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Characterizing trends in clinical genetic testing: A single-center analysis of EHR data from 1.8 million patients over two decades. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-04-16 Lisa Bastarache,Rory J Tinker,Bryce A Schuler,Lucas Richter,John A Phillips,William W Stead,Gillian W Hooker,Josh F Peterson,Douglas M Ruderfer
A lack of structural data in electronic health records (EHRs) makes assessing the impact of genetic testing on clinical practice challenging. We extracted clinical genetic tests from the EHRs of more than 1.8 million patients seen at Vanderbilt University Medical Center from 2002 to 2022. With these data, we quantified the use of clinical genetic testing in healthcare and described how testing patterns
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A non-syndromic orofacial cleft risk locus links tRNA splicing defects to neural crest cell pathologies. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-04-15 Michaela Bartusel,Skylar X Kim,Rizwan Rehimi,Alicia M Darnell,Miloš Nikolić,Julia Heggemann,Petros Kolovos,Wilfred F J van Ijcken,Jade Varineau,Giuliano Crispatzu,Elisabeth Mangold,Samantha A Brugmann,Matthew G Vander Heiden,Magdalena Laugsch,Kerstin U Ludwig,Alvaro Rada-Iglesias,Eliezer Calo
Orofacial clefts are the most common form of congenital craniofacial malformation worldwide. The etiology of these birth defects is multifactorial, involving genetic and environmental factors. However, in most cases, the underlying causes remain unexplained, precluding a molecular understanding of disease mechanisms. Here, we integrated genome-wide association data, targeted resequencing of case and
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First steps toward building natural history of diseases computationally: Lessons learned from the Noonan syndrome use case. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-04-10 Tudor Groza,Warittha Rayabsri,Dylan Gration,Harshini Hariram,Saumya Shekhar Jamuar,Gareth Baynam
Rare diseases (RDs) are conditions affecting fewer than 1 in 2,000 people, with over 7,000 identified, primarily genetic in nature, and more than half impacting children. Although each RD affects a small population, collectively, between 3.5% and 5.9% of the global population, or 262.9-446.2 million people, live with an RD. Most RDs lack established treatment protocols, highlighting the need for proper
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Integration of protein stability and AlphaMissense scores improves bioinformatic impact prediction for p53 missense and in-frame amino acid deletion variants. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-04-08 Nitsan Rotenberg,Cristina Fortuno,Matthew J Varga,Adam C Chamberlin,Lobna Ramadane-Morchadi,Bing-Jian Feng,Miguel de la Hoya,Marcy E Richardson,Amanda B Spurdle
The clinical classification of germline missense variants and single-amino-acid deletions is challenging. The BayesDel and Align-GVGD bioinformatic prediction tools currently used for ClinGen TP53 variant curation expert panel (VCEP) classification do not directly capture changes in protein folding stability, measured using computed destabilization energies (ΔΔG scores). The AlphaMissense tool recently
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ACMG/AMP interpretation of BRCA1 missense variants: Structure-informed scores add evidence strength granularity to the PP3/BP4 computational evidence. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-04-08 Lobna Ramadane-Morchadi,Nitsan Rotenberg,Ada Esteban-Sánchez,Cristina Fortuno,Alicia Gómez-Sanz,Matthew J Varga,Adam Chamberlin,Marcy E Richardson,Kyriaki Michailidou,Pedro Pérez-Segura,Amanda B Spurdle,Miguel de la Hoya
Classification of missense variants is challenging. Lacking compelling clinical and/or functional data, ACMG/AMP lines of evidence are restricted to PM2 (rarity code applied at supporting level) and PP3/BP4 (computational evidence based mostly on multiple-sequence-alignment conservation tools). Currently, the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel uses BayesDel to apply PP3/BP4 to missense
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Computational and functional prioritization identifies genes that rescue behavior and reduce tau protein in fly and human cell models of Alzheimer disease. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-04-07 Morgan C Stephens,Jiayang Li,Megan Mair,Justin Moore,Katy Zhu,Akash Tarkunde,Bismark Amoh,Alma M Perez,Arya Bhakare,Fangfei Guo,Joshua M Shulman,Ismael Al-Ramahi,Juan Botas
Genome-wide association studies (GWASs) in Alzheimer disease (AD) have uncovered over 70 loci significantly associated with AD risk, but identifying the true causal gene(s) at these loci requires systematic functional validation that is rarely performed due to limitations of time and cost. Here, we integrate transcriptome-wide association study (TWAS) with colocalization analysis, fine-mapping, and
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Structural biology in variant interpretation: Perspectives and practices from two studies. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-04-03 Matthew J Varga,Marcy E Richardson,Adam Chamberlin
Structural biology offers a powerful lens through which to assess genetic variants by providing insights into their impact on clinically relevant protein structure and function. Due to the availability of new, user-friendly, web-based tools, structural analyses by wider audiences have become more mainstream. These new tools, including AlphaMissense and AlphaFold, have recently been in the limelight
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EndoPRS: Incorporating endophenotype information to improve polygenic risk scores for clinical endpoints-A study in asthma. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-04-03 Elena V Kharitonova,Quan Sun,Franklin Ockerman,Brian Chen,Laura Y Zhou,Micah R Hysong,Bjoernar Tuftin,Hongyuan Cao,Rasika A Mathias,Paul L Auer,Carole Ober,Laura M Raffield,Alexander P Reiner,Nancy J Cox,Samir N P Kelada,Ran Tao,Yun Li
Polygenic risk score (PRS) prediction of complex diseases can be improved by leveraging related phenotypes. This has motivated the development of several multi-trait PRS methods that jointly model genetically correlated traits. However, these methods do not account for vertical pleiotropy, where one trait acts as a mediator for another. Here, we introduce endoPRS, a weighted lasso model that incorporates
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Opportunities and challenges of local ancestry in genetic association analyses. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-04-03 Quan Sun,Andrea R V R Horimoto,Brian Chen,Frank Ockerman,Karen L Mohlke,Elizabeth Blue,Laura M Raffield,Yun Li
Recently, admixed populations make up an increasing percentage of the US and global populations, and the admixture is not uniform over space or time or across genomes. Therefore, it becomes indispensable to evaluate local ancestry in addition to global ancestry to improve genetic epidemiological studies. Recent advances in representing human genome diversity, coupled with large-scale whole-genome sequencing
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Bayesian causal graphical model for joint Mendelian randomization analysis of multiple exposures and outcomes. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-28 Verena Zuber,Toinét Cronjé,Na Cai,Dipender Gill,Leonardo Bottolo
Current Mendelian randomization (MR) methods do not reflect complex relationships among multiple exposures and outcomes as is typical for real-life applications. We introduce MrDAG, a Bayesian causal graphical model for summary-level MR analysis to detect dependency relations within the exposures, the outcomes, and between them to improve causal effects estimation. MrDAG combines three causal inference
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Increasing the genomic workforce through research capacity building: Designing evaluation plans for maximum impact. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-27 Karyn J Roberts,Weini Ogbagiorgis,Angela Sy,Sarah Williams-Blangero,LaMonica V Stewart,Eron Manusov,Sofia B Fernandez,Rachel D Clarke,Ebony B Madden
More interventions are needed to address the need for workforce diversity and research capacity building (RCB) in genomics. In 2023, the National Human Genome Research Institute and the National Institute on Minority Health and Health Disparities of the National Institutes of Health funded the Diversity Centers for Genome Research Consortium to address this critical gap. The NIH program staff designed
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Interplay and cooperation between GLI2 and master transcription factors promote progression of esophageal squamous cell carcinoma. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-21 Yin-Qiao Liu,Ze-Jun Zheng,Wang-Kai Fang,Yan-Shang Li,Chun Li,Min Yang,Dong-Chen Han,Jun-Hua Zhou,Ying-Hua Xie,Yu-Ying Zhang,Zhuo-Ying Kang,Yi-Wei Xu,Jian-Jun Xie
The establishment of gene expression programs that drive cell identity is governed by tightly regulated transcription factors (TFs) that engage in auto- and cross-regulation in a feedforward manner, forming core regulatory circuitries (CRCs). Here, we identify and validate an important interconnected CRC formed by three master TFs-GLI2, TP63, and RUNX1-in esophageal squamous cell carcinoma (ESCC).
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Fine-mapping in admixed populations using CARMA-X, with applications to Latin American studies. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-21 Zikun Yang,Chen Wang,Yuridia Selene Posadas-Garcia,Valeria Añorve-Garibay,Badri Vardarajan,Andrés Moreno Estrada,Mashaal Sohail,Richard Mayeux,Iuliana Ionita-Laza
Genome-wide association studies (GWASs) in ancestrally diverse populations are rapidly expanding, opening up unique opportunities for novel gene discoveries and increased utility of genetic findings in non-European individuals. A popular technique to identify putative causal variants at GWAS loci is via statistical fine-mapping. Despite tremendous efforts, fine-mapping remains a very challenging task
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Consensus guidelines for assessing eligibility of pathogenic DNA variants for antisense oligonucleotide treatments. Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-21 David Cheerie,Margaret M Meserve,Danique Beijer,Charu Kaiwar,Logan Newton,Ana Lisa Taylor Tavares,Aubrie Soucy Verran,Emma Sherrill,Stefanie Leonard,Stephan J Sanders,Emily Blake,Nour Elkhateeb,Aastha Gandhi,Nicole S Y Liang,Jack T Morgan,Anna Verwillow,Jan Verheijen,Andrew Giles,Sean Williams,Maya Chopra,Laura Croft,Hormos Salimi Dafsari,Alice E Davidson,Jennifer Friedman,Anne Gregor,Bushra Haque
Of the around 7,000 known rare diseases worldwide, disease-modifying treatments are available for fewer than 5%, leaving millions of individuals without specialized therapeutic strategies. In recent years, antisense oligonucleotides (ASOs) have shown promise as individualized genetic interventions for rare genetic diseases. However, there is currently no consensus on which disease-causing DNA variants
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Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-15 Evon DeBose-Scarlett, Andrew K. Ressler, Carol J. Gallione, Gonzalo Sapisochin Cantis, Cassi Friday, Shantel Weinsheimer, Katharina Schimmel, Edda Spiekerkoetter, Helen Kim, James R. Gossage, Marie E. Faughnan, Douglas A. Marchuk
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De novo variants in CDKL1 and CDKL2 are associated with neurodevelopmental symptoms Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-14 Ali H. Bereshneh, Jonathan C. Andrews, Daniel F. Eberl, Guney Bademci, Nicholas A. Borja, Stephanie Bivona, Undiagnosed Diseases Network, Baylor College of Medicine Center for Precision Medicine Models, Wendy K. Chung, Shinya Yamamoto, Michael F. Wangler, Shane McKee, Mustafa Tekin, Hugo J. Bellen, Oguz Kanca
The CDKL (cyclin-dependent kinase-like) family consists of five members in humans, CDKL1–5, that encode serine-threonine kinases. The only member that has been associated with a Mendelian disorder is CDKL5, and variants in CDKL5 cause developmental and epileptic encephalopathy type 2 (DEE2). Here, we study four de novo variants in CDKL2 identified in five individuals, including three unrelated probands
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Actionable genetic variants in 4,198 Scottish participants from the Orkney and Shetland founder populations and implementation of return of results Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-14 Shona M. Kerr, Lucija Klaric, Marisa D. Muckian, Kiera Johnston, Camilla Drake, Mihail Halachev, Emma Cowan, Lesley Snadden, John Dean, Sean L. Zheng, Prisca K. Thami, James S. Ware, Gannie Tzoneva, Alan R. Shuldiner, Zosia Miedzybrodzka, James F. Wilson
The benefits of returning clinically actionable genetic results to participants in research cohorts are accruing, yet such a genome-first approach is challenging. Here, we describe the implementation of return of such results in two founder populations from Scotland. Between 2005 and 2015, we recruited >4,000 adults with grandparents from Orkney and Shetland into the Viking Genes research cohort. The
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Bi-allelic variants in three genes encoding distinct subunits of the vesicular AP-5 complex cause hereditary macular dystrophy Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-12 Karolina Kaminska, Francesca Cancellieri, Mathieu Quinodoz, Abigail R. Moye, Miriam Bauwens, Siying Lin, Lucas Janeschitz-Kriegl, Tamar Hayman, Pilar Barberán-Martínez, Regina Schlaeger, Filip Van den Broeck, Almudena Ávila Fernández, Lidia Fernández-Caballero, Irene Perea-Romero, Gema García-García, David Salom, Pascale Mazzola, Theresia Zuleger, Karin Poths, Tobias B. Haack, Julie Jacob, Sascha Vermeer
Inherited retinal diseases (IRDs) are a genetically heterogeneous group of Mendelian disorders that often lead to progressive vision loss and involve approximately 300 distinct genes. Although variants in these loci account for the majority of molecular diagnoses, other genes associated with IRD await molecular identification. In this study, we uncover bi-allelic assortments of 23 different (22 loss-of-function)
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Artificial variables help to avoid over-clustering in single-cell RNA sequencing Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-12 Alan DenAdel, Michelle L. Ramseier, Andrew W. Navia, Alex K. Shalek, Srivatsan Raghavan, Peter S. Winter, Ava P. Amini, Lorin Crawford
Standard single-cell RNA sequencing (scRNA-seq) pipelines nearly always include unsupervised clustering as a key step in identifying biologically distinct cell types. A follow-up step in these pipelines is to test for differential expression between the identified clusters. When algorithms over-cluster, downstream analyses can produce misleading results. In this work, we present “recall” (calibrated
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Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-12 Charlotte Guillouet, Valeria Agostini, Geneviève Baujat, Dario Cocciadiferro, Tommaso Pippucci, Marion Lesieur-Sebellin, Mathieu Georget, Ulrich Schatz, Christine Fauth, Raymond J. Louie, Curtis Rogers, Jessica M. Davis, Vassiliki Konstantopoulou, Johannes A. Mayr, Arjan Bouman, Martina Wilke, Grace E. VanNoy, Eleina M. England, Kristen L. Park, Kathleen Brown, Margarita Saenz, Antonio Novelli, Maria
The Mediator complex regulates protein-coding gene transcription by coordinating the interaction of upstream enhancers with the basal transcription machinery at the promoter. Pathogenic variants in Mediator subunits typically lead to neurodevelopmental or neurodegenerative disorders with variable clinical presentations, designated as MEDopathies. Here, we report the identification of 25 individuals
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The contribution of coding variants to the heritability of multiple cancer types using UK Biobank whole-exome sequencing data Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-11 Naomi Wilcox, Jonathan P. Tyrer, Joe Dennis, Xin Yang, John R.B. Perry, Eugene J. Gardner, Douglas F. Easton
Genome-wide association studies have been highly successful at identifying common variants associated with cancer; however, they do not explain all the inherited risks of cancer. Family-based studies, targeted sequencing, and, more recently, exome-wide association studies have identified rare coding variants in some genes associated with cancer risk, but the overall contribution of these variants to
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The expanding global genomics landscape: Converging priorities from national genomics programs Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-10 Caitlin Howley, Matilda A. Haas, Wadha A. Al Muftah, Robert B. Annan, Eric D. Green, Bettina Lundgren, Richard H. Scott, Zornitza Stark, Patrick Tan, Kathryn N. North, Tiffany Boughtwood
The global landscape of health genomics is expanding rapidly, with an increasing number of national and international initiatives, many of which are targeted toward accelerating the clinical implementation of genomic technologies and services in the context of local health systems. This includes a range of entities with different levels of maturity, funding sources, and strategies that focus on research
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Single-cell analyses reveal increased gene expression variability in human neurodevelopmental conditions Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-07 Suraj Upadhya, Jenny A. Klein, Anna Nathanson, Kristina M. Holton, Lindy E. Barrett
Interindividual variation in phenotypic penetrance and severity is found in many neurodevelopmental conditions, although the underlying mechanisms remain largely unresolved. Within individuals, homogeneous cell types (i.e., genetically identical and in similar environments) can differ in molecule abundance. Here, we investigate the hypothesis that neurodevelopmental conditions can drive increased variability
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Data-driven insights to inform splice-altering variant assessment Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-07 Patricia J. Sullivan, Julian M.W. Quinn, Pamela Ajuyah, Mark Pinese, Ryan L. Davis, Mark J. Cowley
Disease-causing genetic variants often disrupt mRNA splicing, an intricate process that is incompletely understood. Thus, accurate inference of which genetic variants will affect splicing and what their functional consequences will be is challenging, particularly for variants outside of the essential splice sites. Here, we describe a set of data-driven heuristics that inform the interpretation of human
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This month in The Journal Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-06 Alyson B. Barnes, Sara B. Cullinan
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2024 ASHG Lifetime Achievement Award Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-06 Margaret A. Pericak-Vance
This article is based on the address given by the author at the 2024 meeting of The American Society of Human Genetics (ASHG) in Denver, CO. A video of the original address can be found at the ASHG website.
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2024 ASHG awards and addresses Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-06
Each year at the annual meeting of The American Society of Human Genetics (ASHG), addresses are given in honor of the Society and several award winners. A summary of each of these is provided below. On the following pages, we have printed the Presidential Address as well as the addresses for the Lifetime Achievement, Scientific Achievement, and Leadership awards. Recordings of these addresses, as well
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2024 ASHG Leadership Award Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-06 Cynthia C. Morton
This article is based on the address given by the author at the 2024 meeting of The American Society of Human Genetics (ASHG) in Denver, CO. A video of the original address can be found at the ASHG website.
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2024 ASHG Scientific Achievement Award Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-06 Nadav Ahituv
This article is based on the address given by the author at the 2024 meeting of The American Society of Human Genetics (ASHG) in Denver, CO. The video of the original address can be found at the ASHG website.
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2024 ASHG presidential address: Incomplete penetrance and variable expressivity: Old concepts, new urgency Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-06 Bruce D. Gelb
This article is based on the address given by the author at the 2024 meeting of The American Society of Human Genetics (ASHG) in Denver, CO. A video of the original address can be found at the ASHG website.
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2024 Lifetime Achievement Award: Biology unbalanced: Genes, gene dosage, and disease susceptibility Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-06 James R. Lupski
This article is based on the address given by the author at the 2024 meeting of The American Society of Human Genetics (ASHG) in Denver, CO. A video of the original address can be found at the ASHG website.
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Identifying deleterious noncoding variation through gain and loss of CTCF binding activity Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-05 Colby Tubbs, Mary Lauren Benton, Evonne McArthur, John A. Capra, Douglas M. Ruderfer
CCCTC binding factor (CTCF) regulates gene expression through DNA binding at thousands of genomic loci. Genetic variation in these CTCF binding sites (CBSs) is an important driver of phenotypic variation, yet extracting those that are likely to have functional consequences in whole-genome sequencing remains challenging. To address this, we develop a hypothesis-driven framework to identify and prioritize
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Human leukocyte antigen variation is associated with cytomegalovirus serostatus in healthy individuals Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-05 Juliano A. Boquett, Jürgen Sauter, Alexander H. Schmidt, Martin Maiers, Jill A. Hollenbach
Cytomegalovirus (CMV) is a common β-herpes virus worldwide with an estimated seroprevalence among the general population of 83%. Primary infection is usually benign; however, CMV can cause severe morbidity in newborns in whom it is acquired congenitally, as well as immunocompromised individuals. Understanding the role of immunogenetic variation in risk for CMV infection can provide insight into the
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Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-04 Huw B. Thomas, Leigh A.M. Demain, Alfredo Cabrera-Orefice, Isabelle Schrauwen, Hanan E. Shamseldin, Alessandro Rea, Thashi Bharadwaj, Thomas B. Smith, Monika Oláhová, Kyle Thompson, Langping He, Namanpreet Kaur, Anju Shukla, Musaad Abukhalid, Muhammad Ansar, Sakina Rehman, Saima Riazuddin, Firdous Abdulwahab, Janine M. Smith, Zornitza Stark, Hanifenur Mancilar, Sait Tumer, Fatma N. Esen, Eyyup Uctepe
Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning
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Clinical validation of RNA sequencing for Mendelian disorder diagnostics Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-03-04 Sen Zhao, Kristina Macakova, Jefferson C. Sinson, Hongzheng Dai, Jill Rosenfeld, Gladys E. Zapata, Shenglan Li, Patricia A. Ward, Christiana Wang, Chunjing Qu, Becky Maywald, Undiagnosed Diseases Network, Brendan Lee, Christine Eng, Pengfei Liu
Despite rapid advancements in clinical sequencing, over half of diagnostic evaluations still lack definitive results. RNA sequencing (RNA-seq) has shown promise in research settings for bridging this gap by providing essential functional data for accurate interpretation of diagnostic sequencing results. However, despite advanced research pipelines, clinical translation of diagnostic RNA-seq has not
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Genome-wide prediction of dominant and recessive neurodevelopmental disorder-associated genes Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-26 Ryan S. Dhindsa, Blake A. Weido, Justin S. Dhindsa, Arya J. Shetty, Chloe F. Sands, Slavé Petrovski, Dimitrios Vitsios, Anthony W. Zoghbi
Despite great progress, thousands of neurodevelopmental disorder (NDD) risk genes remain to be discovered. We present a computational approach that accelerates NDD risk gene identification using machine learning. First, we demonstrate that models trained solely on single-cell RNA sequencing data can robustly predict genes implicated in autism spectrum disorder (ASD), developmental and epileptic encephalopathy
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Variability in proliferative and migratory defects in Hirschsprung disease-associated RET pathogenic variants Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-25 Lauren E. Fries, Sree Dharma, Aravinda Chakravarti, Sumantra Chatterjee
Hirschsprung disease (HSCR) exhibits extensive genetic heterogeneity, with 72% of cases involving pathogenic variants in 10 genes forming a gene regulatory network (GRN) essential for enteric nervous system (ENS) development. The receptor tyrosine kinase gene RET is the most significant contributor, implicated in 12%–50% of individuals depending on the phenotype. RET plays a critical role in ENS precursor
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SeqFirst: Building equity access to a precise genetic diagnosis in critically ill newborns Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-24 Tara L. Wenger, Abbey Scott, Lukas Kruidenier, Megan Sikes, Alexandra Keefe, Kati J. Buckingham, Colby T. Marvin, Kathryn M. Shively, Tamara Bacus, Olivia M. Sommerland, Kailyn Anderson, Heidi Gildersleeve, Chayna J. Davis, Jamie Love-Nichols, Katherine E. MacDuffie, Danny E. Miller, Joon-Ho Yu, Amy Snook, Britt Johnson, David L. Veenstra, Julia Parish-Morris, Kirsty McWalter, Kyle Retterer, Deborah
Access to a precise genetic diagnosis (PrGD) in critically ill newborns is limited and inequitable because the complex inclusion criteria used to prioritize testing eligibility omit many patients at high risk for a genetic condition. SeqFirst-neo is a program to test whether a genotype-driven workflow using simple, broad exclusion criteria to assess eligibility for rapid genome sequencing (rGS) increases
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Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-24 Emilio Ugalde-Morales, Rona Wilf, John Pluta, Alexander Ploner, Mengyao Fan, Mohammad Damra, Katja K. Aben, Lynn Anson-Cartwright, Chu Chen, Victoria K. Cortessis, Siamak Daneshmand, Alberto Ferlin, Marija Gamulin, Jourik A. Gietema, Anna Gonzalez-Niera, Tom Grotmol, Robert J. Hamilton, Mark Harland, Trine B. Haugen, Russ Hauser, Michelle A.T. Hildebrandt, Robert Karlsson, Lambertus A. Kiemeney, Jung
Transcriptome-wide association studies (TWASs) have the potential to identify susceptibility genes associated with testicular germ cell tumors (TGCTs). We conducted a comprehensive TGCT TWAS by integrating genome-wide association study (GWAS) summary data with predicted expression models from normal testis, TGCT tissues, and a cross-tissue panel that encompasses shared regulatory features across 22
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Genetic association studies using disease liabilities from deep neural networks Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-21 Lu Yang, Marie C. Sadler, Russ B. Altman
The case-control study is a widely used method for investigating the genetic underpinnings of binary traits. However, long-term, prospective cohort studies often grapple with absent or evolving health-related outcomes. Here, we propose two methods, liability and meta, for conducting genome-wide association studies (GWASs) that leverage disease liabilities calculated from deep patient phenotyping. Analyzing
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Multiple origins and phenotypic implications of an extended human pseudoautosomal region shown by analysis of the UK Biobank Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-20 Nitikorn Poriswanish, James Eales, Xiaoguang Xu, David Scannali, Rita Neumann, Jon H. Wetton, Maciej Tomaszewski, Mark A. Jobling, Celia A. May
The 2.7-Mb major pseudoautosomal region (PAR1) on the short arms of the human X and Y chromosomes plays a critical role in meiotic sex chromosome segregation and male fertility and has been regarded as evolutionarily stable. However, some European Y chromosomes belonging to Y haplogroups (Y-Hgs) R1b and I2a carry an ∼115-kb extension (ePAR [extended PAR]) arising from X-Y non-allelic homologous recombination
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Deciphering the digenic architecture of congenital heart disease using trio exome sequencing data Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-20 Meltem Ece Kars, David Stein, Peter D. Stenson, David N. Cooper, Wendy K. Chung, Peter J. Gruber, Christine E. Seidman, Yufeng Shen, Martin Tristani-Firouzi, Bruce D. Gelb, Yuval Itan
Congenital heart disease (CHD) is the most common congenital anomaly and a leading cause of infant morbidity and mortality. Despite extensive exploration of the monogenic causes of CHD over the last decades, ∼55% of cases still lack a molecular diagnosis. Investigating digenic interactions, the simplest form of oligogenic interactions, using high-throughput sequencing data can elucidate additional
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Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-19 Iris Verbinnen, Sofia Douzgou Houge, Tzung-Chien Hsieh, Hellen Lesmann, Aron Kirchhoff, David Geneviève, Elise Brimble, Lisa Lenaerts, Dorien Haesen, Rebecca J. Levy, Julien Thevenon, Laurence Faivre, Elysa Marco, Jessica X. Chong, Mike Bamshad, Karynne Patterson, Ghayda M. Mirzaa, Kimberly Foss, William Dobyns, Susan M. White, Lynn Pais, Emily O’Heir, Raphaela Itzikowitz, Kirsten A. Donald, Celia
Pathogenic variants resulting in protein phosphatase 2A (PP2A) dysfunction result in mild to severe neurodevelopmental delay. PP2A is a trimer of a catalytic (C) subunit, scaffolding (A) subunit, and substrate binding/regulatory (B) subunit, encoded by 19 different genes. De novo missense variants in PPP2R5D (B56δ) or PPP2R1A (Aα) and de novo missense and loss-of-function variants in PPP2CA (Cα) lead
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Single-cell transcriptomics reveals inter-ethnic variation in immune response to Falciparum malaria Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-18 Tala Shahin, Jakub Jurkovic, Mame Massar Dieng, Vinu Manikandan, Wael Abdrabou, Bana Alamad, Odmaa Bayaraa, Aïssatou Diawara, Samuel Sindié Sermé, Noëlie Béré Henry, Salif Sombie, Dareen Almojil, Marc Arnoux, Nizar Drou, Issiaka Soulama, Youssef Idaghdour
Africa’s environmental, cultural, and genetic diversity can profoundly shape population responses to infectious diseases, including malaria caused by Plasmodium falciparum. Differences in malaria susceptibility among populations are documented, but the underlying mechanisms remain poorly understood. Notably, the Fulani ethnic group in Africa is less susceptible to malaria compared to other sympatric
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Distinct explanations underlie gene-environment interactions in the UK Biobank Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-17 Arun Durvasula, Alkes L. Price
The role of gene-environment (GxE) interaction in disease and complex trait architectures is widely hypothesized but currently unknown. Here, we apply three statistical approaches to quantify and distinguish three different types of GxE interaction for a given trait and environmental (E) variable. First, we detect locus-specific GxE interaction by testing for genetic correlation (rg) < 1 across E bins
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An evolving understanding of multiple causal variants underlying genetic association signals Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-17 Erping Long, Jacob Williams, Haoyu Zhang, Jiyeon Choi
Understanding how genetic variation contributes to phenotypic variation is a fundamental question in genetics. Genome-wide association studies (GWASs) have discovered numerous genetic associations with various human phenotypes, most of which contain co-inherited variants in strong linkage disequilibrium (LD) with indistinguishable statistical significance. The experimental and analytical difficulty
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Contribution of autosomal rare and de novo variants to sex differences in autism Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-14 Mahmoud Koko, F. Kyle Satterstrom, Autism Sequencing Consortium, Branko Aleksic, Mykyta Artomov, Mafalda Barbosa, Elisa Benetti, Catalina Betancur, Monica Biscaldi-Schafer, Anders D. Børglum, Harrison Brand, Alfredo Brusco, Joseph D. Buxbaum, Gabriele Campos, Simona Cardaropoli, Diana Carli, Angel Carracedo, Marcus C.Y. Chan, Andreas G. Chiocchetti, Brian H.Y. Chung, Brett Collins, Ryan L. Collins
Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals using a liability model with differing thresholds. Given the sex differences in
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Identification of CNTN2 as a genetic modifier of PIGA-CDG in a family with incomplete penetrance and in Drosophila Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-12 Holly J. Thorpe, Brent S. Pedersen, Miranda Dietze, Nichole Link, Aaron R. Quinlan, Joshua L. Bonkowsky, Ashley Thomas, Clement Y. Chow
Loss-of-function mutations in the X chromosome gene PIGA lead to phosphatidylinositol glycan class A congenital disorder of glycosylation (PIGA-CDG), an ultra-rare CDG typically presenting with seizures, hypotonia, and neurodevelopmental delay. We identified two brothers (probands) with PIGA-CDG, presenting with epilepsy and mild developmental delay. Both probands carry PIGA c.395C>G (p.Ser132Cys)
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Isogenic hiPSC models of Turner syndrome development reveal shared roles of inactive X and Y in the human cranial neural crest network Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-07 Darcy T. Ahern, Prakhar Bansal, Isaac V. Faustino, Owen M. Chambers, Erin C. Banda, Heather R. Glatt-Deeley, Rachael E. Massey, Yuvabharath Kondaveeti, Stefan F. Pinter
Viable human aneuploidy can be challenging to model in rodents due to syntenic boundaries or primate-specific biology. Human monosomy-X (45,X) causes Turner syndrome (TS), altering craniofacial, skeletal, endocrine, and cardiovascular development, which in contrast remain unaffected in X-monosomic mice. To learn how monosomy-X may impact embryonic development, we turned to 45,X and isogenic euploid
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reg-eQTL: Integrating transcription factor effects to unveil regulatory variants Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-07 Rekha Mudappathi, Tatiana Patton, Hai Chen, Ping Yang, Zhifu Sun, Panwen Wang, Chang-Xin Shi, Junwen Wang, Li Liu
Regulatory single-nucleotide variants (rSNVs) in noncoding regions of the genome play a crucial role in gene transcription by altering transcription factor (TF) binding, chromatin states, and other epigenetic modifications. Existing expression quantitative trait locus (eQTL) methods identify genomic loci associated with gene-expression changes, but they often fall short in pinpointing causal variants
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Misattributed paternity discovery: A critique of medical organizations’ recommendations Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-02-03 Richard Wenzel, Gina Daniel, Jodi Girard, Lily Wood, Eve Sturges
The five authors recently discovered their misattributed paternity (MP), two ascertaining that, decades ago, their pediatricians abetted the paternity deception. From their unique perspective, the authors critique medical organizations’ current MP discovery guidance, identifying shortcomings, contradictions, and clinical and legal hazards. They also discuss opportunities to improve MP discovery management
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Inter-chromosomal insertions at Xq27.1 associated with retinal dystrophy induce dysregulation of LINC00632 and CDR1as/ciRS-7 Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-01-31 Jessica C. Gardner, Katarina Jovanovic, Daniele Ottaviani, Uirá Souto Melo, Joshua Jackson, Rosellina Guarascio, Kalliopi Ziaka, Kwan-Leong Hau, Amelia Lane, Rachel L. Taylor, Niuzheng Chai, Christina Gkertsou, Owen Fernando, Monika Piwecka, Michalis Georgiou, Stefan Mundlos, Graeme C. Black, Anthony T. Moore, Michel Michaelides, Michael E. Cheetham, Alison J. Hardcastle
In two unrelated families with X-linked inherited retinal dystrophy, identification of the causative variants was elusive. Interrogation of the next-generation sequencing (NGS) data revealed a “dark” intergenic region on Xq27.1 with poor coverage. Long-range PCR and DNA walking across this region revealed different inter-chromosomal insertions into the human-specific palindrome on Xq27.1: a 58 kb insertion
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Experience using conventional compared to ancestry-based population descriptors in clinical genomics laboratories Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-01-29 Kathryn E. Hatchell, Sarah R. Poll, Emily M. Russell, Trevor J. Williams, Rachel E. Ellsworth, Flavia M. Facio, Sienna Aguilar, Edward D. Esplin, Alice B. Popejoy, Robert L. Nussbaum, Swaroop Aradhya
Various scientific and professional groups, including the American Medical Association (AMA), American Society of Human Genetics (ASHG), American College of Medical Genetics (ACMG), and the National Academies of Sciences, Engineering, and Medicine (NASEM), have appropriately clarified that certain population descriptors, such as race and ethnicity, are social and cultural constructs with no basis in
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Gene and phenome-based analysis of the shared genetic architecture of eye diseases Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-01-28 Alexandra Scalici, Tyne W. Miller-Fleming, Megan M. Shuey, James T. Baker, Michael Betti, Jibril Hirbo, Ela W. Knapik, Nancy J. Cox
While many eye disorders are linked through defects in vascularization and optic nerve degeneration, genetic correlation studies have yielded variable results despite shared features. For example, glaucoma and myopia both share optic neuropathy as a feature, but genetic correlation studies demonstrated minimal overlap. By leveraging electronic health record (EHR) resources that contain genetic variables
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Sequence variants in HECTD1 result in a variable neurodevelopmental disorder Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-01-28 Gazelle Zerafati-Jahromi, Elias Oxman, Hieu D. Hoang, Wu-Lin Charng, Tanvitha Kotla, Weimin Yuan, Keito Ishibashi, Sonia Sebaoui, Kathryn Luedtke, Bryce Winrow, Rebecca D. Ganetzky, Anna Ruiz, Carmen Manso-Basúz, Nino Spataro, Peter Kannu, Taryn Athey, Christina Peroutka, Caitlin Barnes, Richard Sidlow, George Anadiotis, Kari Magnussen, Irene Valenzuela, Alejandro Moles-Fernandez, Seth Berger, Christina
Dysregulation of genes encoding the homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases has been linked to cancer and structural birth defects. One member of this family, the HECT-domain-containing protein 1 (HECTD1), mediates developmental pathways, including cell signaling, gene expression, and embryogenesis. Through GeneMatcher, we identified 14 unrelated individuals with 15 different variants
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Prenatal gene editing for neurodevelopmental diseases: Ethical considerations Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-01-28 Rami M. Major, Eric T. Juengst
Neurodevelopmental diseases (NDDs) are notoriously difficult to treat because clinical symptoms stem from developmental processes that begin before birth. Prenatal gene editing could fill the treatment gap for NDDs by targeting and permanently correcting the genetic variants that underlie these pathogenic developmental processes. At the same time, there is a risk of unintended edits to the fetus or
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Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-01-24 Shloka Negi, Sarah L. Stenton, Seth I. Berger, Paolo Canigiula, Brandy McNulty, Ivo Violich, Joshua Gardner, Todd Hillaker, Sara M. O’Rourke, Melanie C. O’Leary, Elizabeth Carbonell, Christina Austin-Tse, Gabrielle Lemire, Jillian Serrano, Brian Mangilog, Grace VanNoy, Mikhail Kolmogorov, Eric Vilain, Anne O’Donnell-Luria, Emmanuèle Délot, Karen H. Miga, Jean Monlong, Benedict Paten
More than 50% of families with suspected rare monogenic diseases remain unsolved after whole-genome analysis by short-read sequencing (SRS). Long-read sequencing (LRS) could help bridge this diagnostic gap by capturing variants inaccessible to SRS, facilitating long-range mapping and phasing and providing haplotype-resolved methylation profiling. To evaluate LRS’s additional diagnostic yield, we sequenced
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A unified framework for cell-type-specific eQTL prioritization by integrating bulk and scRNA-seq data Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-01-16 Xinyi Yu, Xianghong Hu, Xiaomeng Wan, Zhiyong Zhang, Xiang Wan, Mingxuan Cai, Tianwei Yu, Jiashun Xiao
Genome-wide association studies (GWASs) have identified numerous genetic variants associated with complex traits, yet the biological interpretation remains challenging, especially for variants in non-coding regions. Expression quantitative trait locus (eQTL) studies have linked these variations to gene expression, aiding in identifying genes involved in disease mechanisms. Traditional eQTL analyses
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Characterizing substructure via mixture modeling in large-scale genetic summary statistics Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-01-16 Hayley R. Stoneman, Adelle M. Price, Nikole Scribner Trout, Riley Lamont, Souha Tifour, Nikita Pozdeyev, Colorado Center for Personalized Medicine, Heather D. Anderson, Christina L. Aquilante, Kelsey Arbogast, Christopher H. Arehart, Ian M. Brooks, Tonya M. Brunetti, Judith Brutus-Lestin, Elizabeth E. Burke, Emily M. Casteel, Joanne B. Cole, Curtis R. Coughlin II, Kristy Crooks, Jacob Crawford, Erin
Genetic summary data are broadly accessible and highly useful, including for risk prediction, causal inference, fine mapping, and incorporation of external controls. However, collapsing individual-level data into summary data, such as allele frequencies, masks intra- and inter-sample heterogeneity, leading to confounding, reduced power, and bias. Ultimately, unaccounted-for substructure limits summary
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Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy Am. J. Hum. Genet. (IF 8.1) Pub Date : 2025-01-16 Rebecca Buchert, Martin D. Burkhalter, Chrisovalantou Huridou, Linda Sofan, Timo Roser, Kirsten Cremer, Javeria Raza Alvi, Stephanie Efthymiou, Tawfiq Froukh, Sughra Gulieva, Ulviyya Guliyeva, Moath Hamdallah, Muriel Holder-Espinasse, Rauan Kaiyrzhanov, Doreen Klingler, Mahmoud Koko, Lars Matthies, Joohyun Park, Marc Sturm, Ana Velic, Stephanie Spranger, Tipu Sultan, Hartmut Engels, Holger Lerche,
Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting