and proinsulin-associated 15q22.2 locus to identify a most likely causal variant, determine its direction of effect, and elucidate plausible target genes. Fine-mapping and conditional analyses of proinsulin levels of 8,635 non-diabetic individuals from the METSIM study support a single association signal represented by a cluster of 16 strongly associated (p 0.8) with the GWAS index SNP rs...
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Ina Kycia, Brooke N. Wolford, Jeroen R. Huyghe, Christian Fuchsberger, Swarooparani Vadlamudi, Romy Kursawe, Ryan P. Welch, Ricardo d ’Oliveira Albanus, Asli Uyar, Shubham Khetan, Nathan Lawlor, Mohan Bolisetty, Anubhuti Mathur, Johanna Kuusisto, Markku Tags: Article Source Type: research

LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections
The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs ∗25 and p.Glu750∗) in LTBP3 were identified in affected members of one family. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Dong-chuan Guo, Ellen S. Regalado, Amelie Pinard, Jiyuan Chen, Kwanghyuk Lee, Christina Rigelsky, Lior Zilberberg, Ellen M. Hostetler, Micheala Aldred, Stephanie E. Wallace, Siddharth K. Prakash, University of Washington Center for Mendelian Genomics, Suz Tags: Report Source Type: research

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome
(The American Journal of Human Genetics 101, 239 –254; August 3, 2017) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Nicole J. Lake, Bryn D. Webb, David A. Stroud, Tara R. Richman, Benedetta Ruzzenente, Alison G. Compton, Hayley S. Mountford, Juliette Pulman, Coralie Zangarelli, Marlene Rio, Nathalie Boddaert, Zahra Assouline, Mingma D. Sherpa, Eric E. Schadt, Sander M. Tags: Correction Source Type: research

This Month in The Journal
Fuchs endothelial corneal dystrophy (FECD) is a common ocular disease caused by the expansion of a trinucleotide repeat in TCF4; greater than 50 copies of the non-coding repeat lead to increased disease risk. Like that of other repeat-expansion disorders, the pathogenicity is attributed to RNA aggregates, the sequestering of RNA splicing factors, and depletion of the encoded protein. These attributes suggest that therapies that use antisense oligonucleotides (ASOs) to target the TCF4 repeat could be effective. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa
(The American Journal of Human Genetics 99; 236 –245, July 7, 2016) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 5, 2018 Category: Genetics & Stem Cells Authors: Andrea Angius, Paolo Uva, Insa Buers, Manuela Oppo, Alessandro Puddu, Stefano Onano, Ivana Persico, Angela Loi, Loredana Marcia, Wolfgang H öhne, Gianmauro Cuccuru, Giorgio Fotia, Manila Deiana, Mara Marongiu, Hatice Tuba Atalay, Sibel Inan, Osama El Ass Tags: Correction Source Type: research

Homozygous Mutations in WEE2 Cause Fertilization Failure and Female Infertility
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. (Source: The American ...
Source: The American Journal of Human Genetics - March 29, 2018 Category: Genetics & Stem Cells Authors: 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 Tags: Article Source Type: research

PheWAS and Beyond: The Landscape of Associations with Medical Diagnoses and Clinical Measures across 38,662 Individuals from Geisinger
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> 0.01 for 38,662 individuals. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 29, 2018 Category: Genetics & Stem Cells Authors: 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 Tags: Article Source Type: research

Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome
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). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 29, 2018 Category: Genetics & Stem Cells Authors: 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 Tags: Report Source Type: research