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.

The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings
The importance of estimating the penetrance of individual variants, i.e., the probability of developing disease given a DNA variant, to guide intervention is ever increasing. We undertake a cross-sectional approach, meta-analyzing unique, large cardiomyopathy referral cohorts and leveraging publicly available population-based cohorts to estimate variant-specific penetrance for rare CM-associated variants. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 30, 2023 Category: Genetics & Stem Cells Authors: Kathryn A. McGurk, Xiaolei Zhang, Pantazis Theotokis, Kate Thomson, Andrew Harper, Rachel J. Buchan, Erica Mazaika, Elizabeth Ormondroyd, William T. Wright, Daniela Macaya, Chee Jian Pua, Birgit Funke, Daniel G. MacArthur, Sanjay K. Prasad, Stuart A. Cook Tags: Article Source Type: research

Dissecting the high-resolution genetic architecture of complex phenotypes by accurately estimating gene-based conditional heritability
Miao et  al. present EHE, a flexible method for estimating heritability at small genomic regions using p values of SNPs. EHE demonstrates higher accuracy and precision than alternative methods. Additionally, EHE allows for isolating non-redundant conditional heritability of nearby genes, providing valuabl e insights into the genetic architecture of complex phenotypes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 25, 2023 Category: Genetics & Stem Cells Authors: Lin Miao, Lin Jiang, Bin Tang, Pak Chung Sham, Miaoxin Li Tags: Article Source Type: research

Advanced variant classification framework reduces the false positive rate of predicted loss-of-function variants in population sequencing data
Our study demonstrates that 27.3% of heterozygous predicted loss-of-function (pLoF) gnomAD variants, in genes associated with autosomal-recessive disease, might not undergo nonsense-mediated decay due to suspected evasion. We provide guidance on how to advance pLoF interpretation in both research and clinical settings. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 25, 2023 Category: Genetics & Stem Cells Authors: Moriel Singer-Berk, Sanna Gudmundsson, Samantha Baxter, Eleanor G. Seaby, Eleina England, Jordan C. Wood, Rachel G. Son, Nicholas A. Watts, Konrad J. Karczewski, Steven M. Harrison, Daniel G. MacArthur, Heidi L. Rehm, Anne O ’Donnell-Luria Tags: Article Source Type: research

An RNA-informed dosage sensitivity map reflects the intrinsic functional nature of genes
We introduce a tissue-specific map of dosage sensitivity (MoDs) of genes. MoDs can be used to better understand pathogenic modes of inheritance (dominance vs. recessiveness), to infer which tissues may be affected and to inform models of the underlying homeostatic mechanism. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 23, 2023 Category: Genetics & Stem Cells Authors: Danyue Dong, Haoyu Shen, Zhenguo Wang, Jiaqi Liu, Zhe Li, Xin Li Tags: Article Source Type: research

GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals
Nucleoside-modified messenger RNA (modRNA) has shown great promise as an enzyme replacement tool. Here, we show that GLA modRNA almost completely abolishes the accumulation of globotriaosylceramides observed in cardiomyocytes derived from individuals with Fabry disease. Moreover, changes in the proteome between Fabry and healthy cardiomyocytes were rescued upon modRNA treatment. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 21, 2023 Category: Genetics & Stem Cells Authors: Menno ter Huurne, Benjamin L. Parker, Ning Qing Liu, Elizabeth Ling Qian, Celine Vivien, Kathy Karavendzas, Richard J. Mills, Jennifer T. Saville, Dad Abu-Bonsrah, Andrea F. Wise, James E. Hudson, Andrew S. Talbot, Patrick F. Finn, Paolo G.V. Martini, Mar Tags: Report Source Type: research

The phenotype-genotype reference map: Improving biobank data science through replication
The phenotype-genotype reference map (PGRM) is a curated set of GWAS associations that facilitates efficient phenome-wide replication studies with biobank data. The PGRM can be used to detect data corruption, assess model parameters, and explore factors that affect replicability of findings. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 21, 2023 Category: Genetics & Stem Cells Authors: Lisa Bastarache, Sarah Delozier, Anita Pandit, Jing He, Adam Lewis, Aubrey C. Annis, Jonathon LeFaive, Joshua C. Denny, Robert J. Carroll, Russ B. Altman, Jacob J. Hughey, Matthew Zawistowski, Josh F. Peterson Tags: Article Source Type: research

Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies
We evaluated genome sequencing (GS) as a single test to displace the sequential application of karyotype, chromosomal microarray, and exome sequencing, three standard-of-care tests used for the assessment of autism and fetal structural anomalies. Our data suggest GS warrants consideration as a first-tier diagnostic approach for these two phenotypes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 17, 2023 Category: Genetics & Stem Cells Authors: Chelsea Lowther, Elise Valkanas, Jessica L. Giordano, Harold Z. Wang, Benjamin B. Currall, Kathryn O ’Keefe, Emma Pierce-Hoffman, Nehir E. Kurtas, Christopher W. Whelan, Stephanie P. Hao, Ben Weisburd, Vahid Jalili, Jack Fu, Isaac Wong, Ryan L. Collins, Tags: Article Source Type: research

AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia
Terhal et  al. describe a sclerosing bone disorder with hip dysplasia due to homozygous truncating variants in AXIN1 leading to a loss of its C-terminal DIX domain. Analysis of primary and genome-edited cells harboring the variants revealed enhanced basal canonical Wnt pathway activity, which was attenuated by a tankyrase inhibitor. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 14, 2023 Category: Genetics & Stem Cells Authors: Paulien Terhal, Anton J. Venhuizen, Davor Lessel, Wen-Hann Tan, Abdulrahman Alswaid, Regina Gr ün, Hamad I. Alzaidan, Simon von Kroge, Nada Ragab, Maja Hempel, Christian Kubisch, Eduardo Novais, Alba Cristobal, Kornelia Tripolszki, Peter Bauer, Björn Fi Tags: Article Source Type: research

Integrative splicing-quantitative-trait-locus analysis reveals risk loci for non-small-cell lung cancer
This study provided a comprehensive catalog of splicing quantitative trait loci (sQTLs) in lung tissues. Integrative sQTL analysis revealed risk loci for non-small-cell lung cancer. Further experiments confirmed that rs35861926 could reduce lung adenocarcinoma risk by promoting FARP1 exon 20 skipping to downregulate the expression level of transcript FARP1-011. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 9, 2023 Category: Genetics & Stem Cells Authors: Yuzhuo Wang, Yue Ding, Su Liu, Cheng Wang, Erbao Zhang, Congcong Chen, Meng Zhu, Jing Zhang, Chen Zhu, Mengmeng Ji, Juncheng Dai, Guangfu Jin, Zhibin Hu, Hongbing Shen, Hongxia Ma Tags: Article Source Type: research

Genetic insights into the age-specific biological mechanisms governing human ovarian aging
Many phenotypic characteristics and the risk of common complex disease change across life, reflecting a range of different age-specific biological processes. Here, we show that 74% of 245 genome-wide significant genetic associations with age at natural menopause show a form of age-specific effect. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 4, 2023 Category: Genetics & Stem Cells Authors: Sven E. Ojavee, Liza Darrous, Marion Patxot, Kristi L äll, Krista Fischer, Reedik Mägi, Zoltan Kutalik, Matthew R. Robinson Tags: Article Source Type: research

Ethical considerations when co-analyzing ancient DNA and data from private genetic databases
The search for genetic connections between ancient and living individuals benefits from access to large genetic databases such as those maintained by genetic testing companies. We discuss the ethical issues we considered during our recent study of African Americans from Catoctin Furnace, Maryland, who were compared with 23andMe, Inc ’s genetic database. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 3, 2023 Category: Genetics & Stem Cells Authors: Éadaoin Harney, Kendra Sirak, Jakob Sedig, Steven Micheletti, Roslyn Curry, Samantha Ancona Esselmann, David Reich Tags: Perspective Source Type: research

HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder
We identified genetic variants of HNRNPC in 13 individuals with intellectual disability and global developmental delay. Through a meta-analysis of multiple cell types, we found that loss of HNRNPC affects alternative splicing, in particular of intellectual disability-associated genes. In  vivo assays confirmed that neurodevelopment was affected by aberrant HNRNPC levels. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 3, 2023 Category: Genetics & Stem Cells Authors: Eva Niggl, Arjan Bouman, Lauren C. Briere, Remco M. Hoogenboezem, Ilse Wallaard, Joohyun Park, Jakob Admard, Martina Wilke, Emilio D.R.O. Harris-Mostert, Minetta Elgersma, Jennifer Bain, Meena Balasubramanian, Siddharth Banka, Paul J. Benke, Miriam Bertra Tags: Article Source Type: research

Genome sequencing and comprehensive rare-variant analysis of 465 families with neurodevelopmental disorders
We performed short-read whole-genome sequencing (WGS) on 692 individuals from 465 families affected by neurodevelopment disorders and identified causal variants, including structural variants, non-coding variants, and mitochondrial variants, in 36% of affected participants. We also used long-read WGS to resolve intractable variants in five cases. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 3, 2023 Category: Genetics & Stem Cells Authors: Alba Sanchis-Juan, Karyn Megy, Jonathan Stephens, Camila Armirola Ricaurte, Eleanor Dewhurst, Kayyi Low, Courtney E. French, Detelina Grozeva, Kathleen Stirrups, Marie Erwood, Amy McTague, Christopher J. Penkett, Olga Shamardina, Salih Tuna, Louise C. Dau Tags: Article Source Type: research

Combined CRISPRi and proteomics screening reveal a cohesin-CTCF-bound allele contributing to increased expression of RUVBL1 and prostate cancer progression
A major goal of post-GWAS studies is to functionally characterize causal SNPs that confer increased risk to disease phenotypes. Here, we applied CRISPRi and proteomics screening to identify regulatory SNPs at prostate-cancer risk loci and functionally characterized the impact of the rs60464856-RUVBL1 locus via in  vitro and in vivo approaches. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 3, 2023 Category: Genetics & Stem Cells Authors: Yijun Tian, Dandan Dong, Zixian Wang, Lang Wu, Jong Y. Park, the PRACTICAL consortium, Gong-Hong Wei, Liang Wang Tags: Article Source Type: research

Beyond the exome: What ’s next in diagnostic testing for Mendelian conditions
Over 50% of individuals with suspected genetic conditions remain undiagnosed after clinical genetic testing. To enhance understanding of the options available beyond exome sequencing, this article offers professionals from any specialty a framework for further investigation and guidance on the next best steps after an inclusive evaluation. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - August 3, 2023 Category: Genetics & Stem Cells Authors: Monica H. Wojcik, Chloe M. Reuter, Shruti Marwaha, Medhat Mahmoud, Michael H. Duyzend, Hayk Barseghyan, Bo Yuan, Philip M. Boone, Emily E. Groopman, Emmanu èle C. Délot, Deepti Jain, Alba Sanchis-Juan, Genomics Research to Elucidate the Genetics of Rare Tags: Review Source Type: research