OUTRIDER: A Statistical Method for Detecting Aberrantly Expressed Genes in RNA Sequencing Data
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. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 29, 2018 Category: Genetics & Stem Cells Authors: Felix Brechtmann, Christian Mertes, Agn ė Matusevičiūtė, Vicente A. Yépez, Žiga Avsec, Maximilian Herzog, Daniel M. Bader, Holger Prokisch, Julien Gagneur Tags: Article Source Type: research

The Genetic Landscape of Diamond-Blackfan Anemia
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 ribosoma...
Source: The American Journal of Human Genetics - November 29, 2018 Category: Genetics & Stem Cells Authors: 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 Tags: Article Source Type: research

Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus
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. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 21, 2018 Category: Genetics & Stem Cells Authors: 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 Jen Tags: Report Source Type: research

MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance
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. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 21, 2018 Category: Genetics & Stem Cells Authors: 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. Barr Tags: Report Source Type: research

Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects
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 ...
Source: The American Journal of Human Genetics - November 21, 2018 Category: Genetics & Stem Cells Authors: Niki T. Loges, Dinu Antony, Ales Maver, Matthew A. Deardorff, Elif Y ýlmaz Güleç, Alper Gezdirici, Tabea Nöthe-Menchen, Inga M. Höben, Lena Jelten, Diana Frank, Claudius Werner, Johannes Tebbe, Kaman Wu, Elizabeth Goldmuntz, Goran Čuturilo, Bryan Kr Tags: Report Source Type: research

Recurrent, Activating Variants in the Receptor Tyrosine Kinase DDR2 Cause Warburg-Cinotti Syndrome
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. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 15, 2018 Category: Genetics & Stem Cells Authors: Linda Xu, Hanne Jensen, Jennifer J. Johnston, Emilio Di Maria, Katja Kloth, Ileana Cristea, Julie C. Sapp, Thomas N. Darling, Laryssa A. Huryn, Lisbeth Tranebj ærg, Elisa Cinotti, Christian Kubisch, Eyvind Rødahl, Ove Bruland, Leslie G. Biesecker, Gunna Tags: Report Source Type: research

Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome
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. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 7, 2018 Category: Genetics & Stem Cells Authors: 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 Tags: Report Source Type: research

Genome Analyses of > 200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders
C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 1, 2018 Category: Genetics & Stem Cells Authors: Symen Ligthart, Ahmad Vaez, Urmo V õsa, Maria G. Stathopoulou, Paul S. de Vries, Bram P. Prins, Peter J. Van der Most, Toshiko Tanaka, Elnaz Naderi, Lynda M. Rose, Ying Wu, Robert Karlsson, Maja Barbalic, Honghuang Lin, René Pool, Gu Zhu, Aurélien Mac Tags: Article Source Type: research

Deciphering the Emerging Complexities of Molecular Mechanisms at GWAS Loci
Genome-wide association studies (GWASs) have identified thousands of loci associated with hundreds of complex diseases and traits, and progress is being made toward elucidating the causal variants and genes underlying these associations. Functional characterization of mechanisms at GWAS loci is a multi-faceted challenge. Challenges include linkage disequilibrium and allelic heterogeneity at each locus, the noncoding nature of most loci, and the time and cost needed for experimentally evaluating the potential mechanistic contributions of genes and variants. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 1, 2018 Category: Genetics & Stem Cells Authors: Maren E. Cannon, Karen L. Mohlke Tags: Review Source Type: research

Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome
(The American Journal of Human Genetics 103, 431 –439; September 6, 2018) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 1, 2018 Category: Genetics & Stem Cells Authors: Shereen G. Ghosh, Kerstin Becker, He Huang, Tracy Dixon-Salazar, Guoliang Chai, Vincenzo Salpietro, Lihadh Al-Gazali, Quinten Waisfisz, Haicui Wang, Keith K. Vaux, Valentina Stanley, Andreea Manole, Ugur Akpulat, Marjan M. Weiss, Stephanie Efthymiou, Mich Tags: Correction Source Type: research

Biallelic Mutations in LRRC56, Encoding a Protein Associated with Intraflagellar Transport, Cause Mucociliary Clearance and Laterality Defects
Primary defects in motile cilia result in dysfunction of the apparatus responsible for generating fluid flows. Defects in these mechanisms underlie disorders characterized by poor mucus clearance, resulting in susceptibility to chronic recurrent respiratory infections, often associated with infertility; laterality defects occur in about 50% of such individuals. Here we report biallelic variants in LRRC56 (known as oda8 in Chlamydomonas) identified in three unrelated families. The phenotype comprises laterality defects and chronic pulmonary infections. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 1, 2018 Category: Genetics & Stem Cells Authors: Serge Bonnefoy, Christopher M. Watson, Kristin D. Kernohan, Moara Lemos, Sebastian Hutchinson, James A. Poulter, Laura A. Crinnion, Ian Berry, Jennifer Simmonds, Pradeep Vasudevan, Chris O ’Callaghan, Robert A. Hirst, Andrew Rutman, Lijia Huang, Taila H Tags: Article Source Type: research

Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability
Over the last decades, a growing spectrum of monogenic disorders of human magnesium homeostasis has been clinically characterized, and genetic studies in affected individuals have identified important molecular components of cellular and epithelial magnesium transport. Here, we describe three infants who are from non-consanguineous families and who presented with a disease phenotype consisting of generalized seizures in infancy, severe hypomagnesemia, and renal magnesium wasting. Seizures persisted despite magnesium supplementation and were associated with significant intellectual disability. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 1, 2018 Category: Genetics & Stem Cells Authors: Karl P. Schlingmann, Sascha Bandulik, Cherry Mammen, Maja Tarailo-Graovac, Rikke Holm, Matthias Baumann, Jens K önig, Jessica J.Y. Lee, Britt Drögemöller, Katrin Imminger, Bodo B. Beck, Janine Altmüller, Holger Thiele, Siegfried Waldegger, William van Tags: Report Source Type: research

NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly
The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 1, 2018 Category: Genetics & Stem Cells Authors: Ina Schanze, Jens Bunt, Jonathan W.C. Lim, Denny Schanze, Ryan J. Dean, Marielle Alders, Patricia Blanchet, Tania Atti é-Bitach, Siren Berland, Steven Boogert, Sangamitra Boppudi, Caitlin J. Bridges, Megan T. Cho, William B. Dobyns, Dian Donnai, Jessica Tags: Article Source Type: research

Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles
Androgenetic complete hydatidiform moles are human pregnancies with no embryos and affect 1 in every 1,400 pregnancies. They have mostly androgenetic monospermic genomes with all the chromosomes originating from a haploid sperm and no maternal chromosomes. Androgenetic complete hydatidiform moles were described in 1977, but how they occur has remained an open question. We identified bi-allelic deleterious mutations in MEI1, TOP6BL/C11orf80, and REC114, with roles in meiotic double-strand breaks formation in women with recurrent androgenetic complete hydatidiform moles. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 1, 2018 Category: Genetics & Stem Cells Authors: Ngoc Minh Phuong Nguyen, Zhao-Jia Ge, Ramesh Reddy, Somayyeh Fahiminiya, Philippe Sauthier, Rashmi Bagga, Feride Iffet Sahin, Sangeetha Mahadevan, Matthew Osmond, Magali Breguet, Kurosh Rahimi, Louise Lapensee, Karine Hovanes, Radhika Srinivasan, Ignatia Tags: Article Source Type: research

The Malaria-Protective Human Glycophorin Structural Variant DUP4 Shows Somatic Mosaicism and Association with Hemoglobin Levels
Glycophorin A and glycophorin B are red blood cell surface proteins and are both receptors for the parasite Plasmodium falciparum, which is the principal cause of malaria in sub-Saharan Africa. DUP4 is a complex structural genomic variant that carries extra copies of a glycophorin A-glycophorin B fusion gene and has a dramatic effect on malaria risk by reducing the risk of severe malaria by up to 40%. Using fiber-FISH and Illumina sequencing, we validate the structural arrangement of the glycophorin locus in the DUP4 variant and reveal somatic variation in copy number of the glycophorin B-glycophorin A fusion gene. (Source...
Source: The American Journal of Human Genetics - November 1, 2018 Category: Genetics & Stem Cells Authors: Walid Algady, Sandra Louzada, Danielle Carpenter, Paulina Brajer, Anna F ärnert, Ingegerd Rooth, Billy Ngasala, Fengtang Yang, Marie-Anne Shaw, Edward J. Hollox Tags: Article Source Type: research

This Month in The Journal
In this issue, Helbig et  al. identify de novo CACNA1E missense mutations in 30 individuals with developmental and epileptic encephalopathy. This clinically and genetically heterogeneous disorder presents early in life and causes intractable seizures as well as developmental delay or regression. The individuals described i n this study also displayed hyperkinetic movement, joint contractures, and macrocephaly. CACNA1E is a voltage-gated calcium channel; its activity is required for appropriate synaptic transmission. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 1, 2018 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara Cullinan Tags: Editors' Corner Source Type: research

Leveraging DNA-Methylation Quantitative-Trait Loci to Characterize the Relationship between Methylomic Variation, Gene Expression, and Complex Traits
Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation has the potential to increase understanding about the mechanisms underpinning health and disease phenotypes. We undertook a comprehensive analysis of common genetic variation on DNA methylation (DNAm) by using the Illumina EPIC array to profile samples from the UK Household Longitudinal study. We identified 12,689,548 significant DNA methylation quantitative trait loci (mQTL) associations (p (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 25, 2018 Category: Genetics & Stem Cells Authors: Eilis Hannon, Tyler J. Gorrie-Stone, Melissa C. Smart, Joe Burrage, Amanda Hughes, Yanchun Bao, Meena Kumari, Leonard C. Schalkwyk, Jonathan Mill Tags: Article Source Type: research

FUT2 Variants Confer Susceptibility to Familial Otitis Media
Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154 ∗) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, li nkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202 ∗) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). (Source: The Amer...
Source: The American Journal of Human Genetics - October 25, 2018 Category: Genetics & Stem Cells Authors: Regie Lyn P. Santos-Cortez, Charlotte M. Chiong, Daniel N. Frank, Allen F. Ryan, Arnaud P.J. Giese, Tori Bootpetch Roberts, Kathleen A. Daly, Matthew J. Steritz, Wasyl Szeremeta, Melquiadesa Pedro, Harold Pine, Talitha Karisse L. Yarza, Melissa A. Scholes Tags: Article Source Type: research

Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex
Hypotrichosis simplex (HS) is a rare form of hereditary alopecia characterized by childhood onset of diffuse and progressive scalp and body hair loss. Although research has identified a number of causal genes, genetic etiology in about 50% of HS cases remains unknown. The present report describes the identification via whole-exome sequencing of five different mutations in the gene LSS in three unrelated families with unexplained, potentially autosomal-recessive HS. Affected individuals showed sparse to absent lanugo-like scalp hair, sparse and brittle eyebrows, and sparse eyelashes and body hair. (Source: The American Jour...
Source: The American Journal of Human Genetics - October 25, 2018 Category: Genetics & Stem Cells Authors: Maria-Teresa Romano, Aylar Tafazzoli, Maximilian Mattern, Sugirthan Sivalingam, Sabrina Wolf, Alexander Rupp, Holger Thiele, Janine Altm üller, Peter Nürnberg, Jürgen Ellwanger, Reto Gambon, Alessandra Baumer, Nicolai Kohlschmidt, Dieter Metze, Stefan Tags: Report Source Type: research

Understanding the Hidden Complexity of Latin American Population Isolates
Most population isolates examined to date were founded from a single ancestral population. Consequently, there is limited knowledge about the demographic history of admixed population isolates. Here we investigate genomic diversity of recently admixed population isolates from Costa Rica and Colombia and compare their diversity to a benchmark population isolate, the Finnish. These Latin American isolates originated during the 16th century from admixture between a few hundred European males and Amerindian females, with a limited contribution from African founders. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 25, 2018 Category: Genetics & Stem Cells Authors: Jazlyn A. Mooney, Christian D. Huber, Susan Service, Jae Hoon Sul, Clare D. Marsden, Zhongyang Zhang, Chiara Sabatti, Andr és Ruiz-Linares, Gabriel Bedoya, Costa Rica/Colombia Consortium for Genetic Investigation of Bipolar Endophenotypes, Nelson Freimer Tags: Article Source Type: research

Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay
We describe four unrelated individuals with a complex multisystem disorder characterized by woolly hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and global developmental delay. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 25, 2018 Category: Genetics & Stem Cells Authors: Marie Morimoto, Helen Waller-Evans, Zineb Ammous, Xiaofei Song, Kevin A. Strauss, Davut Pehlivan, Claudia Gonzaga-Jauregui, Erik G. Puffenberger, Charles R. Holst, Ender Karaca, Karlla W. Brigatti, Emily Maguire, Zeynep H. Coban-Akdemir, Akiko Amagata, C. Tags: Report Source Type: research

Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy
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. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 25, 2018 Category: Genetics & Stem Cells Authors: 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 Kov ács-Nagy, Mirjana Gusic, Elisabeth Gra Tags: Report Source Type: research

ASHG Denounces Attempts to Link Genetics and Racial Supremacy
The American Society of Human Genetics (ASHG) is alarmed to see a societal resurgence of groups rejecting the value of genetic diversity and using discredited or distorted genetic concepts to bolster bogus claims of white supremacy. ASHG denounces this misuse of genetics to feed racist ideologies. In public dialog, our research community should be clear about genetic knowledge related to ancestry and genomic diversity. To that end, ASHG affirms the following: (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 19, 2018 Category: Genetics & Stem Cells Tags: ASHG Perspective Source Type: research

ASHG Perspectives: A New Voice for ASHG
This is the first statement in a series under development by the American Society of Human Genetics (ASHG) and published in The American Journal of Human Genetics. Building on ASHG ’s commitment to support debate in our field and dialog with the public, the series will offer timely, concise ASHG perspectives that have been prioritized by the Board of Directors on topics in research, health, and society. They will address how scientific research informs those issues and could assert ASHG policy positions or note important related field activities. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 19, 2018 Category: Genetics & Stem Cells Authors: David L. Nelson, Bruce R. Korf Tags: Editors' Corner Source Type: research

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refra...
Source: The American Journal of Human Genetics - October 18, 2018 Category: Genetics & Stem Cells Authors: Katherine L. Helbig, Robert J. Lauerer, Jacqueline C. Bahr, Ivana A. Souza, Candace T. Myers, Bet ül Uysal, Niklas Schwarz, Maria A. Gandini, Sun Huang, Boris Keren, Cyril Mignot, Alexandra Afenjar, Thierry Billette de Villemeur, Delphine Héron, Carolin Tags: Article Source Type: research

Missense Mutations of the Pro65 Residue of PCGF2 Cause a Recognizable Syndrome Associated with Craniofacial, Neurological, Cardiovascular, and Skeletal Features
We report the phenotypic characterization of 13 patients (11 unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All the mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 18, 2018 Category: Genetics & Stem Cells Authors: 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. Chun Tags: Report Source Type: research

Phenotype-Specific Enrichment of Mendelian Disorder Genes near GWAS Regions across 62 Complex Traits
Although recent studies provide evidence for a common genetic basis between complex traits and Mendelian disorders, a thorough quantification of their overlap in a phenotype-specific manner remains elusive. Here, we have quantified the overlap of genes identified through large-scale genome-wide association studies (GWASs) for 62 complex traits and diseases with genes containing mutations known to cause 20 broad categories of Mendelian disorders. We identified a significant enrichment of genes linked to phenotypically matched Mendelian disorders in GWAS gene sets; of the total 1,240 comparisons, a higher proportion of pheno...
Source: The American Journal of Human Genetics - October 4, 2018 Category: Genetics & Stem Cells Authors: Malika Kumar Freund, Kathryn S. Burch, Huwenbo Shi, Nicholas Mancuso, Gleb Kichaev, Kristina M. Garske, David Z. Pan, Zong Miao, Karen L. Mohlke, Markku Laakso, P äivi Pajukanta, Bogdan Pasaniuc, Valerie A. Arboleda Tags: Article Source Type: research

Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome
Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological proc...
Source: The American Journal of Human Genetics - October 4, 2018 Category: Genetics & Stem Cells Authors: Christiane K. Bauer, Paolo Calligari, Francesca Clementina Radio, Viviana Caputo, Maria Lisa Dentici, Nadia Falah, Frances High, Francesca Pantaleoni, Sabina Barresi, Andrea Ciolfi, Simone Pizzi, Alessandro Bruselles, Richard Person, Sarah Richards, Megan Tags: Report Source Type: research

A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis
(The American Journal of Human Genetics 102, 995 –1007; May 3, 2018) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 4, 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: Correction Source Type: research

A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation
We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals ’ fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 4, 2018 Category: Genetics & Stem Cells Authors: Carlos R. Ferreira, Zhi-Jie Xia, Aur élie Clément, David A. Parry, Mariska Davids, Fulya Taylan, Prashant Sharma, Coleman T. Turgeon, Bernardo Blanco-Sánchez, Bobby G. Ng, Clare V. Logan, Lynne A. Wolfe, Benjamin D. Solomon, Megan T. Cho, Ganka Douglas Tags: Article Source Type: research

Bi-allelic Loss-of-Function Variants in DNMBP Cause Infantile Cataracts
Infantile and childhood-onset cataracts form a heterogeneous group of disorders; among the many genetic causes, numerous pathogenic variants in additional genes associated with autosomal-recessive infantile cataracts remain to be discovered. We identified three consanguineous families affected by bilateral infantile cataracts. Using exome sequencing, we found homozygous loss-of-function variants in DNMBP: nonsense variant c.811C>T (p.Arg271 ∗) in large family F385 (nine affected individuals; LOD score = 5.18 at θ = 0), frameshift deletion c.2947_2948del (p.Asp983∗) in family F372 (two affected i...
Source: The American Journal of Human Genetics - October 4, 2018 Category: Genetics & Stem Cells Authors: Muhammad Ansar, Hyung-lok Chung, Rachel L. Taylor, Aamir Nazir, Samina Imtiaz, Muhammad T. Sarwar, Alkistis Manousopoulou, Periklis Makrythanasis, Sondas Saeed, Emilie Falconnet, Michel Guipponi, Constantin J. Pournaras, Maqsood A. Ansari, Emmanuelle Ranz Tags: Article Source Type: research

Activating Mutations in PAK1, Encoding p21-Activated Kinase 1, Cause a Neurodevelopmental Disorder
We report th e de novo PAK1 mutations c.392A>G (p.Tyr131Cys) and  c.1286A>G (p.Tyr429Cys) in two unrelated subjects with developmental delay, secondary macrocephaly, seizures, and ataxic gait. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 4, 2018 Category: Genetics & Stem Cells Authors: Frederike L. Harms, Katja Kloth, Annette Bley, Jonas Denecke, Ren é Santer, Davor Lessel, Maja Hempel, Kerstin Kutsche Tags: Article Source Type: research

This Month in The Journal
Clinicians have long appreciated that excess albumin in urine (albuminuria) correlates with later development of cardiovascular and metabolic disease. What has been less clear, however, is the nature of this association, e.g., do the pathways leading to albuminuria cause cardiometabolic dysfunction? In this issue, Haas et  al. use data from the UK Biobank to address this question with greater precision than previously possible. After constructing and validating an albuminuria polygenic risk score from a large genome-wide association study, the authors investigated whether genetically elevated albuminuria is associat e...
Source: The American Journal of Human Genetics - October 4, 2018 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy
We present a study of six individuals from three unrelated f amilies in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 27, 2018 Category: Genetics & Stem Cells Authors: Thi Tuyet Mai Nguyen, Yoshiko Murakami, Kristen M. Wigby, Nissan V. Baratang, Justine Rousseau, Anik St-Denis, Jill A. Rosenfeld, Stephanie C. Laniewski, Julie Jones, Alejandro D. Iglesias, Marilyn C. Jones, Diane Masser-Frye, Angela E. Scheuerle, Denise Tags: Report Source Type: research

ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition
Joubert syndrome (JBTS) is a genetically heterogeneous autosomal-recessive neurodevelopmental ciliopathy. We investigated further the underlying genetic etiology of Joubert syndrome by studying two unrelated families in whom JBTS was not associated with pathogenic variants in known JBTS-associated genes. Combined autozygosity mapping of both families highlighted a candidate locus on chromosome 10 (chr10: 101569997 –109106128, UCSC Genome Browser hg 19), and exome sequencing revealed two missense variants in ARL3 within the candidate locus. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 27, 2018 Category: Genetics & Stem Cells Authors: Sumaya Alkanderi, Elisa Molinari, Ranad Shaheen, Yasmin Elmaghloob, Louise A. Stephen, Veronica Sammut, Simon A. Ramsbottom, Shalabh Srivastava, George Cairns, Noel Edwards, Sarah J. Rice, Nour Ewida, Amal Alhashem, Kathryn White, Colin G. Miles, David H. Tags: Report Source Type: research

Burden Testing of Rare Variants Identified through Exome Sequencing via Publicly Available Control Data
The genetic causes of many Mendelian disorders remain undefined. Factors such as lack of large multiplex families, locus heterogeneity, and incomplete penetrance hamper these efforts for many disorders. Previous work suggests that gene-based burden testing —where the aggregate burden of rare, protein-altering variants in each gene is compared between case and control subjects—might overcome some of these limitations. The increasing availability of large-scale public sequencing databases such as Genome Aggregation Database (gnomAD) can enable burde n testing using these databases as controls, obviating the need ...
Source: The American Journal of Human Genetics - September 27, 2018 Category: Genetics & Stem Cells Authors: Michael H. Guo, Lacey Plummer, Yee-Ming Chan, Joel N. Hirschhorn, Margaret F. Lippincott Tags: Article Source Type: research

Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency
We describe the clinical and molecu lar genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 20, 2018 Category: Genetics & Stem Cells Authors: Charlotte L. Alston, Juliana Heidler, Marris G. Dibley, Laura S. Kremer, Lucie S. Taylor, Carl Fratter, Courtney E. French, Ruth I.C. Glasgow, Ren é G. Feichtinger, Isabelle Delon, Alistair T. Pagnamenta, Helen Dolling, Hugh Lemonde, Neil Aiton, Alf Bjø Tags: Report Source Type: research

Genomic Landscape and Mutational Signatures of Deafness-Associated Genes
The classification of genetic variants represents a major challenge in the post-genome era by virtue of their extraordinary number and the complexities associated with ascribing a clinical impact, especially for disorders exhibiting exceptional phenotypic, genetic, and allelic heterogeneity. To address this challenge for hearing loss, we have developed the Deafness Variation Database (DVD), a comprehensive, open-access resource that integrates all available genetic, genomic, and clinical data together with expert curation to generate a single classification for each variant in 152 genes implicated in syndromic and non-synd...
Source: The American Journal of Human Genetics - September 20, 2018 Category: Genetics & Stem Cells Authors: Hela Azaiez, Kevin T. Booth, Sean S. Ephraim, Bradley Crone, Elizabeth A. Black-Ziegelbein, Robert J. Marini, A. Eliot Shearer, Christina M. Sloan-Heggen, Diana Kolbe, Thomas Casavant, Michael J. Schnieders, Carla Nishimura, Terry Braun, Richard J.H. Smit Tags: Article Source Type: research

An Ancient Fecundability-Associated Polymorphism Creates a GATA2 Binding Site in a Distal Enhancer of HLA-F
Variation in female reproductive traits, such as fertility, fecundity, and fecundability, are heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits have been challenging. Here, we explore the functional significance and evolutionary history of a G/A polymorphism at SNP rs2523393, which is an eQTL for HLA-F and is significantly associated with fecundability (the probability of being pregnant within a single menstrual cycle). We replicated the association between the rs2523393 genotype and HLA-F expression by using GTEx data and demonstrate that HLA-F is upregulate...
Source: The American Journal of Human Genetics - September 20, 2018 Category: Genetics & Stem Cells Authors: Katelyn M. Mika, Xilong Li, Francesco J. DeMayo, Vincent J. Lynch Tags: Article Source Type: research

Biallelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency
We describe the clinical and molecu lar genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 20, 2018 Category: Genetics & Stem Cells Authors: Charlotte L. Alston, Juliana Heidler, Marris G. Dibley, Laura S. Kremer, Lucie S. Taylor, Carl Fratter, Courtney E. French, Ruth I.C. Glasgow, Ren é G. Feichtinger, Isabelle Delon, Alistair T. Pagnamenta, Helen Dolling, Hugh Lemonde, Neil Aiton, Alf Bjø Tags: Report Source Type: research

Genetic Association of Albuminuria with Cardiometabolic Disease and Blood Pressure
Excretion of albumin in urine, or albuminuria, is associated with the development of multiple cardiovascular and metabolic diseases. However, whether pathways leading to albuminuria are causal for cardiometabolic diseases is unclear. We addressed this question using a Mendelian randomization framework in the UK Biobank, a large population-based cohort. We first performed a genome-wide association study for albuminuria in 382,500 individuals and identified 32 new albuminuria loci. We constructed albuminuria genetic risk scores and tested for association with cardiometabolic diseases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 13, 2018 Category: Genetics & Stem Cells Authors: Mary E. Haas, Krishna G. Aragam, Connor A. Emdin, Alexander G. Bick, International Consortium for Blood Pressure, Gibran Hemani, George Davey Smith, Sekar Kathiresan Tags: Article Source Type: research

ClinPred: Prediction Tool to Identify Disease-Relevant Nonsynonymous Single-Nucleotide Variants
Advances in high-throughput DNA sequencing have revolutionized the discovery of variants in the human genome; however, interpreting the phenotypic effects of those variants is still a challenge. While several computational approaches to predict variant impact are available, their accuracy is limited and further improvement is needed. Here, we introduce ClinPred, an efficient tool for identifying disease-relevant nonsynonymous variants. Our predictor incorporates two machine learning algorithms that use existing pathogenicity scores and, notably, benefits from inclusion of normal population allele frequency from the gnomAD ...
Source: The American Journal of Human Genetics - September 13, 2018 Category: Genetics & Stem Cells Authors: Najmeh Alirezaie, Kristin D. Kernohan, Taila Hartley, Jacek Majewski, Toby Dylan Hocking Tags: Article Source Type: research

A Multiplex Homology-Directed DNA Repair Assay Reveals the Impact of More Than 1,000 BRCA1 Missense Substitution Variants on Protein Function
Loss-of-function pathogenic variants in BRCA1 confer a predisposition to breast and ovarian cancer. Genetic testing for sequence changes in BRCA1 frequently reveals a missense variant for which the impact on cancer risk and on the molecular function of BRCA1 is unknown. Functional BRCA1 is required for the homology-directed repair (HDR) of double-strand DNA breaks, a critical activity for maintaining genome integrity and tumor suppression. Here, we describe a multiplex HDR reporter assay for concurrently measuring the effects of hundreds of variants of BRCA1 for their role in DNA repair. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 12, 2018 Category: Genetics & Stem Cells Authors: Lea M. Starita, Muhtadi M. Islam, Tapahsama Banerjee, Aleksandra I. Adamovich, Justin Gullingsrud, Stanley Fields, Jay Shendure, Jeffrey D. Parvin Tags: Article Source Type: research

The Clinical Sequencing Evidence-Generating Research Consortium: Integrating Genomic Sequencing in Diverse and Medically Underserved Populations
The Clinical Sequencing Evidence-Generating Research (CSER) consortium, now in its second funding cycle, is investigating the effectiveness of integrating genomic (exome or genome) sequencing into the clinical care of diverse and medically underserved individuals in a variety of healthcare settings and disease states. The consortium comprises a coordinating center, six funded extramural clinical projects, and an ongoing National Human Genome Research Institute (NHGRI) intramural project. Collectively, these projects aim to enroll and sequence over 6,100 participants in four years. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 6, 2018 Category: Genetics & Stem Cells Authors: Laura M. Amendola, Jonathan S. Berg, Carol R. Horowitz, Frank Angelo, Jeannette T. Bensen, Barbara B. Biesecker, Leslie G. Biesecker, Gregory M. Cooper, Kelly East, Kelly Filipski, Stephanie M. Fullerton, Bruce D. Gelb, Katrina A.B. Goddard, Benyam Hailu, Tags: Commentary Source Type: research

This Month in The Journal
As genetic sequencing becomes more commonplace and  genomic datasets are assembled, there is growing interest in giving research participants access to clinically relevant secondary findings. Recommendations for the return of these findings in the clinical setting are largely formed at this point and are typically based on the ACMG’s list of g enes in which a set of variants is known to cause disease. However, consensus related to the return of these findings outside of a clinical setting is still evolving. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 6, 2018 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

IRF2BPL Is Associated with Neurological Phenotypes
(The American Journal of Human Genetics 103, 245 –260; August 2, 2018) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 6, 2018 Category: Genetics & Stem Cells Authors: Paul C. Marcogliese, Vandana Shashi, Rebecca C. Spillmann, Nicholas Stong, Jill A. Rosenfeld, Mary Kay Koenig, Juli án A. Martínez-Agosto, Matthew Herzog, Agnes H. Chen, Patricia I. Dickson, Henry J. Lin, Moin U. Vera, Noriko Salamon, John M. Graham, Da Tags: Correction Source Type: research

Retraction Notice to: Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements
(The American Journal of Human Genetics 101, 616 –622; October 5, 2017) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 6, 2018 Category: Genetics & Stem Cells Authors: Wolfram Demaerel, Matthew S. Hestand, Elfi Vergaelen, Ann Swillen, Marcos L ópez-Sánchez, Luis A. Pérez-Jurado, Donna M. McDonald-McGinn, Elaine Zackai, Beverly S. Emanuel, Bernice E. Morrow, Jeroen Breckpot, Koenraad Devriendt, Joris R. Vermeesch, Int Tags: Retraction Source Type: research

Mutations in TOP3A Cause a Bloom Syndrome-like Disorder
(The American Journal of Human Genetics 103, 221 –231; August 2, 2018) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 6, 2018 Category: Genetics & Stem Cells Authors: Carol-Anne Martin, Kata Sarl ós, Clare V. Logan, Roshan Singh Thakur, David A. Parry, Anna H. Bizard, Andrea Leitch, Louise Cleal, Nadia Shaukat Ali, Mohammed A. Al-Owain, William Allen, Janine Altmüller, Miriam Aza-Carmona, Bushra A.Y. Barakat, Jimena Tags: Correction Source Type: research

Fetal —not Maternal—APOL1 Genotype Associated with Risk for Preeclampsia in Those with African Ancestry
Black Americans are at increased risk for preeclampsia. Genetic variants in apolipoprotein L1 (APOL1) account for much of the increased risk for kidney disease in blacks. APOL1 is expressed in human placenta and transgenic mice expressing APOL1 develop preeclampsia. We evaluated the role of APOL1 variants in human preeclampsia. We determined maternal and fetal APOL1 genotypes in black women with preeclampsia in two populations. At Einstein Montefiore Center (EMC) Affiliated Hospitals, we studied 121 pregnancies in black women with preeclampsia. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 30, 2018 Category: Genetics & Stem Cells Authors: Kimberly J. Reidy, Rebecca C. Hjorten, Claire L. Simpson, Avi Z. Rosenberg, Stacy D. Rosenblum, Csaba P. Kovesdy, Frances A. Tylavsky, Joseph Myrie, Bianca L. Ruiz, Soulin Haque, Khyobeni Mozhui, George W. Nelson, Victor A. David, Xiaoping Yang, Masako Su Tags: Article Source Type: research

PubCaseFinder: A Case-Report-Based, Phenotype-Driven Differential-Diagnosis System for Rare Diseases
Recently, to speed up the differential-diagnosis process based on symptoms and signs observed from an affected individual in the diagnosis of rare diseases, researchers have developed and implemented phenotype-driven differential-diagnosis systems. The performance of those systems relies on the quantity and quality of underlying databases of disease-phenotype associations (DPAs). Although such databases are often developed by manual curation, they inherently suffer from limited coverage. To address this problem, we propose a text-mining approach to increase the coverage of DPA databases and consequently improve the perform...
Source: The American Journal of Human Genetics - August 30, 2018 Category: Genetics & Stem Cells Authors: Toyofumi Fujiwara, Yasunori Yamamoto, Jin-Dong Kim, Orion Buske, Toshihisa Takagi Tags: Article Source Type: research