Genome-wide Ancestry and Demographic History of African-Descendant Maroon Communities from French Guiana and Suriname
The transatlantic slave trade was the largest forced migration in world history. However, the origins of the enslaved Africans and their admixture dynamics remain unclear. To investigate the demographic history of African-descendant Marron populations, we generated genome-wide data (4.3 million markers) from 107 individuals from three African-descendant populations in South America, as well as 124 individuals from six west African populations. Throughout the Americas, thousands of enslaved Africans managed to escape captivity and establish lasting communities, such as the Noir Marron. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 2, 2017 Category: Genetics & Stem Cells Authors: Cesar Fortes-Lima, Antoine Gessain, Andres Ruiz-Linares, Maria-C átira Bortolini, Florence Migot-Nabias, Gil Bellis, J. Víctor Moreno-Mayar, Berta Nelly Restrepo, Winston Rojas, Efren Avendaño-Tamayo, Gabriel Bedoya, Ludovic Orlando, Antonio Salas, Agn Tags: Article Source Type: research

Local Genetic Correlation Gives Insights into the Shared Genetic Architecture of Complex Traits
Although genetic correlations between complex traits provide valuable insights into epidemiological and etiological studies, a precise quantification of which genomic regions disproportionately contribute to the genome-wide correlation is currently lacking. Here, we introduce ρ-HESS, a technique to quantify the correlation between pairs of traits due to genetic variation at a small region in the genome. Our approach requires GWAS summary data only and makes no distributional assumption on the causal variant effect sizes while accounting for linkage disequilibrium (LD) a nd overlapping GWAS samples. (Source: The America...
Source: The American Journal of Human Genetics - November 2, 2017 Category: Genetics & Stem Cells Authors: Huwenbo Shi, Nicholas Mancuso, Sarah Spendlove, Bogdan Pasaniuc Tags: Article Source Type: research

Natural Selection on Genes Related to Cardiovascular Health in High-Altitude Adapted Andeans
The increase in red blood cell mass (polycythemia) due to the reduced oxygen availability (hypoxia) of residence at high altitude or other conditions is generally thought to be beneficial in terms of increasing tissue oxygen supply. However, the extreme polycythemia and accompanying increased mortality due to heart failure in chronic mountain sickness most likely reduces fitness. Tibetan highlanders have adapted to high altitude, possibly in part via the selection of genetic variants associated with reduced polycythemic response to hypoxia. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 2, 2017 Category: Genetics & Stem Cells Authors: Jacob E. Crawford, Ricardo Amaru, Jihyun Song, Colleen G. Julian, Fernando Racimo, Jade Yu Cheng, Xiuqing Guo, Jie Yao, Bharath Ambale-Venkatesh, Jo ão A. Lima, Jerome I. Rotter, Josef Stehlik, Lorna G. Moore, Josef T. Prchal, Rasmus Nielsen Tags: Article Source Type: research

Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice
Congenital anomalies of the kidney and urinary tract (CAKUT) constitute a major cause of chronic kidney disease in children and 20% of prenatally detected anomalies. CAKUT encompass a spectrum of developmental kidney defects, including renal agenesis, hypoplasia, and cystic and non-cystic dysplasia. More than 50 genes have been reported as mutated in CAKUT-affected case subjects. However, the pathophysiological mechanisms leading to bilateral kidney agenesis (BKA) remain largely elusive. Whole-exome or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with ...
Source: The American Journal of Human Genetics - November 2, 2017 Category: Genetics & Stem Cells Authors: Lara De Tomasi, Pierre David, Camille Humbert, Flora Silbermann, Christelle Arrondel, Fr édéric Tores, Stéphane Fouquet, Audrey Desgrange, Olivier Niel, Christine Bole-Feysot, Patrick Nitschké, Joëlle Roume, Marie-Pierre Cordier, Christine Pietrement Tags: Report Source Type: research

De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability
Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 2, 2017 Category: Genetics & Stem Cells Authors: S ébastien Küry, Geeske M. van Woerden, Thomas Besnard, Martina Proietti Onori, Xénia Latypova, Meghan C. Towne, Megan T. Cho, Trine E. Prescott, Melissa A. Ploeg, Stephan Sanders, Holly A.F. Stessman, Aurora Pujol, Ben Distel, Laurie A. Robak, Jonatha Tags: Article Source Type: research

This Month in Genetics
Our doctors urge us to lower our “bad,” low-density lipoprotein (LDL) cholesterol and increase our “good,” high-density lipoprotein (HDL) cholesterol to decrease our chance of heart disease. This is the focus of many an employee wellness fair, and it’s based on extensive epidemiology. But a curious observation has made ma ny take note: one of the newer classes of cholesterol drugs, the cholesteryl ester transfer protein (CETP) inhibitors, substantially decreases LDL levels but apparently doesn’t have the expected impact on risk of heart disease. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 2, 2017 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors' Corner Source Type: research

This Month in The Journal
As the population ages, an increasing number of people  develop neurodegenerative disease. Frontotemporal lobar degeneration (FTLD) causes early-onset dementia and is fatal in all cases. Information gained from family-based and genome-wide association studies has yielded insights into genetic risk factors, but moving from a risk locus to a disease mech anism is not trivial. In this issue, Gallagher et al. take a closer look at one such FTLD-associated locus, 7p21. Previous studies have zeroed in on one gene in this region, TMEM106B; however, the mechanism by which variation in this gene alters FTLD risk has remai...
Source: The American Journal of Human Genetics - November 2, 2017 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44
(The American Journal of Human Genetics 101, 451 –458; September 7, 2017) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 2, 2017 Category: Genetics & Stem Cells Authors: Lauren M. Watson, Elizabeth Bamber, Ricardo Parolin Schnekenberg, Jonathan Williams, Concei ção Bettencourt, Jennifer Lickiss, Sandeep Jayawant, Katherine Fawcett, Samuel Clokie, Yvonne Wallis, Penny Clouston, David Sims, Henry Houlden, Esther B.E. Beck Tags: Correction Source Type: research

Inferring Relevant Cell Types for Complex Traits by Using Single-Cell Gene Expression
Previous studies have prioritized trait-relevant cell types by looking for an enrichment of genome-wide association study (GWAS) signal within functional regions. However, these studies are limited in cell resolution by the lack of functional annotations from difficult-to-characterize or rare cell populations. Measurement of single-cell gene expression has become a popular method for characterizing novel cell types, and yet limited work has linked single-cell RNA sequencing (RNA-seq) to phenotypes of interest. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 26, 2017 Category: Genetics & Stem Cells Authors: Diego Calderon, Anand Bhaskar, David A. Knowles, David Golan, Towfique Raj, Audrey Q. Fu, Jonathan K. Pritchard Tags: Article Source Type: research

Recurrent De Novo Mutations Disturbing the GTP/GDP Binding Pocket of RAB11B Cause Intellectual Disability and a Distinctive Brain Phenotype
The Rab GTPase family comprises ∼70 GTP-binding proteins, functioning in vesicle formation, transport and fusion. They are activated by a conformational change induced by GTP-binding, allowing interactions with downstream effectors. Here, we report five individuals with two recurrent de novo missense mutations in RAB11B; c.64G>A; p.Val22Met in three individuals and c.202G>A; p.Ala68Thr in two individuals. An overlapping neurodevelopmental phenotype, including severe intellectual disability with absent speech, epilepsy, and hypotonia was observed in all affected individuals. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 26, 2017 Category: Genetics & Stem Cells Authors: Ideke J.C. Lamers, Margot R.F. Reijnders, Hanka Venselaar, Alison Kraus, DDD Study, Sandra Jansen, Bert B.A. de Vries, Gunnar Houge, Gyri Aasland Gradek, Jieun Seo, Murim Choi, Jong-Hee Chae, Ineke van der Burgt, Rolph Pfundt, Stef J.F. Letteboer, Sylvia Tags: Report Source Type: research

A Dementia-Associated Risk Variant near TMEM106B Alters Chromatin Architecture and Gene Expression
Neurodegenerative diseases pose an extraordinary threat to the world ’s aging population, yet no disease-modifying therapies are available. Although genome-wide association studies (GWASs) have identified hundreds of risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Here, we investigated the association between common genetic variants at the 7p21 locus and risk of the neurodegenerative disease frontotemporal lobar degeneration. We showed that variants associated with disease risk correlate with increased expression of the 7p21 gene TMEM106B and no other ge...
Source: The American Journal of Human Genetics - October 19, 2017 Category: Genetics & Stem Cells Authors: Michael D. Gallagher, Marijan Posavi, Peng Huang, Travis L. Unger, Yosef Berlyand, Analise L. Gruenewald, Alessandra Chesi, Elisabetta Manduchi, Andrew D. Wells, Struan F.A. Grant, Gerd A. Blobel, Christopher D. Brown, Alice S. Chen-Plotkin Tags: Article Source Type: research

DOMINO: Using Machine Learning to Predict Genes Associated with Dominant Disorders
In contrast to recessive conditions with biallelic inheritance, identification of dominant (monoallelic) mutations for Mendelian disorders is more difficult, because of the abundance of benign heterozygous variants that act as massive background noise (typically, in a  400:1 excess ratio). To reduce this overflow of false positives in next-generation sequencing (NGS) screens, we developed DOMINO, a tool assessing the likelihood for a gene to harbor dominant changes. Unlike commonly-used predictors of pathogenicity, DOMINO takes into consideration features that a re the properties of genes, rather than of variants. (So...
Source: The American Journal of Human Genetics - October 5, 2017 Category: Genetics & Stem Cells Authors: Mathieu Quinodoz, Beryl Royer-Bertrand, Katarina Cisarova, Silvio Alessandro Di Gioia, Andrea Superti-Furga, Carlo Rivolta Tags: Report Source Type: research

Mendelian Randomization Analysis Identifies CpG Sites as Putative Mediators for Genetic Influences on Cardiovascular Disease Risk
The extent to which genetic influences on cardiovascular disease risk are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits. We identified ten genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits after multiple-testing correction. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 5, 2017 Category: Genetics & Stem Cells Authors: Tom G. Richardson, Jie Zheng, George Davey Smith, Nicholas J. Timpson, Tom R. Gaunt, Caroline L. Relton, Gibran Hemani Tags: Article Source Type: research

Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations
(The American Journal of Human Genetics 101, 218 –226; August 3, 2017) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 5, 2017 Category: Genetics & Stem Cells Authors: Marc A. Coram, Huaying Fang, Sophie I. Candille, Themistocles L. Assimes, Hua Tang Tags: Correction Source Type: research

Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44
(The American Journal of Human Genetics 101, 451 –458; September 7, 2017) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 5, 2017 Category: Genetics & Stem Cells Authors: Lauren M. Watson, Elizabeth Bamber, Ricardo Parolin Schnekenberg, Jonathan Williams, Concei ção Bettencourt, Sandeep Jayawant, Jennifer Lickiss, Katherine Fawcett, Samuel Clokie, Yvonne Wallis, Penny Clouston, David Sims, Henry Houlden, Esther B.E. Beck Tags: Correction Source Type: research

The Contribution of Neanderthals to Phenotypic Variation in Modern Humans
Assessing the genetic contribution of Neanderthals to non-disease phenotypes in modern humans has been difficult because of the absence of large cohorts for which common phenotype information is available. Using baseline phenotypes collected for 112,000 individuals by the UK Biobank, we can now elaborate on previous findings that identified associations between signatures of positive selection on Neanderthal DNA and various modern human traits but not any specific phenotypic consequences. Here, we show that Neanderthal DNA affects skin tone and hair color, height, sleeping patterns, mood, and smoking status in present-day ...
Source: The American Journal of Human Genetics - October 5, 2017 Category: Genetics & Stem Cells Authors: Michael Dannemann, Janet Kelso Tags: Article Source Type: research

This Month in Genetics
The classic founder populations that have partnered with researchers to map disease-related genes include the Amish communities, the Ashkenazi Jewish and Finnish populations, and French Canadians. A recent genome-wide analysis of populations from across South Asia suggests that multiple groups therein have experienced more extreme founder events than many of our previous best examples. These groups, many of which encompass one million people or more, can serve as sources of gene discovery, but —perhaps more importantly—the recognition of their population history could help to identify couples at risk of having ...
Source: The American Journal of Human Genetics - October 5, 2017 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors' Corner Source Type: research

This Month in The Journal
Although the physiological role of secreted metabolites of mitochondrial oxidation, e.g., serum acylcarnitine, is not well understood, these metabolites can serve as biomarkers for metabolic disease. Accordingly, genome-wide association studies (GWASs) have used these markers as phenotypes for analysis. For example, a GWAS demonstrated that serum acylcarnitine is associated with SNPs in SLC22A1, which encodes a cation transporter that appears to be highly expressed in the liver. In this issue, Kim et  al. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - October 5, 2017 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Female Infertility Caused by Mutations in the Oocyte-Specific Translational Repressor PATL2
We report two families affected by female-limited infertility caused by oocyte maturation failure. Positional m apping and whole-exome sequencing revealed two homozygous, likely deleterious variants in PATL2, each of which fully segregates with the phenotype within the respective family. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 28, 2017 Category: Genetics & Stem Cells Authors: Sateesh Maddirevula, Serdar Coskun, Saad Alhassan, Atif Elnour, Hessa S. Alsaif, Niema Ibrahim, Firdous Abdulwahab, Stefan T. Arold, Fowzan S. Alkuraya Tags: Report Source Type: research

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs
Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5% –1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 28, 2017 Category: Genetics & Stem Cells Authors: Maria Nicla Loviglio, Thomas Arbogast, Aia Elise J ønch, Stephan C. Collins, Konstantin Popadin, Camille S. Bonnet, Giuliana Giannuzzi, Anne M. Maillard, Sébastien Jacquemont, 16p11.2 Consortium, Binnaz Yalcin, Nicholas Katsanis, Christelle Golzio, Alex Tags: Article Source Type: research

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects
The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 28, 2017 Category: Genetics & Stem Cells Authors: Roberta De Mori, Marta Romani, Stefano D ’Arrigo, Maha S. Zaki, Elisa Lorefice, Silvia Tardivo, Tommaso Biagini, Valentina Stanley, Damir Musaev, Joel Fluss, Alessia Micalizzi, Sara Nuovo, Barbara Illi, Luisa Chiapparini, Lucia Di Marcotullio, Mahmoud Y Tags: Article Source Type: research

Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest
Oocyte maturation arrest results in female infertility, but the genetic determinants of human oocyte maturation arrest remain largely unknown. Previously, we identified TUBB8 mutations responsible for human oocyte maturation arrest, indicating the important role of genetic factors in the disorder. However, TUBB8 mutations account for only around 30% of individuals with oocyte maturation arrest; thus, the disorder is likely to involve other genetic factors that are as yet unknown. Here, we initially identified a homozygous nonsense mutation of PATL2 (c.784C>T [p.Arg262 ∗]) in a consanguineous family with a phenoty...
Source: The American Journal of Human Genetics - September 28, 2017 Category: Genetics & Stem Cells Authors: Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang, Xiaoyan Mao, Xueqian Wang, Zheng Yan, Bin Li, Yao Xu, Min Yu, Jing Fu, Jian Mu, Zhou Zhou, Qiaoli Li, Li Jin, Lin He, Qing Sang, Lei Wang Tags: Report Source Type: research

Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements
Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A –D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 28, 2017 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: Report Source Type: research

FDXR Mutations Cause Sensorial Neuropathies and Expand the Spectrum of Mitochondrial Fe-S-Synthesis Diseases
Hearing loss and visual impairment in childhood have mostly genetic origins, some of them being related to sensorial neuronal defects. Here, we report on eight subjects from four independent families affected by auditory neuropathy and optic atrophy. Whole-exome sequencing revealed biallelic mutations in FDXR in affected subjects of each family. FDXR encodes the mitochondrial ferredoxin reductase, the sole human ferredoxin reductase implicated in the biosynthesis of iron-sulfur clusters (ISCs) and in heme formation. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 28, 2017 Category: Genetics & Stem Cells Authors: Antoine Paul, Anthony Drecourt, Floriane Petit, Delphine Dupin Deguine, Christelle Vasnier, Myriam Oufadem, C écile Masson, Crystel Bonnet, Saber Masmoudi, Isabelle Mosnier, Laurence Mahieu, Didier Bouccara, Josseline Kaplan, Georges Challe, Christelle D Tags: Report Source Type: research

Fine Mapping and Functional Analysis Reveal a Role of SLC22A1 in Acylcarnitine Transport
Genome-wide association studies have identified a signal at the SLC22A1 locus for serum acylcarnitines, intermediate metabolites of mitochondrial oxidation whose plasma levels associate with metabolic diseases. Here, we refined the association signal, performed conditional analyses, and examined the linkage structure to find coding variants of SLC22A1 that mediate independent association signals at the locus. We also employed allele-specific expression analysis to find potential regulatory variants of SLC22A1 and demonstrated the effect of one variant on the splicing of SLC22A1. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 21, 2017 Category: Genetics & Stem Cells Authors: Hye In Kim, Johannes Raffler, Wenyun Lu, Jung-Jin Lee, Deepti Abbey, Danish Saleheen, Joshua D. Rabinowitz, Michael J. Bennett, Nicholas J. Hand, Christopher Brown, Daniel J. Rader Tags: Article Source Type: research

Prospects of Fine-Mapping Trait-Associated Genomic Regions by Using Summary Statistics from Genome-wide Association Studies
During the past few years, various novel statistical methods have been developed for fine-mapping with the use of summary statistics from genome-wide association studies (GWASs). Although these approaches require information about the linkage disequilibrium (LD) between variants, there has not been a comprehensive evaluation of how estimation of the LD structure from reference genotype panels performs in comparison with that from the original individual-level GWAS data. Using population genotype data from Finland and the UK Biobank, we show here that a reference panel of 1,000 individuals from the target population is adeq...
Source: The American Journal of Human Genetics - September 21, 2017 Category: Genetics & Stem Cells Authors: Christian Benner, Aki S. Havulinna, Marjo-Riitta J ärvelin, Veikko Salomaa, Samuli Ripatti, Matti Pirinen Tags: Article Source Type: research

De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures
Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 21, 2017 Category: Genetics & Stem Cells Authors: Candace T. Myers, Nicholas Stong, Emily I. Mountier, Katherine L. Helbig, Saskia Freytag, Joseph E. Sullivan, Bruria Ben Zeev, Andreea Nissenkorn, Michal Tzadok, Gali Heimer, Deepali N. Shinde, Arezoo Rezazadeh, Brigid M. Regan, Karen L. Oliver, Michelle Tags: Article Source Type: research

Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features
Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de  novo and two of unknown origin) in BPTF on 17q24.2. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 21, 2017 Category: Genetics & Stem Cells Authors: Pawe ł Stankiewicz, Tahir N. Khan, Przemyslaw Szafranski, Leah Slattery, Haley Streff, Francesco Vetrini, Jonathan A. Bernstein, Chester W. Brown, Jill A. Rosenfeld, Surya Rednam, Sarah Scollon, Katie L. Bergstrom, Donald W. Parsons, Sharon E. Plon, Mart Tags: Article Source Type: research

Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies
Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. (Source: The Ame...
Source: The American Journal of Human Genetics - September 21, 2017 Category: Genetics & Stem Cells Authors: Ren é G. Feichtinger, Monika Oláhová, Yoshihito Kishita, Caterina Garone, Laura S. Kremer, Mikako Yagi, Takeshi Uchiumi, Alexis A. Jourdain, Kyle Thompson, Aaron R. D’Souza, Robert Kopajtich, Charlotte L. Alston, Johannes Koch, Wolfgang Sperl, Elisa Tags: Article Source Type: research

Variant Interpretation: Functional Assays to the Rescue
Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Many computational approaches to predicting variant effects have been developed, but they can identify only a small fraction of pathogenic variants with the high confidence that is required in the clinic. (Source: The Am...
Source: The American Journal of Human Genetics - September 7, 2017 Category: Genetics & Stem Cells Authors: Lea M. Starita, Nadav Ahituv, Maitreya J. Dunham, Jacob O. Kitzman, Frederick P. Roth, Georg Seelig, Jay Shendure, Douglas M. Fowler Tags: Commentary Source Type: research

A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility
Empty follicle syndrome (EFS) is defined as the failure to aspirate oocytes from mature ovarian follicles during in  vitro fertilization. Except for some cases caused by pharmacological or iatrogenic problems, the etiology of EFS remains enigmatic. In the present study, we describe a large family with a dominant inheritance pattern of female infertility characterized by recurrent EFS. Genome-wide linkage analyse s and whole-exome sequencing revealed a paternally transmitted heterozygous missense mutation of c.400 G>A (p.Ala134Thr) in zona pellucida glycoprotein 3 (ZP3). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 7, 2017 Category: Genetics & Stem Cells Authors: Tailai Chen, Yuehong Bian, Xiaoman Liu, Shigang Zhao, Keliang Wu, Lei Yan, Mei Li, Zhenglin Yang, Hongbin Liu, Han Zhao, Zi-Jiang Chen Tags: Report Source Type: research

CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays
In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. (Source: The Am...
Source: The American Journal of Human Genetics - September 7, 2017 Category: Genetics & Stem Cells Authors: Christian Windpassinger, Juliette Piard, Carine Bonnard, Majid Alfadhel, Shuhui Lim, Xavier Bisteau, St éphane Blouin, Nur’Ain B. Ali, Alvin Yu Jin Ng, Hao Lu, Sumanty Tohari, S. Zakiah A. Talib, Noémi van Hul, Matias J. Caldez, Lionel Van Maldergem, Tags: Article Source Type: research

Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44
The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 7, 2017 Category: Genetics & Stem Cells Authors: Lauren M. Watson, Elizabeth Bamber, Ricardo Parolin Schnekenberg, Jonathan Williams, Concei ção Bettencourt, Jennifer Lickiss, Katherine Fawcett, Samuel Clokie, Yvonne Wallis, Penny Clouston, David Sims, Henry Houlden, Esther B.E. Becker, Andrea H. Ném Tags: Report Source Type: research

A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis
Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. (Source: The American Jo...
Source: The American Journal of Human Genetics - September 7, 2017 Category: Genetics & Stem Cells Authors: Michael Ng, Dipti Thakkar, Lorraine Southam, Paul Werker, Roel Ophoff, Kerstin Becker, Michael Nothnagel, Andre Franke, Peter N ürnberg, Ana Isabel Espirito-Santo, David Izadi, Hans Christian Hennies, Jagdeep Nanchahal, Eleftheria Zeggini, Dominic Furnis Tags: Article Source Type: research

RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes
We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between −2.5 to −5 SD. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 7, 2017 Category: Genetics & Stem Cells Authors: Margot R.F. Reijnders, Nurhuda M. Ansor, Maria Kousi, Wyatt W. Yue, Perciliz L. Tan, Katie Clarkson, Jill Clayton-Smith, Ken Corning, Julie R. Jones, Wayne W.K. Lam, Grazia M.S. Mancini, Carlo Marcelis, Shehla Mohammed, Rolph Pfundt, Maian Roifman, Ronald Tags: Report Source Type: research

This Month in The Journal
In screening pregnancies for genetic conditions, non-invasive prenatal testing is becoming an attractive option. It uses easily obtainable maternal blood, which contains small amounts of circulating cell-free fetal DNA, and it is less invasive than procedures such as amniocentesis. However, distinguishing between the fetal and maternal alleles is difficult and can be especially complicated when the mother is a carrier for the mutation of interest and when only a low fetal fraction of DNA within the total cell-free DNA is obtained. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 7, 2017 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors' Corner Source Type: research

This Month in Genetics
One possible explanation for the development of autism is an imbalance of neuronal excitation and inhibition. This hypothesis has been supported by rodent models, but typically involving wild-type animals. Selimbeyoglu et  al. decided that there might be more translational capacity for such studies if they incorporated a genetic model of autism. Starting with mice lacking CNTNAP2, which have social behavioral deficits, they used optogenetic methods to alter the excitation/inhibition balance in neurons and were able to rescue these social deficits. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - September 7, 2017 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors' Corner Source Type: research

Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder
Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. By leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection, we systematically evaluated the potential role of PMMs in autism risk. Initial re-evaluation of published single-nucleotide variant (SNV) de novo mutations showed evidence consistent with putative PMMs for 11% of mutations. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 31, 2017 Category: Genetics & Stem Cells Authors: Deidre R. Krupp, Rebecca A. Barnard, Yannis Duffourd, Sara A. Evans, Ryan M. Mulqueen, Raphael Bernier, Jean-Baptiste Rivi ère, Eric Fombonne, Brian J. O’Roak Tags: Article Source Type: research

Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes
Haploinsufficiency (HI) is the best characterized mechanism through which dominant mutations exert their effect and cause disease. Non-haploinsufficiency (NHI) mechanisms, such as gain-of-function and dominant-negative mechanisms, are often characterized by the spatial clustering of mutations, thereby affecting only particular regions or base pairs of a gene. Variants leading to haploinsufficency might occasionally cluster as well, for example in critical domains, but such clustering is on the whole less pronounced with mutations often spread throughout the gene. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 31, 2017 Category: Genetics & Stem Cells Authors: Stefan H. Lelieveld, Laurens Wiel, Hanka Venselaar, Rolph Pfundt, Gerrit Vriend, Joris A. Veltman, Han G. Brunner, Lisenka E.L.M. Vissers, Christian Gilissen Tags: Report Source Type: research

Unified Sequence-Based Association Tests Allowing for Multiple Functional Annotations and Meta-Analysis of Noncoding Variation in Metabochip Data
Substantial progress has been made in the functional annotation of genetic variation in the human genome. Integrative analysis that incorporates such functional annotations into sequencing studies can aid the discovery of disease-associated genetic variants, especially those with unknown function and located outside protein-coding regions. Direct incorporation of one functional annotation as weight in existing dispersion and burden tests can suffer substantial loss of power when the functional annotation is not predictive of the risk status of a variant. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 24, 2017 Category: Genetics & Stem Cells Authors: Zihuai He, Bin Xu, Seunggeun Lee, Iuliana Ionita-Laza Tags: Article Source Type: research

Sensitive Monogenic Noninvasive Prenatal Diagnosis by Targeted Haplotyping
During pregnancy, cell-free DNA (cfDNA) in maternal blood encompasses a small percentage of cell-free fetal DNA (cffDNA), an easily accessible source for determination of fetal disease status in risk families through non-invasive procedures. In case of monogenic heritable disease, background maternal cfDNA prohibits direct observation of the maternally inherited allele. Non-invasive prenatal diagnostics (NIPD) of monogenic diseases therefore relies on parental haplotyping and statistical assessment of inherited alleles from cffDNA, techniques currently unavailable for routine clinical practice. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 24, 2017 Category: Genetics & Stem Cells Authors: Carlo Vermeulen, Geert Geeven, Elzo de Wit, Marjon J.A.M. Verstegen, Rumo P.M. Jansen, Melissa van Kranenburg, Ewart de Bruijn, Sara L. Pulit, Evelien Kruisselbrink, Zahra Shahsavari, Davood Omrani, Fatemeh Zeinali, Hossein Najmabadi, Theodora Katsila, Ch Tags: Article Source Type: research

The Genetic Legacy of Zoroastrianism in Iran and India: Insights into Population Structure, Gene Flow, and Selection
Zoroastrianism is one of the oldest extant religions in the world, originating in Persia (present-day Iran) during the second millennium BCE. Historical records indicate that migrants from Persia brought Zoroastrianism to India, but there is debate over the timing of these  migrations. Here we present genome-wide autosomal, Y chromosome, and mitochondrial DNA data from Iranian and Indian Zoroastrians and neighboring modern-day Indian and Iranian populations and conduct a comprehensive genome-wide genetic analysis in these groups. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 24, 2017 Category: Genetics & Stem Cells Authors: Saioa L ópez, Mark G. Thomas, Lucy van Dorp, Naser Ansari-Pour, Sarah Stewart, Abigail L. Jones, Erik Jelinek, Lounès Chikhi, Tudor Parfitt, Neil Bradman, Michael E. Weale, Garrett Hellenthal Tags: Article Source Type: research

A Scalable Bayesian Method for Integrating Functional Information in Genome-wide Association Studies
Genome-wide association studies (GWASs) have identified many complex loci. However, most loci reside in noncoding regions and have unknown biological functions. Integrative analysis that incorporates known functional information into GWASs can help elucidate the underlying biological mechanisms and prioritize important functional variants. Hence, we develop a flexible Bayesian variable selection model with efficient computational techniques for such integrative analysis. Different from previous approaches, our method models the effect-size distribution and probability of causality for variants with different annotations an...
Source: The American Journal of Human Genetics - August 24, 2017 Category: Genetics & Stem Cells Authors: Jingjing Yang, Lars G. Fritsche, Xiang Zhou, Gon çalo Abecasis, International Age-Related Macular Degeneration Genomics Consortium Tags: Article Source Type: research

Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 17, 2017 Category: Genetics & Stem Cells Authors: Ekaterina L. Ivanova, Fr édéric Tran Mau-Them, Saima Riazuddin, Kimia Kahrizi, Vincent Laugel, Elise Schaefer, Anne de Saint Martin, Karen Runge, Zafar Iqbal, Marie-Aude Spitz, Mary Laura, Nathalie Drouot, Bénédicte Gérard, Jean-François Deleuze, Ar Tags: Article Source Type: research

Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia
Pontocerebellar hypoplasia (PCH) represents a group of recessive developmental disorders characterized by impaired growth of the pons and cerebellum, which frequently follows a degenerative course. Currently, there are 10 partially overlapping clinical subtypes and 13 genes known mutated in PCH. Here, we report biallelic TBC1D23 mutations in six individuals from four unrelated families manifesting a non-degenerative form of PCH. In addition to reduced volume of pons and cerebellum, affected individuals had microcephaly, psychomotor delay, and ataxia. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 17, 2017 Category: Genetics & Stem Cells Authors: Isaac Marin-Valencia, Andreas Gerondopoulos, Maha S. Zaki, Tawfeg Ben-Omran, Mariam Almureikhi, Ercan Demir, Alicia Guemez-Gamboa, Anne Gregor, Mahmoud Y. Issa, Bart Appelhof, Susanne Roosing, Damir Musaev, Basak Rosti, Sara Wirth, Valentina Stanley, Fran Tags: Report Source Type: research

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health
Phenotypes are rarely consistent across genetic backgrounds and environments, but instead vary in many ways depending on allelic variants, unlinked genes, epigenetic factors, and environmental exposures. In the extreme, individuals carrying the same causal DNA sequence variant but on different backgrounds can be classified as having distinct conditions. Similarly, some individuals that carry disease alleles are nevertheless healthy despite affected family members in the same environment. These genetic background effects often result from the action of so-called “modifier genes” that modulate the phenotypic mani...
Source: The American Journal of Human Genetics - August 3, 2017 Category: Genetics & Stem Cells Authors: Jesse D. Riordan, Joseph H. Nadeau Tags: Review Source Type: research

Human Germline Genome Editing
With CRISPR/Cas9 and other genome-editing technologies, successful somatic and germline genome editing are becoming feasible. To respond, an American Society of Human Genetics (ASHG) workgroup developed this position statement, which was approved by the ASHG Board in March 2017. The workgroup included representatives from the UK Association of Genetic Nurses and Counsellors, Canadian Association of Genetic Counsellors, International Genetic Epidemiology Society, and US National Society of Genetic Counselors. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 3, 2017 Category: Genetics & Stem Cells Authors: Kelly E. Ormond, Douglas P. Mortlock, Derek T. Scholes, Yvonne Bombard, Lawrence C. Brody, W. Andrew Faucett, Nanibaa ’ A. Garrison, Laura Hercher, Rosario Isasi, Anna Middleton, Kiran Musunuru, Daniel Shriner, Alice Virani, Caroline E. Young Tags: ASHG Position Statement Source Type: research

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood
Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5 –7 years, we identified a heterozygous variant, c.628G>A in UBTF, enc...
Source: The American Journal of Human Genetics - August 3, 2017 Category: Genetics & Stem Cells Authors: Simon Edvardson, Claudia M. Nicolae, Pankaj B. Agrawal, Cyril Mignot, Katelyn Payne, Asuri Narayan Prasad, Chitra Prasad, Laurie Sadler, Caroline Nava, Thomas E. Mullen, Amber Begtrup, Berivan Baskin, Z öe Powis, Avraham Shaag, Boris Keren, George-Lucian Tags: Report Source Type: research

William J. “Jack” Schull (1922–2017): Gentleman, Scientist
I can hardly write a disinterested memoir of Jack Schull. Like many others, I owe the nature of my career, and whatever successes I ’ve had, to him. Still, perhaps heartfelt paeans need some motivation to ring true. Yet, although I can (and will) mention a few things about him, I fear that doing so risks being like today’s citation counts, which mistake a person’s list for a person’s worth. To me, the thing for which he is most widely respected, admired, and perhaps envied is simply being Jack. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 3, 2017 Category: Genetics & Stem Cells Authors: Kenneth M. Weiss Tags: Obituary Source Type: research

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy
Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in  silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and n o previous genetic diagnosis. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 3, 2017 Category: Genetics & Stem Cells Authors: Ilaria Guella, Marna B. McKenzie, Daniel M. Evans, Sarah E. Buerki, Eric B. Toyota, Margot I. Van Allen, Epilepsy Genomics Study, Mohnish Suri, Frances Elmslie, Deciphering Developmental Disorders Study, Marleen E.H. Simon, Koen L.I. van Gassen, Delphine Tags: Report Source Type: research