The American Journal of Human Genetics This is an RSS file. You can use it to subscribe to this data in your favourite RSS reader or to display this data on your own website or blog.

Comprehensive genetic and phenotype analysis of 95 individuals with mosaic tuberous sclerosis complex
We characterize TSC1/TSC2 mosaicism, analyzing 330 samples from different tissues from 95 individuals with TSC. Mosaic variant allele frequency was significantly higher in TSC1 than in TSC2. The mosaic variant was not present in blood in 18% of individuals with TSC, highlighting the value of analyzing multiple tissue samples. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - May 3, 2023 Category: Genetics & Stem Cells Authors: Katarzyna Klonowska, Krinio Giannikou, Joannes M. Grevelink, Barbara Boeszoermenyi, Aaron R. Thorner, Zachary T. Herbert, Antara Afrin, Alison M. Treichel, Lana Hamieh, Katarzyna Kotulska, Sergiusz Jozwiak, Joel Moss, Thomas N. Darling, David J. Kwiatkows Tags: Report Source Type: research

Genetic heritage of the Baphuthi highlights an over-ethnicized notion of “Bushman” in the Maloti-Drakensberg, southern Africa
To safely gain insight into ancient communities from contemporary people, we need to acknowledge that notions of identity change. The genomes of the southern African Baphuthi show that references to KhoeSan antecedents in their history most likely reflect the subjective, inconsistent use of “KhoeSan” terminology and not genetics. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 26, 2023 Category: Genetics & Stem Cells Authors: Ryan Joseph Daniels, Maria Eugenia D'Amato, Mpasi Lesaoana, Mohaimin Kasu, Karen Ehlers, Paballo Abel Chauke, Puseletso Lecheko, Sam Challis, Kirk Rockett, Francesco Montinaro, Miguel Gonz ález-Santos, Cristian Capelli Tags: Article Source Type: research

Autism-specific PTEN p.Ile135Leu variant and an autism genetic background combine to dysregulate cortical neurogenesis
Fu et  al. performed bidirectional genome editing on iPSCs derived from individuals with autism and controls. They uncovered that the PTEN p.Ile135Leu variant, found in an ASD-affected individual with macrocephaly, dysregulated cortical neurogenesis in an ASD-genetic-background-dependent fashion by using 2D neural progenitor cells and 3D cortical organoids. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 24, 2023 Category: Genetics & Stem Cells Authors: Shuai Fu, Luke A.D. Bury, Jaejin Eum, Anthony Wynshaw-Boris Tags: Article Source Type: research

De novo variants implicate chromatin modification, transcriptional regulation, and retinoic acid signaling in syndromic craniosynostosis
Craniosynostosis is the most frequent congenital cranial deformity. Analysis of exome sequence data from 526 probands with syndromic craniosynostosis identified 13 genes surpassing thresholds for genome-wide significance, implicating regulation of chromatin modification, gene transcription, and osteoblast differentiation in disease pathogenesis. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 21, 2023 Category: Genetics & Stem Cells Authors: Andrew T. Timberlake, Stephen McGee, Garrett Allington, Emre Kiziltug, Erin M. Wolfe, Amy L. Stiegler, Titus J. Boggon, May Sanyoura, Michelle Morrow, Tara L. Wenger, Erica M. Fernandes, Oana Caluseriu, John A. Persing, Sheng Chih Jin, Richard P. Lifton, Tags: Article Source Type: research

POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies
Smallwood et  al. describe a series of individuals with heterozygous variants in POLR1A in association with variable craniofacial, heart, and brain anomalies. Adverse effects of POLR1A perturbation are demonstrated on mouse development in vivo, as well as on rRNA transcription in vitro. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 18, 2023 Category: Genetics & Stem Cells Authors: Kelly Smallwood, Kristin E.N. Watt, Satoru Ide, Kristina Baltrunaite, Chad Brunswick, Katherine Inskeep, Corrine Capannari, Margaret P. Adam, Amber Begtrup, Debora R. Bertola, Laurie Demmer, Erin Demo, Orrin Devinsky, Emily R. Gallagher, Maria J. Guillen Tags: Article Source Type: research

SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability
Thanks to a large international data-sharing effort, in silico structural protein modeling, DNA methylation episignature analyses, and in  vivo splicing assays in Drosophila, Bogaert et al. demonstrate that haploinsufficiency of SRSF1, which encodes a pre-mRNA splicing factor, causes a syndromic neurodevelopmental disorder with mild to moderate intellectual disability. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 17, 2023 Category: Genetics & Stem Cells Authors: Elke Bogaert, Aurore Garde, Thierry Gautier, Kathleen Rooney, Yannis Duffourd, Pontus LeBlanc, Emma van Reempts, Frederic Tran Mau-Them, Ingrid M. Wentzensen, Kit Sing Au, Kate Richardson, Hope Northrup, Vincent Gatinois, David Genevi ève, Raymond J. Lou Tags: Article Source Type: research

Dissecting the polygenic basis of atherosclerosis via disease-associated cell state signatures
Using single-cell RNA sequencing, researchers identified 12 atherosclerosis-associated cell states and found that Vcam1+ smooth muscle cell state contributed the most to the genetic heritability of coronary artery disease. A hybrid polygenic risk score (PRS) that considers cell-type-specific regulatory elements demonstrated improved performance over a classical PRS. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 14, 2023 Category: Genetics & Stem Cells Authors: Tiit Örd, Tapio Lönnberg, Valtteri Nurminen, Aarthi Ravindran, Henri Niskanen, Miika Kiema, Kadri Õunap, Maleeha Maria, Pierre R. Moreau, Pashupati P. Mishra, Senthil Palani, Jenni Virta, Heidi Liljenbäck, Einari Aavik, Anne Roivainen, Seppo Ylä-Hert Tags: Article Source Type: research

Bi-allelic variants in INTS11 are associated with a complex neurological disorder
Here we describe fifteen individuals who carry damaging bi-allelic variants in INTS11 and who present with neurological symptoms. Modeling experiments in Drosophila identified two strong and five mild LoF alleles of INTS11. Our results provide compelling evidence that the integrity of the Integrator RNA endonuclease is critical for brain development. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 12, 2023 Category: Genetics & Stem Cells Authors: Burak Tepe, Erica L. Macke, Marcello Niceta, Monika Weisz Hubshman, Oguz Kanca, Laura Schultz-Rogers, Yuri A. Zarate, G. Bradley Schaefer, Jorge Luis Granadillo De Luque, Daniel J. Wegner, Benjamin Cogne, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Er Tags: Article Source Type: research

Fast and accurate Bayesian polygenic risk modeling with variational inference
We present VIPRS, a fast and accurate variational Bayesian method for estimating polygenic risk scores from genome-wide association study (GWAS) data. The method is shown to be robust and competitively accurate against popular baselines and scales well to dense genotype array data. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 7, 2023 Category: Genetics & Stem Cells Authors: Shadi Zabad, Simon Gravel, Yue Li Tags: Article Source Type: research

Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets
This study investigates epistasis in the genetic architecture of common diseases by using long-range linkage disequilibrium patterns. One significant and four near-significant associations across five disease phenotypes were identified, highlighting the pleiotropic and conserved nature of variants under epistatic selection. These findings provide insights into the genetic mechanisms underlying complex diseases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 6, 2023 Category: Genetics & Stem Cells Authors: Pankhuri Singhal, Yogasudha Veturi, Scott M. Dudek, Anastasia Lucas, Alex Frase, Kristel van Steen, Steven J. Schrodi, David Fasel, Chunhua Weng, Rion Pendergrass, Daniel J. Schaid, Iftikhar J. Kullo, Ozan Dikilitas, Patrick M.A. Sleiman, Hakon Hakonarson Tags: Article Source Type: research

This month in The Journal
There are numerous examples of mosaic genetic variants contributing to Mendelian diseases, but the technical difficulties in detecting mosaicism have limited our understanding of just how widespread the phenomenon is. To gain a more comprehensive view of the frequency of mosaicism and its clinical impacts, Truty et  al. identified mosaic single-nucleotide variants and copy-number variants in a cohort of more than one million individuals referred for genetic testing. They found 5,939 mosaic variants, most unique to a single individual, of which 39% were predicted to be pathogenic or likely pathogenic (P/LP). (Source: The A...
Source: The American Journal of Human Genetics - April 6, 2023 Category: Genetics & Stem Cells Authors: Kylee L. Spencer, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Scalable mixed model methods for set-based association studies on large-scale categorical data analysis and its application to exome-sequencing data in UK Biobank
To analyze rare variants, Bi et  al. proposed POLMM-GENE, an approach that is scalable for large-scale sequencing datasets. POLMM-GENE fully utilizes the categorical nature of phenotypes, which avoids inflated type I error rates or power loss. It can identify gene-phenotype associations, providing valuable insights into missing t rait heritability. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - April 4, 2023 Category: Genetics & Stem Cells Authors: Wenjian Bi, Wei Zhou, Peipei Zhang, Yaoyao Sun, Weihua Yue, Seunggeun Lee Tags: Article Source Type: research

Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage
We identified homozygous loss-of-function variants in ESAM, encoding an endothelial cell adhesion molecule, in thirteen individuals (including four fetuses) showing intracerebral hemorrhage in prenatal age and neurodevelopmental disorders. Our findings contribute to expand an emerging group of diseases caused by alterations of tight-junction genes (e.g., JAM2, JAM3, OCLN). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 29, 2023 Category: Genetics & Stem Cells Authors: Mauro Lecca, Davut Pehlivan, Dami à Heine Suñer, Karin Weiss, Thibault Coste, Markus Zweier, Yavuz Oktay, Nada Danial-Farran, Vittorio Rosti, Maria Paola Bonasoni, Alessandro Malara, Gianluca Contrò, Roberta Zuntini, Marzia Pollazzon, Rosario Pascarell Tags: Report Source Type: research

Trio RNA sequencing in a cohort of medically complex children
In this study we applied a trio RNA sequencing approach in a cohort of children with medical complexity who previously underwent genome sequencing. We find that trio analysis, while sometimes helpful in ruling out false-positive RNA-level aberrations, did not increase the diagnostic yield beyond singleton analysis. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 28, 2023 Category: Genetics & Stem Cells Authors: Ashish R. Deshwar, Kyoko E. Yuki, Huayun Hou, Yijing Liang, Tayyaba Khan, Alper Celik, Arun Ramani, Roberto Mendoza-Londono, Christian R. Marshall, Michael Brudno, Adam Shlien, M. Stephen Meyn, Robin Z. Hayeems, Brandon J. McKinlay, Panagiota Klentrou, Mi Tags: Report Source Type: research

Deletion mapping of regulatory elements for GATA3 in T  cells reveals a distal enhancer involved in allergic diseases
To map regulatory elements for GATA3, we deleted genome sequences in human T  cells. We discovered a regulatory sequence 1 Mb downstream of GATA3 that contains variants associated with allergic disease, demonstrating how deletions can identify regulatory sequences and help interpret hits from genome-wide association studies. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - March 28, 2023 Category: Genetics & Stem Cells Authors: Hsiuyi V. Chen, Michael H. Lorenzini, Shanna N. Lavalle, Karthyayani Sajeev, Ariana Fonseca, Patrick C. Fiaux, Arko Sen, Ishika Luthra, Aaron J. Ho, Aaron R. Chen, Karthik Guruvayurappan, Carolyn O ’Connor, Graham McVicker Tags: Report Source Type: research