Management of Secondary Genomic Findings
Secondary genomic findings are increasingly being returned to individuals as opportunistic screening results. A secondary finding offers the chance to identify and mitigate disease that may otherwise be unrecognized in an individual. As a form of screening, secondary findings must be considered differently from sequencing results in a diagnostic setting. For these reasons, clinicians should employ an evaluation and long-term management strategy that accounts for both the increased disease risk associated with a secondary finding and the lower positive predictive value of a screening result compared to an indication-based t...
Source: The American Journal of Human Genetics - July 2, 2020 Category: Genetics & Stem Cells Authors: Alexander E. Katz, Robert L. Nussbaum, Benjamin D. Solomon, Heidi L. Rehm, Marc S. Williams, Leslie G. Biesecker Tags: Review Source Type: research

This Month in The Journal
Labels are ubiquitous in our lives: we place nearly everyone and everything into discrete categories. Oftentimes, this process of categorization is meant to simplify complex tasks or focus attention. The terms race, ethnicity, and ancestry (REA) are interrelated, and imperfect, terms that we use to classify ourselves. But beyond placing people into categories, how are these terms used in practice? Are they helpful, or do they hinder the very tasks they are meant to facilitate? In this issue, Popejoy et  al. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - July 2, 2020 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects
A recent genome-wide association study of Huntington disease (HD) implicated genes involved in DNA maintenance processes as modifiers of onset, including multiple genome-wide significant signals in a chr15 region containing the DNA repair gene Fanconi-Associated Nuclease 1 (FAN1). Here, we have carried out detailed genetic, molecular, and cellular investigation of the modifiers at this locus. We find that missense changes within or near the DNA-binding domain (p.Arg507His and p.Arg377Trp) reduce FAN1's DNA-binding activity and its capacity to rescue mitomycin C-induced cytotoxicity, accounting for two infrequent onset-hast...
Source: The American Journal of Human Genetics - June 25, 2020 Category: Genetics & Stem Cells Authors: Kyung-Hee Kim, Eun Pyo Hong, Jun Wan Shin, Michael J. Chao, Jacob Loupe, Tammy Gillis, Jayalakshmi S. Mysore, Peter Holmans, Lesley Jones, Michael Orth, Darren G. Monckton, Jeffrey D. Long, Seung Kwak, Ramee Lee, James F. Gusella, Marcy E. MacDonald, Jong Tags: Article Source Type: research

Genome-wide Enrichment of De Novo Coding Mutations in Orofacial Cleft Trios
Although de novo mutations (DNMs) are known to increase an individual ’s risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions o f coding DNMs to an individual’s OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. (Source: The ...
Source: The American Journal of Human Genetics - June 22, 2020 Category: Genetics & Stem Cells Authors: Madison R. Bishop, Kimberly K. Diaz Perez, Miranda Sun, Samantha Ho, Pankaj Chopra, Nandita Mukhopadhyay, Jacqueline B. Hetmanski, Margaret A. Taub, Lina M. Moreno-Uribe, Luz Consuelo Valencia-Ramirez, Claudia P. Restrepo Mu ñeton, George Wehby, Jacqueli Tags: Article Source Type: research

De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay
We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 17, 2020 Category: Genetics & Stem Cells Authors: Lisenka E.L.M. Vissers, Sreehari Kalvakuri, Elke de Boer, Sinje Geuer, Machteld Oud, Inge van Outersterp, Michael Kwint, Melde Witmond, Simone Kersten, Daniel L. Polla, Dilys Weijers, Amber Begtrup, Kirsty McWalter, Anna Ruiz, Elisabeth Gabau, Jenny E.V. Tags: Report Source Type: research

Population-Specific Recombination Maps from Segments of Identity by Descent
We present a method and software, called IBDrecomb, for using segments of identity by descent to infer recombination rates. IBDrecomb can be applied to sequenced population cohorts to obtain high-resolution, population-specific recombination maps. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 12, 2020 Category: Genetics & Stem Cells Authors: Ying Zhou, Brian L. Browning, Sharon R. Browning Tags: Article Source Type: research

High-Throughput Reclassification of SCN5A Variants
Partial or complete loss-of-function variants in SCN5A are the most common genetic cause of the arrhythmia disorder Brugada syndrome (BrS1). However, the pathogenicity of SCN5A variants is often unknown or disputed; 80% of the 1,390 SCN5A missense variants observed in at least one individual to date are variants of uncertain significance (VUSs). The designation of VUS is a barrier to the use of sequence data in clinical care. We selected 83 variants: 10 previously studied control variants, 10 suspected benign variants, and 63 suspected Brugada syndrome-associated variants, selected on the basis of their frequency in the ge...
Source: The American Journal of Human Genetics - June 12, 2020 Category: Genetics & Stem Cells Authors: Andrew M. Glazer, Yuko Wada, Bian Li, Ayesha Muhammad, Olivia R. Kalash, Matthew J. O ’Neill, Tiffany Shields, Lynn Hall, Laura Short, Marcia A. Blair, Brett M. Kroncke, John A. Capra, Dan M. Roden Tags: Article Source Type: research

Evidence of Polygenic Adaptation in Sardinia at Height-Associated Loci Ascertained from the Biobank Japan
Adult height is one of the earliest putative examples of polygenic adaptation in humans. However, this conclusion was recently challenged because residual uncorrected stratification from large-scale consortium studies was considered responsible for the previously noted genetic difference. It thus remains an open question whether height loci exhibit signals of polygenic adaptation in any human population. We re-examined this question, focusing on one of the shortest European populations, the Sardinians, in addition to mainland European populations. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 12, 2020 Category: Genetics & Stem Cells Authors: Minhui Chen, Carlo Sidore, Masato Akiyama, Kazuyoshi Ishigaki, Yoichiro Kamatani, David Schlessinger, Francesco Cucca, Yukinori Okada, Charleston W.K. Chiang Tags: Article Source Type: research

Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis
The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 8, 2020 Category: Genetics & Stem Cells Authors: Lynn M. Boyden, Jing Zhou, Ronghua Hu, Theodore Zaki, Erin Loring, Jared Scott, Heiko Traupe, Amy S. Paller, Richard P. Lifton, Keith A. Choate Tags: Report Source Type: research

Natural Selection Shapes Codon Usage in the Human Genome
Synonymous codon usage has been identified as a determinant of translational efficiency and mRNA stability in model organisms and human cell lines. However, whether natural selection shapes human codon content to optimize translation efficiency is unclear. Furthermore, aside from those that affect splicing, synonymous mutations are typically ignored as potential contributors to disease. Using genetic sequencing data from nearly 200,000 individuals, we uncover clear evidence that natural selection optimizes codon content in the human genome. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 8, 2020 Category: Genetics & Stem Cells Authors: Ryan S. Dhindsa, Brett R. Copeland, Anthony M. Mustoe, David B. Goldstein Tags: Article Source Type: research

Clinical Genetics Lacks Standard Definitions and Protocols for the Collection and Use of Diversity Measures
Genetics researchers and clinical professionals rely on diversity measures such as race, ethnicity, and ancestry (REA) to stratify study participants and patients for a variety of applications in research and precision medicine. However, there are no comprehensive, widely accepted standards or guidelines for collecting and using such data in clinical genetics practice. Two NIH-funded research consortia, the Clinical Genome Resource (ClinGen) and Clinical Sequencing Evidence-generating Research (CSER), have partnered to address this issue and report how REA are currently collected, conceptualized, and used. (Source: The Ame...
Source: The American Journal of Human Genetics - June 5, 2020 Category: Genetics & Stem Cells Authors: Alice B. Popejoy, Kristy R. Crooks, Stephanie M. Fullerton, Lucia A. Hindorff, Gillian W. Hooker, Barbara A. Koenig, Natalie Pino, Erin M. Ramos, Deborah I. Ritter, Hannah Wand, Matt W. Wright, Michael Yudell, James Y. Zou, Sharon E. Plon, Carlos D. Busta Tags: Article Source Type: research

Homozygous Mutations in BTG4 Cause Zygotic Cleavage Failure and Female Infertility
Zygotic cleavage failure (ZCF) is a unique early embryonic phenotype resulting in female infertility and recurrent failure of in  vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). With this phenotype, morphologically normal oocytes can be retrieved and successfully fertilized, but they fail to undergo cleavage. Until now, whether this phenotype has a Mendelian inheritance pattern and which underlying genetic factors play a role in its development remained to be elucidated. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 4, 2020 Category: Genetics & Stem Cells Authors: Wei Zheng, Zhou Zhou, Qianqian Sha, Xiangli Niu, Xiaoxi Sun, Juanzi Shi, Lei Zhao, Shuoping Zhang, Jing Dai, Sufen Cai, Fei Meng, Liang Hu, Fei Gong, Xiaoran Li, Jing Fu, Rong Shi, Guangxiu Lu, Biaobang Chen, Hengyu Fan, Lei Wang, Ge Lin, Qing Sang Tags: Article Source Type: research

This Month in The Journal
The G-protein-coupled receptor CaSR monitors and maintains homeostasis of blood calcium levels. Heterozygous mutations in CASR cause two distinct disorders: familial hypocalciuric hypercalcemia type 1 (FHH1) and autosomal-dominant hypocalcemia type 1 (ADH1). Medical intervention is not usually warranted for FHH1; however, the serum profiles mirror those observed in primary hyperparathyroidism, a condition typically treated by parathyroidectomy. More detailed testing is required to differentiate between the two disorders and avoid unnecesary medical procedures. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 4, 2020 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

The American Journal of Human Genetics Welcomes Human Genetics and Genomics Advances to the ASHG Publications Family
As of this month, AJHG welcomes its new sibling journal, Human Genetics and Genomics Advances (HGGA), to the family of ASHG scientific publications. We see this as an exciting opportunity for ASHG and its members, and we would like to use this editorial to address two important issues: first, why launch a new journal at this time, and second, how will AJHG and HGGA relate to one another? (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - June 4, 2020 Category: Genetics & Stem Cells Authors: Michael J. Bamshad, Bruce R. Korf Tags: Editors' Corner Source Type: research

Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome
IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. (Source: The American Jo...
Source: The American Journal of Human Genetics - June 3, 2020 Category: Genetics & Stem Cells Authors: Huijun Wang, Aytaj Humbatova, Yuanxiang Liu, Wen Qin, Mingyang Lee, Nicole Cesarato, Fanny Kort üm, Sheetal Kumar, Maria Teresa Romano, Shangzhi Dai, Ran Mo, Sugirthan Sivalingam, Susanne Motameny, Yuan Wu, Xiaopeng Wang, Xinwu Niu, Songmei Geng, Dorothe Tags: Article Source Type: research

Bi-allelic Missense Pathogenic Variants in TRIP13 Cause Female Infertility Characterized by Oocyte Maturation Arrest
Normal oocyte meiosis is a prerequisite for successful human reproduction, and abnormalities in the process will result in infertility. In 2016, we identified mutations in TUBB8 as responsible for human oocyte meiotic arrest. However, the underlying genetic factors for most affected individuals remain unknown. TRIP13, encoding an AAA-ATPase, is a key component of the spindle assembly checkpoint, and recurrent homozygous nonsense variants and a splicing variant in TRIP13 are reported to cause Wilms tumors in children. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 29, 2020 Category: Genetics & Stem Cells Authors: Zhihua Zhang, Bin Li, Jing Fu, Rong Li, Feiyang Diao, Caihong Li, Biaobang Chen, Jing Du, Zhou Zhou, Jian Mu, Zheng Yan, Ling Wu, Shuai Liu, Wenjing Wang, Lin Zhao, Jie Dong, Lin He, Xiaozhen Liang, Yanping Kuang, Xiaoxi Sun, Qing Sang, Lei Wang Tags: Article Source Type: research

A Genetic History of the Near East from an aDNA Time Course Sampling Eight Points in the Past 4,000 Years
The Iron and Classical Ages in the Near East were marked by population expansions carrying cultural transformations that shaped human history, but the genetic impact of these events on the people who lived through them is little-known. Here, we sequenced the whole genomes of 19 individuals who each lived during one of four time periods between 800 BCE and 200 CE in Beirut on the Eastern Mediterranean coast at the center of the ancient world ’s great civilizations. We combined these data with published data to traverse eight archaeological periods and observed any genetic changes as they arose. (Source: The American J...
Source: The American Journal of Human Genetics - May 28, 2020 Category: Genetics & Stem Cells Authors: Marc Haber, Joyce Nassar, Mohamed A. Almarri, Tina Saupe, Lehti Saag, Samuel J. Griffith, Claude Doumet-Serhal, Julien Chanteau, Muntaha Saghieh-Beydoun, Yali Xue, Christiana L. Scheib, Chris Tyler-Smith Tags: Report Source Type: research

Non-parametric Polygenic Risk Prediction via Partitioned GWAS Summary Statistics
In complex trait genetics, the ability to predict phenotype from genotype is the ultimate measure of our understanding of genetic architecture underlying the heritability of a trait. A complete understanding of the genetic basis of a trait should allow for predictive methods with accuracies approaching the trait ’s heritability. The highly polygenic nature of quantitative traits and most common phenotypes has motivated the development of statistical strategies focused on combining myriad individually non-significant genetic effects. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 28, 2020 Category: Genetics & Stem Cells Authors: Sung Chun, Maxim Imakaev, Daniel Hui, Nikolaos A. Patsopoulos, Benjamin M. Neale, Sekar Kathiresan, Nathan O. Stitziel, Shamil R. Sunyaev Tags: Article Source Type: research

Hi-C Identifies Complex Genomic Rearrangements and TAD-Shuffling in Developmental Diseases
Genome-wide analysis methods, such as array comparative genomic hybridization (CGH) and whole-genome sequencing (WGS), have greatly advanced the identification of structural variants (SVs) in the human genome. However, even with standard high-throughput sequencing techniques, complex rearrangements with multiple breakpoints are often difficult to resolve, and predicting their effects on gene expression and phenotype remains a challenge. Here, we address these problems by using high-throughput chromosome conformation capture (Hi-C) generated from cultured cells of nine individuals with developmental disorders (DDs). (Source...
Source: The American Journal of Human Genetics - May 28, 2020 Category: Genetics & Stem Cells Authors: Uir á Souto Melo, Robert Schöpflin, Rocio Acuna-Hidalgo, Martin Atta Mensah, Björn Fischer-Zirnsak, Manuel Holtgrewe, Marius-Konstantin Klever, Seval Türkmen, Verena Heinrich, Ilina Datkhaeva Pluym, Eunice Matoso, Sérgio Bernardo de Sousa, Pedro Lour Tags: Article Source Type: research

Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement
Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 28, 2020 Category: Genetics & Stem Cells Authors: Sabrina Mechaussier, Basamat Almoallem, Christina Zeitz, Kristof Van Schil, Laila Jeddawi, Jo Van Dorpe, Alfredo Due ñas Rey, Christel Condroyer, Olivier Pelle, Michel Polak, Nathalie Boddaert, Nadia Bahi-Buisson, Mara Cavallin, Jean-Louis Bacquet, Alexa Tags: Article Source Type: research

Polymorphic Inversions Underlie the Shared Genetic Susceptibility of Obesity-Related Diseases
The burden of several common diseases including obesity, diabetes, hypertension, asthma, and depression is increasing in most world populations. However, the mechanisms underlying the numerous epidemiological and genetic correlations among these disorders remain largely unknown. We investigated whether common polymorphic inversions underlie the shared genetic influence of these disorders. We performed an inversion association analysis including 21 inversions and 25 obesity-related traits on a total of 408,898 Europeans and validated the results in 67,299 independent individuals. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 28, 2020 Category: Genetics & Stem Cells Authors: Juan R. Gonz ález, Carlos Ruiz-Arenas, Alejandro Cáceres, Ignasi Morán, Marcos López-Sánchez, Lorena Alonso, Ignacio Tolosana, Marta Guindo-Martínez, Josep M. Mercader, Tonu Esko, David Torrents, Josefa González, Luis A. Pérez-Jurado Tags: Article Source Type: research

Philip Leder, MD, 1934 –2020, In Memoriam
Philip Leder, MD, died on February 2, 2020, at the age of 85 from complications of Parkinson ’s disease. Appropriately for a man who was devoted to his family, he was surrounded by his wife, Aya, and other family members. Over his long career, Phil was a towering figure in wide-ranging fields of molecular biology, cancer, immunology, and developmental biology, and his influence on these f ields was immense. In addition to his outstanding scientific contributions, Phil was foremost a truly decent human being, a remarkable lecturer and teacher, and a dedicated mentor to more than a hundred students and postdoctoral fel...
Source: The American Journal of Human Genetics - May 28, 2020 Category: Genetics & Stem Cells Authors: Cynthia Casson Morton, Anthony Wynshaw-Boris Tags: Obituary Source Type: research

De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas
SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or in...
Source: The American Journal of Human Genetics - May 21, 2020 Category: Genetics & Stem Cells Authors: Dara Tolchin, Jessica P. Yeager, Priya Prasad, Naghmeh Dorrani, Alvaro Serrano Russi, Julian A. Martinez-Agosto, Abdul Haseeb, Marco Angelozzi, G.W.E. Santen, Claudia Ruivenkamp, Saadet Mercimek-Andrews, Christel Depienne, Alma Kuechler, Barbara Mikat, He Tags: Article Source Type: research

An Integrated Deep-Mutational-Scanning Approach Provides Clinical Insights on PTEN Genotype-Phenotype Relationships
In this study, we combined two recent deep mutational scanning (DMS) datasets probing the effects of single amino acid variation on enzyme activity and steady-state cellular abundance with a large, well-curated clinical cohort of PTEN-variant carriers. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 21, 2020 Category: Genetics & Stem Cells Authors: Taylor L. Mighell, Stetson Thacker, Eric Fombonne, Charis Eng, Brian J. O ’Roak Tags: Article Source Type: research

Localizing Components of Shared Transethnic Genetic Architecture of Complex Traits from GWAS Summary Data
Despite strong transethnic genetic correlations reported in the literature for many complex traits, the non-transferability of polygenic risk scores across populations suggests the presence of population-specific components of genetic architecture. We propose an approach that models GWAS summary data for one trait in two populations to estimate genome-wide proportions of population-specific/shared causal SNPs. In simulations across various genetic architectures, we show that our approach yields approximately unbiased estimates with in-sample LD and slight upward-bias with out-of-sample LD. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 21, 2020 Category: Genetics & Stem Cells Authors: Huwenbo Shi, Kathryn S. Burch, Ruth Johnson, Malika K. Freund, Gleb Kichaev, Nicholas Mancuso, Astrid M. Manuel, Natalie Dong, Bogdan Pasaniuc Tags: Article Source Type: research

Systems Genetics in Human Endothelial Cells Identifies Non-coding Variants Modifying Enhancers, Expression, and Complex Disease Traits
The identification of causal variants and mechanisms underlying complex disease traits in humans is important for the progress of human disease genetics; this requires finding strategies to detect functional regulatory variants in disease-relevant cell types. To achieve this, we collected genetic and transcriptomic data from the aortic endothelial cells of up to 157 donors and four epigenomic phenotypes in up to 44 human donors representing individuals of both sexes and three major ancestries. We found thousands of expression quantitative trait loci (eQTLs) at all ranges of effect sizes not detected by the Gene-Tissue Expr...
Source: The American Journal of Human Genetics - May 21, 2020 Category: Genetics & Stem Cells Authors: Lindsey K. Stolze, Austin C. Conklin, Michael B. Whalen, Maykel L ópez Rodríguez, Kadri Õunap, Ilakya Selvarajan, Anu Toropainen, Tiit Örd, Jin Li, Anna Eshghi, Alice E. Solomon, Yun Fang, Minna U. Kaikkonen, Casey E. Romanoski Tags: Article Source Type: research

Characterizing the Causal Pathway for Genetic Variants Associated with Neurological Phenotypes Using Human Brain-Derived Proteome Data
In this study, we integrated human proteome data derived from brain tissue to evaluate whether targeted proteins putatively mediate the effects of genetic variants on seven neurological phenotypes (Alzheimer disease, amyotrophic lateral sclerosis, depression, insomnia, intelligence, neuroticism, and schizophrenia). Applying the principles of Mendelian randomization (MR) systematically across the genome highlighted 43 effects between genetically predicted proteins derived from the dorsolateral prefrontal cortex and these outcomes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 14, 2020 Category: Genetics & Stem Cells Authors: Nelson K. Kibinge, Caroline L. Relton, Tom R. Gaunt, Tom G. Richardson Tags: Article Source Type: research

Expansion of GGC Repeat in GIPC1 Is Associated with Oculopharyngodistal Myopathy
Oculopharyngodistal myopathy (OPDM) is an adult-onset inherited neuromuscular disorder characterized by progressive ptosis, external ophthalmoplegia, and weakness of the masseter, facial, pharyngeal, and distal limb muscles. The myopathological features are presence of rimmed vacuoles (RVs) in the muscle fibers and myopathic changes of differing severity. Inheritance is variable, with either putative autosomal-dominant or autosomal-recessive pattern. Here, using a comprehensive strategy combining whole-genome sequencing (WGS), long-read whole-genome sequencing (LRS), linkage analysis, repeat-primed polymerase chain reactio...
Source: The American Journal of Human Genetics - May 14, 2020 Category: Genetics & Stem Cells Authors: Jianwen Deng, Jiaxi Yu, Pidong Li, Xinghua Luan, Li Cao, Juan Zhao, Meng Yu, Wei Zhang, He Lv, Zhiying Xie, LingChao Meng, Yiming Zheng, Yawen Zhao, Qiang Gang, Qingqing Wang, Jing Liu, Min Zhu, Xueyu Guo, Yanan Su, Yu Liang, Fan Liang, Tomohiro Hayashi, Tags: Article Source Type: research

Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling
The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 14, 2020 Category: Genetics & Stem Cells Authors: Thuy-Linh Le, Yunia Sribudiani, Xiaomin Dong, C éline Huber, Chelsea Kois, Geneviève Baujat, Christopher T. Gordon, Valerie Mayne, Louise Galmiche, Valérie Serre, Nicolas Goudin, Mohammed Zarhrate, Christine Bole-Feysot, Cécile Masson, Patrick Nitschk Tags: Article Source Type: research

Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy
Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 7, 2020 Category: Genetics & Stem Cells Authors: Benjamin Cogn é, Xenia Latypova, Lokuliyanage Dona Samudita Senaratne, Ludovic Martin, Daniel C. Koboldt, Georgios Kellaris, Lorraine Fievet, Guylène Le Meur, Dominique Caldari, Dominique Debray, Mathilde Nizon, Eirik Frengen, Sara J. Bowne, 99 Lives Co Tags: Report Source Type: research

Common Genetic Variants Modulate the Electrocardiographic Tpeak-to-Tend Interval
Sudden cardiac death is responsible for half of all deaths from cardiovascular disease. The analysis of the electrophysiological substrate for arrhythmias is crucial for optimal risk stratification. A prolonged T-peak-to-Tend (Tpe) interval on the electrocardiogram is an independent predictor of increased arrhythmic risk, and Tpe changes with heart rate are even stronger predictors. However, our understanding of the electrophysiological mechanisms supporting these risk factors is limited. We conducted genome-wide association studies (GWASs) for resting Tpe and Tpe response to exercise and recovery in ∼30,000 individual...
Source: The American Journal of Human Genetics - May 7, 2020 Category: Genetics & Stem Cells Authors: Julia Ram írez, Stefan van Duijvenboden, William J. Young, Michele Orini, Pier D. Lambiase, Patricia B. Munroe, Andrew Tinker Tags: Article Source Type: research

Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population
The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequ...
Source: The American Journal of Human Genetics - May 7, 2020 Category: Genetics & Stem Cells Authors: Ridge Dershem, Caroline M. Gorvin, Raghu P.R. Metpally, Sarathbabu Krishnamurthy, Diane T. Smelser, Fadil M. Hannan, David J. Carey, Rajesh V. Thakker, Gerda E. Breitwieser, Regeneron Genetics Center Tags: Article Source Type: research

Predictive Utility of Polygenic Risk Scores for Coronary Heart Disease in Three Major Racial and Ethnic Groups
Because polygenic risk scores (PRSs) for coronary heart disease (CHD) are derived from mainly European ancestry (EA) cohorts, their validity in African ancestry (AA) and Hispanic ethnicity (HE) individuals is unclear. We investigated associations of “restricted” and genome-wide PRSs with CHD in three major racial and ethnic groups in the U.S. The eMERGE cohort (mean age 48 ± 14 years, 58% female) included 45,645 EA, 7,597 AA, and 2,493 HE individuals. We assessed two restricted PRSs (PRSTikkanen and PRSTada; 28 and 50 variants, respectivel y) and two genome-wide PRSs (PRSmetaGRS and PRSLDPred; 1.7 M...
Source: The American Journal of Human Genetics - May 7, 2020 Category: Genetics & Stem Cells Authors: Ozan Dikilitas, Daniel J. Schaid, Matthew L. Kosel, Robert J. Carroll, Christopher G. Chute, Joshua A. Denny, Alex Fedotov, QiPing Feng, Hakon Hakonarson, Gail P. Jarvik, Ming Ta Michael Lee, Jennifer A. Pacheco, Robb Rowley, Patrick M. Sleiman, C. Michae Tags: Article Source Type: research

Mantis-ml: Disease-Agnostic Gene Prioritization from High-Throughput Genomic Screens by Stochastic Semi-supervised Learning
Access to large-scale genomics datasets has increased the utility of hypothesis-free genome-wide analyses. However, gene signals are often insufficiently powered to reach experiment-wide significance, triggering a process of laborious triaging of genomic-association-study results. We introduce mantis-ml, a multi-dimensional, multi-step machine-learning framework that allows objective assessment of the biological relevance of genes to disease studies. Mantis-ml is an automated machine-learning framework that follows a multi-model approach of stochastic semi-supervised learning to rank disease-associated genes through iterat...
Source: The American Journal of Human Genetics - May 7, 2020 Category: Genetics & Stem Cells Authors: Dimitrios Vitsios, Slav é Petrovski Tags: Article Source Type: research

This Month in The Journal
Through its histone methyltransferase activity, the polycomb repressive complex 2 (PRC2) regulates trimethylation of lysine 27 of histone H3 (H3K27me3), a mark that drives chromatin condensation and transcriptional repression. This complex, required for genomic silencing, is composed of EZH2, EED, and SUZ12. Mutations in each of these genes can cause disorders characterized by overgrowth and intellectual disability. In recent years, many groups have identified distinct DNA methylation signatures in the blood of individuals with disorders caused by pathogenic variation in genes involved in epigenetic processes. (Source: The...
Source: The American Journal of Human Genetics - May 7, 2020 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Analysis of U8 snoRNA Variants in Zebrafish Reveals How Bi-allelic Variants Cause Leukoencephalopathy with Calcifications and Cysts
How mutations in the non-coding U8 snoRNA cause the neurological disorder leukoencephalopathy with calcifications and cysts (LCC) is poorly understood. Here, we report the generation of a mutant U8 animal model for interrogating LCC-associated pathology. Mutant U8 zebrafish exhibit defective central nervous system development, a disturbance of ribosomal RNA (rRNA) biogenesis and tp53 activation, which monitors ribosome biogenesis. Further, we demonstrate that fibroblasts from individuals with LCC are defective in rRNA processing. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 30, 2020 Category: Genetics & Stem Cells Authors: Andrew P. Badrock, Carolina Uggenti, Ludivine Wacheul, Siobhan Crilly, Emma M. Jenkinson, Gillian I. Rice, Paul R. Kasher, Denis L.J. Lafontaine, Yanick J. Crow, Raymond T. O ’Keefe Tags: Article Source Type: research

Insufficient Evidence for “Autism-Specific” Genes
Despite evidence that deleterious variants in the same genes are implicated across multiple neurodevelopmental and neuropsychiatric disorders, there has been considerable interest in identifying genes that, when mutated, confer risk that is largely specific for autism spectrum disorder (ASD). Here, we review the findings and limitations of recent efforts to identify relatively “autism-specific” genes, efforts which focus on rare variants of large effect size that are thought to account for the observed phenotypes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 30, 2020 Category: Genetics & Stem Cells Authors: Scott M. Myers, Thomas D. Challman, Raphael Bernier, Thomas Bourgeron, Wendy K. Chung, John N. Constantino, Evan E. Eichler, Sebastien Jacquemont, David T. Miller, Kevin J. Mitchell, Huda Y. Zoghbi, Christa Lese Martin, David H. Ledbetter Tags: Commentary Source Type: research

De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy
We identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-dependent kinase protein family member that predominantly regulates gene transcription. These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features. CDK19 is conserved between vertebrate and invertebrate model organisms, but currently abnormalities in CDK19 are not known to be associated with a human disorder. Loss of Cdk8, the fly homolog of CDK19, causes larval lethality, which is suppressed by expression of human CDK19 reference cDNA. (Source: The American Jou...
Source: The American Journal of Human Genetics - April 23, 2020 Category: Genetics & Stem Cells Authors: Hyung-lok Chung, Xiao Mao, Hua Wang, Ye-Jin Park, Paul C. Marcogliese, Jill A. Rosenfeld, Lindsay C. Burrage, Pengfei Liu, David R. Murdock, Shinya Yamamoto, Michael F. Wangler, Undiagnosed Diseases Network, Hsiao-Tuan Chao, Hongyu Long, Li Feng, Carlos A Tags: Report Source Type: research

Accurate and Scalable Construction of Polygenic Scores in Large Biobank Data Sets
Accurate construction of polygenic scores (PGS) can enable early diagnosis of diseases and facilitate the development of personalized medicine. Accurate PGS construction requires prediction models that are both adaptive to different genetic architectures and scalable to biobank scale datasets with millions of individuals and tens of millions of genetic variants. Here, we develop such a method called Deterministic Bayesian Sparse Linear Mixed Model (DBSLMM). DBSLMM relies on a flexible modeling assumption on the effect size distribution to achieve robust and accurate prediction performance across a range of genetic architec...
Source: The American Journal of Human Genetics - April 23, 2020 Category: Genetics & Stem Cells Authors: Sheng Yang, Xiang Zhou Tags: Article Source Type: research

Non-coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases
We conducted genome sequencing to search for rare variation contributing to early-onset Alzheimer ’s disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 435 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than one in 10,000 or private), computationa l prediction of deleteriousness (CADD) (10 or 15 thresholds), and molecular function (protein loss-of-function [LoF] only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory region...
Source: The American Journal of Human Genetics - April 23, 2020 Category: Genetics & Stem Cells Authors: J. Nicholas Cochran, Ethan G. Geier, Luke W. Bonham, J. Scott Newberry, Michelle D. Amaral, Michelle L. Thompson, Brittany N. Lasseigne, Anna M. Karydas, Erik D. Roberson, Gregory M. Cooper, Gil D. Rabinovici, Bruce L. Miller, Richard M. Myers, Jennifer S Tags: Article Source Type: research

Pleiotropy-Based Decomposition of Genetic Risk Scores: Association and Interaction Analysis for Type 2 Diabetes and CAD
Genetic risk for a disease in the population may be represented as a genetic risk score (GRS) constructed as the sum of inherited risk alleles, weighted by allelic effects established in an independent population. While this formulation captures overall genetic risk, it typically does not address risk due to specific biological mechanisms or pathways that may nevertheless be important for interpretation or treatment response. Here, a GRS for disease is resolved into independent or nearly independent components pertaining to biological mechanisms inferred from pleiotropic relationships. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 16, 2020 Category: Genetics & Stem Cells Authors: Daniel I. Chasman, Franco Giulianini, Olga V. Demler, Miriam S. Udler Tags: Article Source Type: research

Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities
We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 9, 2020 Category: Genetics & Stem Cells Authors: Alison M. Muir, Jennifer L. Cohen, Sarah E. Sheppard, Pavithran Guttipatti, Tsz Y. Lo, Natalie Weed, Dan Doherty, Danielle DeMarzo, Christina R. Fagerberg, Lars Kj ærsgaard, Martin J. Larsen, Patrick Rump, Katharina Löhner, Yoel Hirsch, David A. Zeevi, Tags: Article Source Type: research

Assessing Digital Phenotyping to Enhance Genetic Studies of Human Diseases
In this study, we use genetic parameters, including genetic correlation, to evaluate whether GWAS performed using cases in the UK Biobank ascertained from hospital records, questionnaire responses, and family history of disease implicate similar disease genetics across a range of effect sizes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 9, 2020 Category: Genetics & Stem Cells Authors: Christopher DeBoever, Yosuke Tanigawa, Matthew Aguirre, Greg McInnes, Adam Lavertu, Manuel A. Rivas Tags: Article Source Type: research

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes
Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 2, 2020 Category: Genetics & Stem Cells Authors: Sanaa Choufani, William T. Gibson, Andrei L. Turinsky, Brian H.Y. Chung, Tianren Wang, Kopal Garg, Alessandro Vitriolo, Ana S.A. Cohen, Sharri Cyrus, Sarah Goodman, Eric Chater-Diehl, Jack Brzezinski, Michael Brudno, Luk Ho Ming, Susan M. White, Sally Ann Tags: Article Source Type: research

Genotyping Array Design and Data Quality Control in the Million Veteran Program
The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide a genome-wide scan of the entire cohort, in parallel with whole-genome sequencing, methylation, and other ‘omics assays. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 2, 2020 Category: Genetics & Stem Cells Authors: Haley Hunter-Zinck, Yunling Shi, Man Li, Bryan R. Gorman, Sun-Gou Ji, Ning Sun, Teresa Webster, Andrew Liem, Paul Hsieh, Poornima Devineni, Purushotham Karnam, Xin Gong, Lakshmi Radhakrishnan, Jeanette Schmidt, Themistocles L. Assimes, Jie Huang, Cuiping Tags: Article Source Type: research

Co-localization between Sequence Constraint and Epigenomic Information Improves Interpretation of Whole-Genome Sequencing Data
We describe here a co-localization approach that aims to identify constrained sequences that co-localize with tissue- or cell-type-specific regulatory regions, and we show that the resulting score is particularly well suited for the identification of rare regulatory variants. For 127 tissues and cell types in the ENCODE/Roadmap Epigenomics Project, we provide catalogs of putative tissue- or cell-type-specific regulatory regions under sequence constraint. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 2, 2020 Category: Genetics & Stem Cells Authors: Danqing Xu, Chen Wang, Krzysztof Kiryluk, Joseph D. Buxbaum, Iuliana Ionita-Laza Tags: Article Source Type: research

Reproductive Choice and Research
Laws should recognize the reproductive rights of women —including the option to terminate a pregnancy—and their ability to advance medical research through the donation of fetal tissue for research. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 2, 2020 Category: Genetics & Stem Cells Tags: ASHG Perspective Source Type: research

This Month in The Journal
Identity by descent (IBD) is used for a variety of purposes, including exploring population history, quantifying mutation rate, and classifying relationships. IBD-based approaches are more accurate, particularly in admixed populations, than methods that simply rely on allele frequency in a given population. However, IBD-based approaches are computationally burdensome because they  require phased genotyping data, a necessity that is problematic for applications using large datasets such as those from biobanks. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 2, 2020 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Incidence, Origin, and Predictive Model for the Detection and Clinical Management of Segmental Aneuploidies in Human Embryos
Despite next-generation sequencing, which now allows for the accurate detection of segmental aneuploidies from in  vitro fertilization embryo biopsies, the origin and characteristics of these aneuploidies are still relatively unknown. Using a multifocal biopsy approach (four trophectoderms [TEs] and one inner cell mass [ICM] analyzed per blastocyst; n = 390), we determine the origin of the aneuploidy and the d iagnostic predictive value of segmental aneuploidy detection in TE biopsies toward the ICM’s chromosomal constitution. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 26, 2020 Category: Genetics & Stem Cells Authors: Laura Girardi, Munevver Serdarogullari, Cristina Patassini, Maurizio Poli, Marco Fabiani, Silvia Caroselli, Onder Coban, Necati Findikli, Fazilet Kubra Boynukalin, Mustafa Bahceci, Rupali Chopra, Rita Canipari, Danilo Cimadomo, Laura Rienzi, Filippo Ubald Tags: Article Source Type: research

Genetic Architecture of Gene Expression in European and African Americans: An eQTL Mapping Study in GENOA
Most existing expression quantitative trait locus (eQTL) mapping studies have been focused on individuals of European ancestry and are underrepresented in other populations including populations with African ancestry. Lack of large-scale well-powered eQTL mapping studies in populations with African ancestry can both impede the dissemination of eQTL mapping results that would otherwise benefit individuals with African ancestry and hinder the comparable analysis for understanding how gene regulation is shaped through evolution. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 26, 2020 Category: Genetics & Stem Cells Authors: Lulu Shang, Jennifer A. Smith, Wei Zhao, Minjung Kho, Stephen T. Turner, Thomas H. Mosley, Sharon L.R. Kardia, Xiang Zhou Tags: Article Source Type: research