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Functional characterization of 5p15.33 risk locus in uveal melanoma reveals rs452384 as a functional variant and NKX2.4 as an allele-specific interactor
Derrien et  al. identified rs452384 as a functional variant implicated in uveal melanoma risk at the multi-cancer 5p15.33 risk locus, mediating allele-specific expression and differentially binding NKX2.4 and GATA4 transcription factors. These findings unravel some of the complex regulatory mechanisms in uvea l melanoma susceptibility. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 1, 2022 Category: Genetics & Stem Cells Authors: Anne-C éline Derrien, Alexandre Houy, Olivier Ganier, Florent Dingli, Massih Ningarhari, Lenha Mobuchon, María Isabel Espejo Díaz, Damarys Loew, Nathalie Cassoux, Olivier Cussenot, Géraldine Cancel-Tassin, Raphael Margueron, Josselin Noirel, Jessica Z Tags: Article Source Type: research

Consequences of chromosome gain: A new view on trisomy syndromes
Chromosome gains are detrimental for the development of the human embryo. As such, autosomal trisomies almost always result in spontaneous abortion, and the rare embryos surviving until live birth suffer from a plethora of pathological defects. There is no treatment currently available to ameliorate the consequences of trisomies, such as Down syndrome (trisomy of chromosome 21). Identifying the source of the phenotypes observed in cells with extra chromosomes is crucial for understanding the underlying molecular causes of trisomy syndromes. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 1, 2022 Category: Genetics & Stem Cells Authors: Maria Krivega, Clara M. Stiefel, Zuzana Storchova Tags: Review Source Type: research

A minimal role for synonymous variation in human disease
There have been recent claims that synonymous mutations may be nearly as important as other forms of protein-coding variation in causing human disease. In this commentary, we argue that there is insufficient evidence to overturn the large body of evidence that synonymous mutations are predominantly neutral. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 1, 2022 Category: Genetics & Stem Cells Authors: Ryan S. Dhindsa, Quanli Wang, Dimitrios Vitsios, Oliver S. Burren, Fengyuan Hu, James E. DiCarlo, Leonid Kruglyak, Daniel G. MacArthur, Matthew E. Hurles, Slav é Petrovski Tags: Commentary Source Type: research

Genomic Medicine Year in Review: 2022
Starting in 2019, AJHG has published an annual feature1,2,3 identifying ten key advances in applying genomic information to clinical care that were reported in the previous 12  months of published literature. The Genomic Medicine Working Group of the National Advisory Council for Human Genome Research of the National Human Genome Research Institute (NHGRI) has authored these reviews on the basis of its broader effort to identify notable accomplishments in genomic medicin e on a monthly basis and post them on a searchable website (see web resources). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 1, 2022 Category: Genetics & Stem Cells Authors: Teri A. Manolio, Jahnavi Narula, Carol J. Bult, Rex L. Chisholm, Patricia A. Deverka, Geoffrey S. Ginsburg, Madison Goldrich, Eric D. Green, Gail P. Jarvik, George A. Mensah, Erin M. Ramos, Mary V. Relling, Dan M. Roden, Robb Rowley, Marc S. Williams Tags: Year in Review Source Type: research

Addressing the challenges of polygenic scores in human genetic research
The genotyping of millions of human samples has made it possible to evaluate variants across the human genome for their possible association with risks for numerous diseases and other traits by using genome-wide association studies (GWASs). The associations between phenotype and genotype found in GWASs make possible the construction of polygenic scores (PGSs), which aim to predict a trait or disease outcome in an individual on the basis of their genotype (in the disease case, the term polygenic risk score [PRS] is often used). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 1, 2022 Category: Genetics & Stem Cells Authors: John Novembre, Catherine Stein, Samira Asgari, Claudia Gonzaga-Jauregui, Andrew Landstrom, Amy Lemke, Jun Li, Chloe Mighton, Matthew Taylor, Sarah Tishkoff Tags: ASHG Guidance Source Type: research

This month in The Journal
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Source: The American Journal of Human Genetics - December 1, 2022 Category: Genetics & Stem Cells Authors: Kylee L. Spencer, Sara B. Cullinan Tags: Editors' Corner Source Type: research

Statistical phasing of 150,119 sequenced genomes in the UK Biobank
We present an open-source pipeline for filtering, phasing, and indexing 150,119  UK Biobank genomes. This pipeline makes it possible to apply haplotype-based methods to these data. We use the pipeline to phase 406 million single-nucleotide variants on chromosomes 1–22 and X at a cost of £2,309. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 29, 2022 Category: Genetics & Stem Cells Authors: Brian L. Browning, Sharon R. Browning Tags: Report Source Type: research

Massively parallel reporter assays and variant scoring identified functional variants and target genes for melanoma loci and highlighted cell-type specificity
Long et  al. used massively parallel reporter assays combined with variant scoring to identify functional variants from 78% of known melanoma GWAS loci, including those specific to cell of origin versus cancer contexts. Linking prioritized functional variants to eQTLs identified target genes as validated b y CRISPRi. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 23, 2022 Category: Genetics & Stem Cells Authors: Erping Long, Jinhu Yin, Karen M. Funderburk, Mai Xu, James Feng, Alexander Kane, Tongwu Zhang, Timothy Myers, Alyxandra Golden, Rohit Thakur, Hyunkyung Kong, Lea Jessop, Eun Young Kim, Kristine Jones, Raj Chari, Mitchell J. Machiela, Kai Yu, Melanoma Meta Tags: Article Source Type: research

Understanding changes in genetic literacy over time and in genetic research participants
We compare data from a survey to assess genetic literacy from general population samples in 2013 and 2021 and from individuals enrolled in an autism genetic research study in 2021. The results suggest that familiarity with genetic concepts is higher in 2021 and in research participants, with room for improvement. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 22, 2022 Category: Genetics & Stem Cells Authors: India D. Little, Laura M. Koehly, Chris Gunter Tags: Article Source Type: research

A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism
Heterozygous pathogenic variants in DNM1 cause developmental and epileptic encephalopathy. Here, we perform RNA sequencing in brain samples and find non-canonical, alternatively spliced transcripts are the most abundant. We highlight the importance of considering relevant isoforms for variant interpretation and the possibility of intronic variants causing disease through dominant-negative mechanisms. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 21, 2022 Category: Genetics & Stem Cells Authors: Shridhar Parthasarathy, Sarah McKeown Ruggiero, Antoinette Gelot, Fernanda C Soardi, Beth ânia F R Ribeiro, Douglas E V Pires, David B Ascher, Alain Schmitt, Caroline Rambaud, Alfonso Represa, Hongbo M Xie, Laina Lusk, Olivia Wilmarth, Pamela Pojomovsky Tags: Article Source Type: research

Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria
We developed an approach to calibrate computational predictors to the American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines for clinical variant classification. We observed that predictors can provide much stronger evidence for variant pathogenicity/benignity than previously thought and propose updated recommendations for their clinical use. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 21, 2022 Category: Genetics & Stem Cells Authors: Vikas Pejaver, Alicia B. Byrne, Bing-Jian Feng, Kymberleigh A. Pagel, Sean D. Mooney, Rachel Karchin, Anne O ’Donnell-Luria, Steven M. Harrison, Sean V. Tavtigian, Marc S. Greenblatt, Leslie G. Biesecker, Predrag Radivojac, Steven E. Brenner, ClinGen Se Tags: Article Source Type: research

A scoping review of guidelines for the use of race, ethnicity, and ancestry reveals widespread consensus but also points of ongoing disagreement
The appropriate use of race, ethnicity, and ancestry in science and medicine is a source of much discussion. In this review of normative guidance on this topic, the authors find the body of work to be largely concordant but in disagreement about how population categories should be defined and used. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 17, 2022 Category: Genetics & Stem Cells Authors: Madelyn Mauro, Danielle S. Allen, Bege Dauda, Santiago J. Molina, Benjamin M. Neale, Anna C.F. Lewis Tags: Review Source Type: research

Estimating the genome-wide mutation rate from thousands of unrelated individuals
Genotype errors make it difficult to accurately estimate mutation rates in humans from parent-offspring data. We use identity by descent in whole-genome sequence data from population samples to accurately detect germline mutations that have occurred in the past 100 generations and hence estimate the genome-wide mutation rate. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 11, 2022 Category: Genetics & Stem Cells Authors: Xiaowen Tian, Ruoyi Cai, Sharon R. Browning Tags: Article Source Type: research

TCEAL1 loss-of-function results in an X-linked dominant neurodevelopmental syndrome and drives the neurological disease trait in Xq22.2 deletions
Applying a gene-first approach and worldwide gene-matching, we identify eight individuals with variants in TCEAL1, a candidate gene for the early-onset neurological disease trait (EONDT) in females with Xq22.2 deletion. The neurodevelopmental disorder observed overlaps that described in Xq22.2 deletion females, implicating TCEAL1 as the driver gene. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 10, 2022 Category: Genetics & Stem Cells Authors: Hadia Hijazi, Linda M. Reis, Davut Pehlivan, Jonathan A. Bernstein, Michael Muriello, Erin Syverson, Devon Bonner, Mehrdad A. Estiar, Ziv Gan-Or, Guy A. Rouleau, Ekaterina Lyulcheva, Lynn Greenhalgh, Marine Tessarech, Estelle Colin, Agn ès Guichet, Domin Tags: Report Source Type: research

Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics
Using data from 386,000 Asian- and European-ancestry women, we conducted extensive genome- and transcriptome-wide association studies that identified 222 risk loci and 137 genes in association with breast cancer risk. These studies, along with pathway analyses, provide a comprehensive understanding of and new biological insights into the genetics of breast cancer. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - November 9, 2022 Category: Genetics & Stem Cells Authors: Guochong Jia, Jie Ping, Xiang Shu, Yaohua Yang, Qiuyin Cai, Sun-Seog Kweon, Ji-Yeob Choi, Michiaki Kubo, Sue K. Park, Manjeet K. Bolla, Joe Dennis, Qin Wang, Xingyi Guo, Bingshan Li, Ran Tao, Kristan J. Aronson, Tsun L. Chan, Yu-Tang Gao, Mikael Hartman, Tags: Article Source Type: research